Jansen, K. L. R. (1996)

Using ketamine to induce the near -death experience: mechanism of action and therapeutic potential.

Yearbook for Ethnomedicine and the Study of Consciousness (Jahrbuch furr Ethnomedizin und Bewubtseinsforschung) Issue 4, 1995 (Ed.s C. Ratsch; J. R. Baker); VWB, Berlin, pp55-81.

"Near-death experiences (NDE's) can be induced using the dissociative drug ketamine. Advances in neuroscience have recently provided us with new insights as to the mechanisms involved at the mind -brain interface. On the 'brain' side, it is now clear that these NDE's are due to blockade of brain receptors (drug binding sites) for the neurotransmitter glutamate. These binding sites are called the N-methyl-D-aspartate (NMDA) receptors. Conditions which precipitate NDE's (low oxygen, low blood flow, low blood sugar, temporal lobe epilepsy etc.) have been shown to release a flood of glutamate, over-activating NMDA receptors. This overactivation can kill brain cells ('excito' toxicity). Ketamine prevents excitotoxicity. Conditions which trigger a glutamate flood may also trigger a flood of ketamine-like brain chemicals which bind to NMDA receptors to protect cells, leading to an altered state of consciousness like that produced by ketamine." [Full Text] Jansen, K. L. R.

The Ketamine Model of the Near Death Experience: A Central Role for the NMDA Receptor

[Full Text] YANGZHENG FENG, JOHN E. PILETZ, and MICHAEL H. LEBLANC

Agmatine Suppresses Nitric Oxide Production and Attenuates Hypoxic-Ischemic Brain Injury in Neonatal Rats

Pediatr Res 52: 606-611. 2002.

"Nitric oxide and excitatory amino acids contribute to hypoxic-ischemic brain injury. Agmatine, an endogenous neurotransmitter or neuromodulator, is an inhibitor of nitric oxide synthase and an antagonist of N-methyl-D-aspartate receptors. Does agmatine reduce brain injury in the rat pup hypoxic-ischemic model? Seven-day old rat pups had right carotid arteries ligated followed by 2.5 h of hypoxia (8% oxygen). Agmatine or vehicle was administered by i.p. injection at 5 min after reoxygenation and once daily thereafter fr 3 d. Brain damage was evaluated by weight deficit of the right hemisphere at 22 d after hypoxia by a blinded observer. Agmatine treatments significantly reduced weight loss in the right hemisphere from -30.5 +/- 3.6% in vehicle-treated pups (n = 22) to -15.6 +/- 4.4% in the group treated with 50 mg/kg (n = 18, p < 0.05) and to -15.0 +/- 3.7% in the group treated with 100 mg/kg (n = 18, p < 0.05), but the group treated with 150 mg/kg showed no reduction. Other pups received agmatine or vehicle at 5 min after reoxygenation, and brain biochemistry was assessed. Levels of endogenous brain agmatine rose 2- to 3-fold owing to hypoxic-ischemic (3 h), whereas pups treated with agmatine (100 mg/kg) showed 50-fold higher brain agmatine levels (3 h). Agmatine (100 mg/kg) blocked a hypoxia-induced increase in brain nitric oxide metabolites at 6 h (vehicle-treated, +60.2 +/- 15.2%; agmatine-treated, +4.2 +/- 8.4%; p < 0.05). Agmatine thus reduces brain injury in the neonatal rat hypoxic-ischemic model, probably by blunting the rise in nitric oxide metabolites normally seen after hypoxia." [Full Text] Zhu MY, Piletz JE, Halaris A, Regunathan S.

Effect of agmatine against cell death induced by NMDA and glutamate in neurons and PC12 cells.

Cell Mol Neurobiol. 2003 Oct;23(4-5):865-72.

"1. AIMS: Agmatine is an endogenous guanido amine and has been shown to be neuroprotective in vitro and in vivo. The aims of this study are to investigate whether agmatine is protective against cell death induced by different agents in cultured neurons and PC12 cells. 2. METHODS: Cell death in neurons, cultured from neonatal rat cortex, was induced by incubating with (a) NMDA (100 microM) for 10 min, (b) staurosporine (protein kinase inhibitor, 100 nM) for 24 h, and (c) calcimycin (calcium ionophore, 100 nM) for 24 h in the presence and absence of agmatine (1 micro M to 1 mM). Cell death in PC12 cells was induced by exposure to glutamate (10 mM), staurosporine (100 nM), and calcimycin (100 nM). The activity of lactate dehydrogenase (LDH) in the medium was measured as the marker of cell death and normalized to cellular LDH activity. 3. RESULTS: Agmatine significantly reduced the medium LDH in NMDA-treated neurons but failed to reduce the release of LDH induced by staurosporin or calcimycin. In PC12 cells, agmatine significantly reduced LDH release induced by glutamate exposure, but not by staurosporine or calcimycin. Agmatine itself neither increased LDH release nor directly inhibited the enzyme activity. 4. CONCLUSION: We conclude that agmatine protects against NMDA excitotoxicity in neurons and PC12 cells but not the cell death induced by protein kinase blockade or increase in cellular calcium." [Abstract] Gilad GM, Salame K, Rabey JM, Gilad VH.

Agmatine treatment is neuroprotective in rodent brain injury models.

Life Sci. 1996;58(2):PL 41-6.

"Agmatine is a naturally occurring guanidino compound, found in bacteria and plants, with several proposed nervous system-related functions suggestive of beneficial effects in central nervous system injury. Here evidence is presented that agmatine can exert potent neuroprotection in both in vitro and in vivo rodent models of neurotoxic and ischemic brain injuries. The cumulative evidence lead us to suggest that agmatine, a relatively nontoxic compound, be tried for potential therapeutic use after neurotrauma and in neurodegenerative disorders." [Abstract] Parnia S, Fenwick P.

Near death experiences in cardiac arrest: visions of a dying brain or visions of a new science of consciousness.

Resuscitation. 2002 Jan;52(1):5-11.

"Very little is known about the dying process and in particular the state of the human mind at the end of life. Cardiac arrest is the final step in the dying process irrespective of cause, and is also the closest physiological model of the dying process. Recent studies in cardiac arrest survivors have indicated that although the majority of cardiac arrest survivors have no memory recall from the event, nevertheless approximately 10% develop memories that are consistent with typical near death experiences. These include an ability to 'see' and recall specific detailed descriptions of the resuscitation, as verified by resuscitation staff. Many studies in humans and animals have indicated that brain function ceases during cardiac arrest, thus raising the question of how such lucid, well-structured thought processes with reasoning and memory formation can occur at such a time. This has led to much interest as regards the potential implications for the study of consciousness and its relationship with the brain, which still remains an enigma. In this article, we will review published research examining brain physiology and function during cardiac arrest as well as its potential relationship with near death experiences during this time. Finally, we will explore the contribution that near death experiences during cardiac arrest may make to the wider understanding of human consciousness." [Abstract] van Lommel P, van Wees R, Meyers V, Elfferich I.

Near-death experience in survivors of cardiac arrest: a prospective study in the Netherlands.

Lancet. 2001 Dec 15;358(9298):2039-45.

"BACKGROUND: Some people report a near-death experience (NDE) after a life-threatening crisis. We aimed to establish the cause of this experience and assess factors that affected its frequency, depth, and content. METHODS: In a prospective study, we included 344 consecutive cardiac patients who were successfully resuscitated after cardiac arrest in ten Dutch hospitals. We compared demographic, medical, pharmacological, and psychological data between patients who reported NDE and patients who did not (controls) after resuscitation. In a longitudinal study of life changes after NDE, we compared the groups 2 and 8 years later. FINDINGS: 62 patients (18%) reported NDE, of whom 41 (12%) described a core experience. Occurrence of the experience was not associated with duration of cardiac arrest or unconsciousness, medication, or fear of death before cardiac arrest. Frequency of NDE was affected by how we defined NDE, the prospective nature of the research in older cardiac patients, age, surviving cardiac arrest in first myocardial infarction, more than one cardiopulmonary resuscitation (CPR) during stay in hospital, previous NDE, and memory problems after prolonged CPR. Depth of the experience was affected by sex, surviving CPR outside hospital, and fear before cardiac arrest. Significantly more patients who had an NDE, especially a deep experience, died within 30 days of CPR (p<0.0001). The process of transformation after NDE took several years, and differed from those of patients who survived cardiac arrest without NDE. INTERPRETATION: We do not know why so few cardiac patients report NDE after CPR, although age plays a part. With a purely physiological explanation such as cerebral anoxia for the experience, most patients who have been clinically dead should report one." [Abstract] [Full Text] G.M. Woerlee

Cardiac Arrest and NDEs

"Restoration of some degree of blood circulation through the brains of these people, means that some degree of brain function, and hence some EEG activity was also restored. And in some of these people undergoing cardiac resuscitation, the efficiency of the cardiac massage was such that enough blood and oxygen was pumped around their bodies to restore partial, or even full consciousness, together with the appropriate EEG activity. Accordingly, statements claiming that all people are unconscious, and all people have a flat EEG while undergoing active cardiac resuscitation are pure speculation, and likely to be quite incorrect." [Full Text] On Site link: EEG Alone Cannot Diagnose Brain Death Parnia S, Waller DG, Yeates R, Fenwick P.

A qualitative and quantitative study of the incidence, features and aetiology of near death experiences in cardiac arrest survivors.

Resuscitation. 2001 Feb;48(2):149-56.

"AIM: To carry out a prospective study of cardiac arrest survivors to understand the qualitative features as well as incidence, and possible aetiology of near death experiences (NDEs) in this group of patients. METHOD: All survivors of cardiac arrests during a 1 year period were interviewed within a week of their arrest, regarding memories of their unconscious period. Reported memories were assessed by the Greyson NDE Scale. The postulated role of physiological, psychological and transcendental factors were studied. Physiological parameters such as oxygen status were extracted from the medical notes. Patients' religious convictions were documented in the interviews and hidden targets were used to test the transcendental theories on potential out of body claims. Those with memories were compared to those without memories. RESULTS: 11.1% of 63 survivors reported memories. The majority had NDE features. There appeared to be no differences on all physiological measured parameters apart from partial pressure of oxygen during the arrest which was higher in the NDE group. CONCLUSIONS: Memories are rare after resuscitation from cardiac arrest. The majority of those that are reported have features of NDE and are pleasant. The occurrence of NDE during cardiac arrest raises questions about the possible relationship between the mind and the brain. Further large-scale studies are needed to understand the aetiology and true significance of NDE." [Abstract] Greyson B.

Incidence and correlates of near-death experiences in a cardiac care unit.

Gen Hosp Psychiatry. 2003 Jul-Aug;25(4):269-76.

"Near-death experiences, unusual experiences during a close brush with death, may precipitate pervasive attitudinal and behavior changes. The incidence and psychological correlates of such experiences, and their association with proximity to death, are unclear. We conducted a 30-month survey to identify near-death experiences in a tertiary care center cardiac inpatient service. In a consecutive sample of 1595 patients admitted to the cardiac inpatient service (mean age 63 years, 61% male), of whom 7% were admitted with cardiac arrest, patients who described near-death experiences were matched with comparison patients on diagnosis, gender, and age. Near-death experiences were reported by 10% of patients with cardiac arrest and 1% of other cardiac patients (P<.001). Near-death experiencers were younger than other patients (P=.001), were more likely to have lost consciousness (P<.001) and to report prior purportedly paranormal experiences (P=.009), and had greater approach-oriented death acceptance (P=.01). Near-death experiencers and comparison patients did not differ in sociodemographic variables, social support, quality of life, acceptance of their illness, cognitive function, capacity for physical activities, degree of cardiac dysfunction, objective proximity to death, or coronary prognosis." [Abstract] Greyson B.

Near-death experiences in a psychiatric outpatient clinic population.

Psychiatr Serv. 2003 Dec;54(12):1649-51.

"Near-death experiences, or mystical experiences during encounters with death, are reported to have beneficial effects despite their phenomenologic similarity to pathological states. This study explored the prevalence of near-death experiences and associated psychological distress by using a cross-sectional survey of 832 psychiatric outpatients. Standardized measures of near-death experiences and psychological distress were administered via questionnaire at clinic intake. A total of 272 patients (33 percent) reported encounters with death, and these patients were found to have greater psychological distress than other patients. Sixty-one of the patients who had been close to death (22 percent) reported having near-death experiences, and these patients were found to have less psychological distress than patients who did not have near-death experiences after brushes with death." [Abstract] Tong F.

Out-of-body experiences: from Penfield to present.

Trends Cogn Sci. 2003 Mar;7(3):104-106.

"Can the brain, when stimulated, yield entirely novel experiences? Blanke et al. (2002) describe a patient who reported spontaneous out-of-body experiences during electrical stimulation of her angular gyrus. These findings, although apparently extraordinary, agree with much earlier reports from a patient tested by Wilder Penfield. Such studies can provide clues about the nature of conscious experience."

...

"The similarities between the two patient reports, which occurred over 60 years apart, are striking. In both cases, vestibular illusions are tightly linked to out-of-body experiences, and the sites of stimulation are in quite close proximity. Both sets of stimulation sites encompassed the right temporal-parietal region posterior to the postcentral gyrus, close to multisensory areas implicated in vestibular processing [3,4] and also spatial neglect [5,6], although Penfields schematically drawn sites appear to be more anterior than Blanke et al.s." [Abstract] [PDF] Blanke O, Ortigue S, Landis T, Seeck M.

Stimulating illusory own-body perceptions.

Nature. 2002 Sep 19;419(6904):269-70.

"'Out-of-body' experiences (OBEs) are curious, usually brief sensations in which a person's consciousness seems to become detached from the body and take up a remote viewing position. Here we describe the repeated induction of this experience by focal electrical stimulation of the brain's right angular gyrus in a patient who was undergoing evaluation for epilepsy treatment. Stimulation at this site also elicited illusory transformations of the patient's arm and legs (complex somatosensory responses) and whole-body displacements (vestibular responses), indicating that out-of-body experiences may reflect a failure by the brain to integrate complex somatosensory and vestibular information." [Abstract]

Olaf Blanke , Theodor Landis , Laurent Spinelli , and Margitta Seeck

Out-of-body experience and autoscopy of neurological origin

Brain. 2004 Feb;127(Pt 2):243-58. Epub 2003 Dec 08.

"During an out-of-body experience (OBE), the experient seems to be awake and to see his body and the world from a location outside the physical body. A closely related experience is autoscopy (AS), which is characterized by the experience of seeing one's body in extrapersonal space. Yet, despite great public interest and many case studies, systematic neurological studies of OBE and AS are extremely rare and, to date, no testable neuroscientific theory exists. The present study describes phenomenological, neuropsychological and neuroimaging correlates of OBE and AS in six neurological patients. We provide neurological evidence that both experiences share important central mechanisms. We show that OBE and AS are frequently associated with pathological sensations of position, movement and perceived completeness of one's own body. These include vestibular sensations (such as floating, flying, elevation and rotation), visual body-part illusions (such as the illusory shortening, transformation or movement of an extremity) and the experience of seeing one's body only partially during an OBE or AS. We also find that the patient's body position prior to the experience influences OBE and AS. Finally, in five patients, brain damage or brain dysfunction is localized to the temporo-parietal junction (TPJ). These results suggest that the complex experiences of OBE and AS represent paroxysmal disorders of body perception and cognition (or body schema). The processes of body perception and cognition, and the unconscious creation of central representation(s) of one's own body based on proprioceptive, tactile, visual and vestibular information-as well as their integration with sensory information of extrapersonal space-is a prerequisite for rapid and effective action with our surroundings. Based on our findings, we speculate that ambiguous input from these different sensory systems is an important mechanism of OBE and AS, and thus the intriguing experience of seeing one's body in a position that does not coincide with its felt position. We suggest that OBE and AS are related to a failure to integrate proprioceptive, tactile and visual information with respect to one's own body (disintegration in personal space) and by a vestibular dysfunction leading to an additional disintegration between personal (vestibular) space and extrapersonal (visual) space. We argue that both disintegrations (personal; personal-extrapersonal) are necessary for the occurrence of OBE and AS, and that they are due to a paroxysmal cerebral dysfunction of the TPJ in a state of partially and briefly impaired consciousness." [Abstract] Stagg C, Hindley P, Tales A, Butler S.

Visual mismatch negativity: the detection of stimulus change.

Neuroreport. 2004 Mar 22;15(4):659-63.

"Mismatch negativity is an event related potential generated by a mechanism which detects stimulus change. Such a mechanism is important to enable attention to be switched to important changes in the environment. The effect has been extensively studied in the auditory modality. The present investigation was designed to establish whether the enhanced negativity in the visual event related potential evoked by deviant stimuli presented infrequently among a sequence of repeated standard stimuli is really associated with the detection of stimulus change. The experiment set out to distinguish effects associated with stimulus change from those related to the physical attributes ofthe stimuli or to differences in the refractory state of receptors or neurons. The findings support the hypothesis that deviance-related negativity reflects the operation of a change detection mechanism and not the refractory state of elements of the visual system." [Abstract] Daniel C. Javitt, Mitchell Steinschneider, Charles E. Schroeder, and Joseph C. Arezzo

Role of cortical N-methyl-D-aspartate receptors in auditory sensory memory and mismatch negativity generation: Implications for schizophrenia

PNAS 93: 11962-11967. 1996.

"Working memory refers to the ability of the brain to store and manipulate information over brief time periods, ranging from seconds to minutes. As opposed to long-term memory, which is critically dependent upon hippocampal processing, critical substrates for working memory are distributed in a modality-specific fashion throughout cortex. N-methyl-D-aspartate (NMDA) receptors play a crucial role in the initiation of long-term memory. Neurochemical mechanisms underlying the transient memory storage required for working memory, however, remain obscure. Auditory sensory memory, which refers to the ability of the brain to retain transient representations of the physical features (e.g., pitch) of simple auditory stimuli for periods of up to approximately 30 sec, represents one of the simplest components of the brain working memory system. Functioning of the auditory sensory memory system is indexed by the generation of a well-defined event-related potential, termed mismatch negativity (MMN). MMN can thus be used as an objective index of auditory sensory memory functioning and a probe for investigating underlying neurochemical mechanisms. Monkeys generate cortical activity in response to deviant stimuli that closely resembles human MMN. This study uses a combination of intracortical recording and pharmacological micromanipulations in awake monkeys to demonstrate that both competitive and noncompetitive NMDA antagonists block the generation of MMN without affecting prior obligatory activity in primary auditory cortex. These findings suggest that, on a neurophysiological level, MMN represents selective current flow through open, unblocked NMDA channels. Furthermore, they suggest a crucial role of cortical NMDA receptors in the assessment of stimulus familiarity/unfamiliarity, which is a key process underlying working memory performance." [Abstract/PDF] Astikainen P, Ruusuvirta T, Korhonen T.

Somatosensory event-related potentials in the rabbit cerebral and cerebellar cortices: a correspondence with mismatch responses in humans.

Neurosci Lett. 2001 Feb 9;298(3):222-4. [Abstract] Kreitschmann-Andermahr I, Rosburg T, Demme U, Gaser E, Nowak H, Sauer H.

Effect of ketamine on the neuromagnetic mismatch field in healthy humans.

Brain Res Cogn Brain Res. 2001 Aug;12(1):109-16. [Abstract] Umbricht D, Schmid L, Koller R, Vollenweider FX, Hell D, Javitt DC.

Ketamine-induced deficits in auditory and visual context-dependent processing in healthy volunteers: implications for models of cognitive deficits in schizophrenia.

Arch Gen Psychiatry. 2000 Dec;57(12):1139-47. [Abstract] Matsuhashi M, Ikeda A, Ohara S, Matsumoto R, Yamamoto J, Takayama M, Satow T, Begum T, Usui K, Nagamine T, Mikuni N, Takahashi J, Miyamoto S, Fukuyama H, Shibasaki H.

Multisensory convergence at human temporo-parietal junction - epicortical recording of evoked responses.

Clin Neurophysiol. 2004 May;115(5):1145-60.

"OBJECTIVE: Previous lesion studies in patients and functional imaging studies in normal subjects have led to the notion that the temporo-parietal junction (TPJ) has an integrative function for multisensory inputs. However, its electrophysiological properties such as response latencies and distributions of responses to various stimulus modalities in humans have not been fully investigated. The aim of the study is to clarify this issue. METHODS: We recorded evoked potentials to different kinds of sensory stimuli including somatosensory, auditory and visual modalities in 6 patients with intractable partial epilepsy, who underwent chronic implantation of subdural electrodes in TPJ for presurgical evaluation. RESULTS: In 5 out of 6 subjects, at least one electrode located in TPJ for each subject showed a maximum somatosensory evoked response commonly to electric, passive joint motion and pain stimuli. These electrodes showed the maximum responses also to tone stimuli in all of 4 subjects studied, and to visual motion stimuli in 3 out of 5 subjects studied. The polarity was consistent regardless of the stimulus modality within each individual subject, although the anatomical location, polarity and latency varied among subjects. CONCLUSIONS: A small area in TPJ for each individual subject receives sensory information of multiple modalities possibly coming from different receptive sites, although the electrophysiological properties of the responses may vary among subjects. Significance: We confirmed the convergence of somatosensory, auditory and visual evoked responses at human TPJ." [Abstract] BRANDT, THOMAS, DIETERICH, MARIANNE

The Vestibular Cortex: Its Locations, Functions, and Disorders

Ann NY Acad Sci 1999 871: 293-312

"Evidence is presented that the multisensory parieto-insular cortex is the human homologue of the parieto-insular vestibular cortex (PIVC) in the monkey and is involved in the perception of verticality and self-motion. Acute lesions (patients with middle cerebral artery infarctions) of this area caused contraversive tilts of perceived vertical, body lateropulsion, and, rarely, rotational vertigo. Brain activation studies using positron emission tomography or functional magnetic resonance tomography showed that PIVC was activated by caloric irrigation of the ears or by galvanic stimulation of the mastoid. This indicates that PIVC receives input from both the semicircular canals and otoliths. PIVC was also activated during small-field optokinetic stimulation, but not when the nystagmus was suppressed by fixation. Activation of vestibular cortex areas, visual motion-sensitive areas, and ocular motor areas exhibited a significant right-hemispheric dominance. The vestibular cortex intimately interacts with the visual cortex to match the two 3-D orientation maps (perception of verticality, room-tilt illusion) and mediates self-motion perception by means of a reciprocal inhibitory visual-vestibular interaction. This mechanism of an inhibitory interaction allows a shift of the dominant sensorial weight during self-motion perception from one sensory modality (visual or vestibular) to the other, depending on which mode of stimulation prevails: body acceleration (vestibular input) or constant velocity motion (visual input)." [Abstract] Berkels R, Taubert D, Grundemann D, Schomig E.

Agmatine signaling: odds and threads.

Cardiovasc Drug Rev. 2004 Spring;22(1):7-16.

"Agmatine is a metabolite of L-arginine. It is formed by the decarboxylation of L-arginine via arginine decarboxylase in bacteria, plants and mammals. It is becoming clear that it has multiple physiological functions as a potential transmitter. Agmatine binds to alpha2-adrenoceptors and to imidazoline binding sites. It blocks NMDA receptors and other ligand-gated cation channels. It also inhibits nitric oxide synthase, induces release of peptide hormones and antizyme and plays a role during cell proliferation by interacting with the generation and transport of polyamines. Although the precise function of endogenously released agmatine is presently still unclear, this review will summarize several aspects concerning the biological function of agmatine." [Abstract] Greenberg S, Finkelstein A, Gurevich J, Brazowski E, Rosenfeld F, Shapira I I, George J, Laniado S, Keren G.

The Effect of Agmatine on Ischemic and Nonischemic Isolated Rat Heart.

J Cardiovasc Pharmacol Ther. 1999 Jul;4(3):151-158.

"OBJECTIVE: the natural polyamines play a protective role during ischemic injury. We studied the effects of agmatine on ischemic and nonischemic isolated rat hearts. METHODS: Thirty-one rats were randomly assigned to one of four experimental groups. Sixteen rats were injected with saline (group 1, n = 9; group 3, n = 7), and 15 rats were injected with 100 mg/kg of agmatine (group 2, n = 8; group 4, n = 7). Injections were given twice: 24 hours and 1 hour before the experiment. Using the modified Langendorf model, rat hearts were perfused with Krebs-Henseleit solution for 105 minutes during phase 1 of the experiment (groups 1 and 2). During phase 2, hearts were exposed to 45 minutes of global ischemia (groups 3 and 4). RESULTS: During phase 1, no statistically significant differences were observed between the agmatine and the control groups. During phase 2, agmatine caused a significant increase in left ventricular pressure (P <.003). At the end of reperfusion, P(max) was 111% +/- 10% from the baseline levels versus only 82% +/- 5% in the control group. After 20 minutes of reperfusion, dP/dt (first-time derivative of the ventricular pressure) in the agmatine group reached full recovery of 106% +/- 12% versus only 64% +/- 14% in the saline group (P =.059). Agmatine also caused a significant increase in coronary flow rate (P <.004) throughout the reperfusion period. Quantitative immunohistochemical staining disclosed reduced cell damage in the agmatine-treated hearts (P <.02) versus the control group. CONCLUSION: Agmatine injection given before induced ischemia improves hemodynamic recovery by mechanisms that may be attributed to its vasodilatory properties." [Abstract] Pinthong D, Wright IK, Hanmer C, Millns P, Mason R, Kendall DA, Wilson VG.

Agmatine recognizes alpha 2-adrenoceptor binding sites but neither activates nor inhibits alpha 2-adrenoceptors.

Naunyn Schmiedebergs Arch Pharmacol. 1995 Jan;351(1):10-6.

"It has been suggested that agmatine (decarboxylated arginine) is an endogenous clonidine-displacing substance (CDS) which recognizes alpha 2-adrenoceptor and non-adrenoceptor, imidazoline binding sites. We have examined the effect of agmatine at alpha 2-adrenoceptor binding sites and pre- and postjunctional alpha 2-adrenoceptors. Agmatine produced a concentration-dependent inhibition of 1 nmol/l 3H-clonidine binding to both rat (pKi-5.10 +/- 0.05) and bovine (pKi-4.77 +/- 0.38) cerebral cortex membranes. However, agmatine (0.1-100 microM) failed to activate pre-junctional alpha 2-adrenoceptors regulating transmitter release in the guinea-pig isolated ileum and rat isolated vas deferens, nor did it activate postjunctional alpha 2-adrenoceptors of the porcine isolated palmar lateral vein which mediate contraction or inhibition of forskolin-stimulated cyclic AMP formation. High concentrations of agmatine (10-30-fold the pKi at alpha 2-adrenoceptor binding sites) failed to influence alpha 2-adrenoceptor activation by either clonidine or UK-14304 (5-bromo-6-[2-imidazolin-2-ylamino]-quinoxaline bitartrate) in any of the peripheral preparations examined. Moreover, even in a preparation where an interaction with alpha 2-adrenoceptor binding sites on cell membranes can be demonstrated, the rat cerebral cortex, agmatine failed to inhibit forskolin-stimulated cyclic AMP in the intact tissue or affect the inhibition produced by the selective alpha 2-adrenoceptor agonist UK-14304. Agmatine was also devoid of agonist activity in two preparations, the rat isolated thoracic aorta and the rat isolated gastric fundus, in which CDS has been reported to produce non-adrenoceptor effects. Thus, we have confirmed that agmatine recognizes alpha 2-adrenoceptor binding sites and, therefore, is a CDS." [Abstract] Molderings GJ, Menzel S, Kathmann M, Schlicker E, Gothert M.

Dual interaction of agmatine with the rat alpha(2D)-adrenoceptor: competitive antagonism and allosteric activation.

Br J Pharmacol. 2000 Aug;130(7):1706-12.

"In segments of rat vena cava preincubated with [(3)H]-noradrenaline and superfused with physiological salt solution, the influence of agmatine on the electrically evoked [(3)H]-noradrenaline release, the EP(3) prostaglandin receptor-mediated and the alpha(2D)-adrenoceptor-mediated inhibition of evoked [(3)H]-noradrenaline release was investigated. Agmatine (0.1-10 microM) by itself was without effect on evoked [(3)H]-noradrenaline release. In the presence of 10 microM agmatine, the prostaglandin E(2)(PGE(2))-induced EP(3)-receptor-mediated inhibition of [(3)H]-noradrenaline release was not modified, whereas the alpha(2D)-adrenoceptor-mediated inhibition of [(3)H]-noradrenaline release induced by noradrenaline, moxonidine or clonidine was more pronounced than in the absence of agmatine. However, 1 mM agmatine antagonized the moxonidine-induced inhibition of [(3)H]-noradrenaline release. Agmatine concentration-dependently inhibited the binding of [(3)H]-clonidine and [(3)H]-rauwolscine to rat brain cortex membranes (K(i) values 6 microM and 12 microM, respectively). In addition, 30 and 100 microM agmatine increased the rate of association and decreased the rate of dissociation of [(3)H]-clonidine resulting in an increased affinity of the radioligand for the alpha(2D)-adrenoceptors. [(14)C]-agmatine labelled specific binding sites on rat brain cortex membranes. In competition experiments. [(14)C]-agmatine was inhibited from binding to its specific recognition sites by unlabelled agmatine, but not by rauwolscine and moxonidine. In conclusion, the present data indicate that agmatine both acts as an antagonist at the ligand recognition site of the alpha(2D)-adrenoceptor and enhances the effects of alpha(2)-adrenoceptor agonists probably by binding to an allosteric binding site of the alpha(2D)-adrenoceptor which seems to be labelled by [(14)C]-agmatine." [Abstract] Colucci R, Blandizzi C, Carignani D, Placanica G, Lazzeri G, Del Tacca M.

Effects of imidazoline derivatives on cholinergic motility in guinea-pig ileum: involvement of presynaptic alpha2-adrenoceptors or imidazoline receptors?

Naunyn Schmiedebergs Arch Pharmacol. 1998 Jun;357(6):682-91.

"The present study investigates the possibility that imidazoline receptors mediate modulation of cholinergic motor functions of the guinea-pig ileum. For this purpose, the effects of a series of compounds with known affinity for alpha2-adrenoceptors and/or imidazoline recognition sites were examined on the cholinergic twitch contractions evoked by electrical field stimulation (0.1 Hz) of longitudinal muscle-myenteric plexus preparations. Additional experiments were carried out on ileal strips preincubated with [3H]choline, superfused with physiological salt solution containing hemicholinium-3, and subjected to electrical field stimulation (1 Hz). The stimulation-induced outflow of radioactivity was taken as an index of endogenous acetylcholine release. Alpha-methyl-noradrenaline, noradrenaline, clonidine, medetomidine, oxymetazoline and xylazine caused a concentration-dependent inhibition of twitch responses (IC50 from 0.13 to 1.05 microM; Emax from 85.9 to 92.5%). Rilmenidine and agmatine were less potent in reducing the twitch activity, and the latter compound acted also with low intrinsic activity (IC50=44.9 microM; Emax=35.5%). In interaction experiments, the inhibitory action of clonidine on twitch responses was competitively antagonized by RX 821002 (2-(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline), idazoxan, rauwolscine, yohimbine and BRL 44408 (2-[2H-(1-methyl-1,3-dihydroisoindole)-methyl] -4,5-dihydroimidazoline), whereas prazosin (10 microM), ARC 239 (2-(2,4-(O-methoxy-phenyl)-piperazin-1-yl)-ethyl-4,4-dimethyl- 1,3-(2H,4H)-isoquinolindione; 10 microM) and BRL 41992 (1,2-dimethyl-2,3,9,13b-tetrahydro-1H-dibenzo[c,f]imidazol[1,5-a]a zepine; 10 microM) were without effect. Rauwolscine antagonized the inhibitory effects of various agonists on ileal twitch activity in a competitive manner and with similar potency. Agmatine and idazoxan did not significantly modify the twitch contractions when tested in the presence of alpha2-adrenoceptor blockade by rauwolscine (3 microM) or RX 821002 (1 microM). Linear regression analysis showed that the affinity values of antagonists correlated with their affinity at the alpha2A and alpha2D binding sites as well as at previously classified alpha2A/D adrenoceptor subtypes, whereas no significant correlation was obtained when comparing the potency estimates of agonists and antagonists with the affinity at I1 or I2 binding sites. When tested on the electrically induced outflow of tritium, alpha-methyl-noradrenaline, noradrenaline, clonidine, medetomidine, oxymetazoline, xylazine and rilmenidine yielded inhibitory concentration-response curves which were shifted rightward to a similar extent in the presence of rauwolscine (3 microM). In the absence of further drugs, agmatine significantly reduced the evoked tritium outflow at the highest concentrations tested (10 and 100 microM), whereas idazoxan (up to 100 microM) was without effect. When RX 821002 (1 microM) was added to the superfusion medium, neither agmatine nor idazoxan modified the evoked outflow of radioactivity. The results argue against modulation by imidazoline receptors of acetylcholine release from myenteric plexus nerve terminals. They provide evidence that compounds endowed with imidazoline-like structures affect the cholinergic motor activity of the guinea-pig ileum by interacting with presynaptic alpha2-adrenoceptors belonging to the alpha2D subtype." [Abstract] Piletz JE, Zhu H, Chikkala DN.

Comparison of ligand binding affinities at human I1-imidazoline binding sites and the high affinity state of alpha-2 adrenoceptor subtypes.

J Pharmacol Exp Ther. 1996 Nov;279(2):694-702.

"To identify selective compounds for nonadrenergic I1-imidazoline receptors (I1), the affinities of 22 ligands for [125I]p-iodoclonidine binding have been compared at human platelet I1-imidazoline binding sites (analyzed under norepinephrine mask of alpha-2 AR) and at human alpha-2A, alpha-2B and alpha-2C adrenoceptors stably expressed on transfected Chinese hamster ovary cells. Competition curves at the platelet I1-imidazoline binding site were biphasic for most compounds. Only tizanidine and BDF,6143 displayed monophasic I1 competition curves. Agmatine, an endogenous neurotransmitter candidate for the I1-imidazoline receptor, was identified as the most selective agent for a subcomponent of platelet I1 sites. The affinity of agmatine at the high affinity component of platelet I1 sites was 1400-fold selective over alpha-2A adrenoceptors, 5000-fold selective over alpha-2B adrenoceptors and 800-fold selective over alpha-2C adrenoceptors. Moxonidine and tizanidine also displayed selectivities for a high affinity component of the platelet I1 binding sites over alpha-2 adrenoceptors. Naphazoline was the most selective compound for the high affinity state of the alpha-2A adrenoceptor, displaying 7-, 23- and 9-fold higher affinity than alpha-2B, alpha-2C and platelet I1-midazoline binding sites, respectively. No single selective compound was identified for the alpha-2B adrenoceptor. Norepinephrine displayed, respectively, 18- and 31-fold selectivity for the high affinity state of the alpha-2C adrenoceptor as compared to alpha-2A- or alpha-2B adrenoceptors, and was > 100,000- fold selective over platelet I1-imidazoline sites. Thus, human alpha-2 adrenoceptors and the platelet I1-imidazoline binding site can be clearly discriminated based on their affinities for certain compounds." [Abstract]

Galea E, Regunathan S, Eliopoulos V, Feinstein DL, Reis DJ.

Inhibition of mammalian nitric oxide synthases by agmatine, an endogenous polyamine formed by decarboxylation of arginine.

Biochem J. 1996 May 15;316 ( Pt 1):247-9.

"Agmatine, decarboxylated arginine, is a metabolic product of mammalian cells. Considering the close structural similarity between L-arginine and agmatine, we investigated the interaction of agmatine and nitric oxide synthases (NOSs), which use L-arginine to generate nitric oxide (NO) and citrulline. Brain, macrophages and endothelial cells were respectively used as sources for NOS isoforms I, II and III. Enzyme activity was measured by the production of nitrites or L-citrulline. Agmatine was a competitive NOS inhibitor but not an NO precursor. Ki values were approx. 660 microM (NOS I), 220 microM (NOS II) and 7.5 mM (NOS III). Structurally related polyamines did not inhibit NOS activity. Agmatine, therefore, may be an endogenous regulator of NO production in mammals." [Abstract] Demady, Damon R., Jianmongkol, Suree, Vuletich, Jennifer L., Bender, Andrew T., Osawa, Yoichi

Agmatine Enhances the NADPH Oxidase Activity of Neuronal NO Synthase and Leads to Oxidative Inactivation of the Enzyme

Mol Pharmacol 2001 59: 24-29

"It is established that agmatine, an endogenously formed decarboxylated arginine, is a weak competitive inhibitor of neuronal nitric-oxide synthase (nNOS) with an apparent Ki value of 660 microM [Biochem J 316:247-249, 1996]. Although agmatine is known to bind to alpha-adrenergic and imidazoline receptors, it has been suggested that some of the pharmacological actions of agmatine, such as the prevention of morphine tolerance, may be due to the inhibition of nNOS. In the current study, we have discovered that agmatine, at concentrations much lower than the reported Ki value, leads to a time-, concentration-, NADPH-, and calmodulin-dependent irreversible inactivation of nNOS. The kinetics of inactivation could be described by an apparent dissociation constant for the initial reversible complex (Ki) and a pseudo first-order inactivation constant (k(inact)) of 29 microM and 0.01 min(-1), respectively. As determined by high-performance liquid chromatography analysis, the mechanism of inactivation involves alteration of the prosthetic heme moiety of nNOS, in part to protein-bound products. Moreover, we discovered that agmatine causes a 3-fold increase in the NADPH oxidase activity of nNOS leading to the production of H2O2 and is a likely cause for the inactivation of the enzyme. Both the inactivation of nNOS and the oxidative stress produced should now be considered in the pharmacological actions of agmatine as well as provide insight into the potential biological effects of endogenously formed agmatine." [Full Text] Zheng JQ, Weng XC, Gai XD, Li J, Xiao WB.

Mechanism underlying blockade of voltage-gated calcium channels by agmatine in cultured rat hippocampal neurons.

Acta Pharmacol Sin. 2004 Mar;25(3):281-5.

"AIM: To investigate whether agmatine could selectively block a given type of the voltage-gated calcium channels (VGCC) and whether related receptors are involved in the blocking effect of agmatine on VGCC. METHODS: The whole-cell patch recording technique was performed to record VGCC currents in the cultured neonatal rat hippocampal neurons. RESULTS: Verapamil (100 micromol/L), a selective blocker of L-type calcium channel, significantly inhibited VGCC current by 80 %+/- 7 %. Agmatine (100 micromol/L) could further depress the remained currents by 25 %+/-6 %. The alpha 2-adrenoceptor antagonist yohimbine (10 micromol/L) and the I2 imidazoline receptor antagonist idazoxon (10 and 40 micromol/L) had no significant effect on VGCC currents when used respectively. When the mixture of yohimbine and agmatine was applied, VGCC currents were still depressed remarkably. However, the blocking effect of agmatine was decreased by 29 %+/- 8 % in the presence of idazoxon (10 micromol/L). The effect of idazoxon did not increase at a higher concentration (40 micromol/L). CONCLUSION: Agmatine could block the L- and other types of VGCC currents in the cultured rat hippocampal neurons. Blocking effect of agmatine on VGCC was partially related to I2 imidazoline receptor and had no relationship with alpha 2-adrenoceptors." [Abstract] Choi SH, Choi DH, Lee JJ, Park MS, Chun BG.

Imidazoline drugs stabilize lysosomes and inhibit oxidative cytotoxicity in astrocytes.

Free Radic Biol Med. 2002 Mar 1;32(5):394-405.

"Oxidative stress is a primary pathogenesis in the brain, which is particularly vulnerable to oxidative stress. Maintenance of astrocyte functions under oxidative stress is essential to prevent neuronal injuries and to recover neuronal functions in various pathologic conditions. Imidazoline drugs have affinities for imidazoline receptors, which are highly distributed in the brain, and have been shown to be neuroprotective. This study presented the protective effects of several imidazoline drugs against oxidative cytotoxicity, in primary cultures of astrocytes. Imidazoline drugs, such as idazoxan, guanabenz, guanfacine, BU224, and RS-45041-190, showed protective effects against naphthazarin-induced oxidative cytotoxicity, as evidenced by LDH release and Hoechst 33342/propidium iodide staining. The imidazoline drugs stabilized lysosomes and inhibited naphthazarin-induced lysosomal destabilization, as evidenced by acridine orange relocation. Guanabenz inhibited, the leakage of lysosomal cathepsin D to cytosol, the decreased mitochondrial potential, and the release of mitochondrial cytochrome c, which were induced by naphthazarin. The lysosomal destabilization by oxidative stress and other apoptotic signals and subsequent cathepsin D leakage to the cytosol can induce apoptotic changes of mitochondria and eventually cell death. Therefore, lysosomal stabilization by imidazoline drugs may be ascribed to their protective effects against oxidative cytotoxicity." [Abstract]

Yang, Xian-Cheng, Reis, Donald J.

Agmatine Selectively Blocks the N-Methyl-D-Aspartate Subclass of Glutamate Receptor Channels in Rat Hippocampal Neurons

J Pharmacol Exp Ther 1999 288: 544-549

"We investigated in rat hippocampus neurons whether 4-(aminobutyl)guanidine (agmatine), formed by decarboxylation of L-arginine by arginine decarboxylase and metabolized to urea and putrescine, can modulate the function of N-methyl-D-aspartate (NMDA) receptor channels. In cultured hippocampal neurons studied by whole-cell patch clamp, extracellular-applied agmatine produced a voltage- and concentration-dependent block of NMDA but not alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid nor kainate currents. Analysis of the voltage dependence of the block suggests that agmatine binds at a site located within the NMDA channel pore with a dissociation constant of 952 microM at 0 mV and an electric distance of 0.62. We also tested effects of several agmatine analogs. Arcaine (1,4-butyldiguanidine) also produced a similar voltage-dependent block of the NMDA current, whereas putrescine (1, 4-butyldiamine) had little effect, suggesting that the guanidine group of agmatine is the active moiety when blocking the NMDA channel. Moreover, spermine (an endogenous polyamine) potentiated the NMDA current even in the presence of blocker agmatine or arcaine, suggesting that the guanidine-containing compounds agmatine and arcaine interact with the NMDA channel at a binding site different from that of spermine. Our results indicate that in hippocampal neurons agmatine selectively modulates the NMDA subclass of glutamate receptor channels mediated by the interaction between the guanidine group and the channel pore. The results support other data that agmatine may function as an endogenous neurotransmitter/neuromodulator in brain." [Full Text] Gibson DA, Harris BR, Rogers DT, Littleton JM.

Radioligand binding studies reveal agmatine is a more selective antagonist for a polyamine-site on the NMDA receptor than arcaine or ifenprodil.

Brain Res. 2002 Oct 11;952(1):71-7.

"Ifenprodil, arcaine and agmatine have all been reported to inhibit the NMDA receptor by actions at polyamine-sites, however the specific sites with which these compounds interact is unknown. Here we used radioligand binding of [3H]MK-801 to a membrane preparation from rat cerebral cortex to investigate the interactions of these compounds with the NMDA receptor complex. In the absence of exogenous polyamines, agmatine reduced [3H]MK-801 binding only at concentrations over 500 micro M, as opposed to the putative polyamine-site antagonists arcaine and ifenprodil which directly reduce ligand binding at much lower concentrations (5 micro M) in the absence of polyamines. In our studies, all three compounds significantly reduced spermidine-potentiated [3H]MK-801 binding, however agmatine was the only compound effective at concentrations below those that produced direct inhibition of [3H]MK-801 binding. Under these conditions, agmatine had a K(i)=14.8 micro M for spermidine-potentiated [3H]MK-801 binding and displayed characteristics of a competitive antagonist. Agmatine, as well as ifenprodil and arcaine, also displaced [3H]spermidine from rat cortical membranes at concentrations similar to those that were effective at reducing spermidine-potentiated [3H]MK-801 binding. In conclusion, these data suggest that agmatine reduces the potentiating effects of polyamines by competitive antagonism at a specific site on the NMDA receptor complex, and that these actions of agmatine differ from those of ifenprodil and arcaine." [Abstract] Gabriel Olmos, Nuria DeGregorio-Rocasolano, M. Paz Regalado, Teresa Gasull, M. Assumpció Boronat, Ramón Trullas, Alvaro Villarroel, Juan Lerma, and Jesús A. García-Sevilla

Protection by imidazol(ine) drugs and agmatine of glutamate-induced neurotoxicity in cultured cerebellar granule cells through blockade of NMDA receptor

Br J Pharmacol 1999 127: 1317-1326.

"This study was designed to assess the potential neuroprotective effect of several imidazol(ine) drugs and agmatine on glutamate-induced necrosis and on apoptosis induced by low extracellular K+ in cultured cerebellar granule cells. Exposure (30 min) of energy deprived cells to L-glutamate (1-100 microM) caused a concentration-dependent neurotoxicity, as determined 24 h later by a decrease in the ability of the cells to metabolize 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) into a reduced formazan product. L-glutamate-induced neurotoxicity (EC50=5 microM) was blocked by the specific NMDA receptor antagonist MK-801 (dizocilpine). Imidazol(ine) drugs and agmatine fully prevented neurotoxicity induced by 20 microM (EC100) L-glutamate with the rank order (EC50 in microM): antazoline (13)>cirazoline (44)>LSL 61122 [2-styryl-2-imidazoline] (54)>LSL 60101 [2-(2-benzofuranyl) imidazole] (75)>idazoxan (90)>LSL 60129 [2-(1,4-benzodioxan-6-yl)-4,5-dihydroimidazole](101)>RX82 1002 (2-methoxy idazoxan) (106)>agmatine (196). No neuroprotective effect of these drugs was observed in a model of apoptotic neuronal cell death (reduction of extracellular K+) which does not involve stimulation of NMDA receptors. Imidazol(ine) drugs and agmatine fully inhibited [3H]-(+)-MK-801 binding to the phencyclidine site of NMDA receptors in rat brain. The profile of drug potency protecting against L-glutamate neurotoxicity correlated well (r=0.90) with the potency of the same compounds competing against [3H]-(+)-MK-801 binding. In HEK-293 cells transfected to express the NR1-1a and NR2C subunits of the NMDA receptor, antazoline and agmatine produced a voltage- and concentration-dependent block of glutamate-induced currents. Analysis of the voltage dependence of the block was consistent with the presence of a binding site for antazoline located within the NMDA channel pore with an IC50 of 10-12 microM at 0 mV. It is concluded that imidazol(ine) drugs and agmatine are neuroprotective against glutamate-induced necrotic neuronal cell death in vitro and that this effect is mediated through NMDA receptor blockade by interacting with a site located within the NMDA channel pore." [Abstract] Milhaud D, Fagni L, Bockaert J, Lafon-Cazal M.

Imidazoline-induced neuroprotective effects result from blockade of NMDA receptor channels in neuronal cultures.

Neuropharmacology. 2000 Sep;39(12):2244-54.

"Imidazolines have been shown to be neuroprotective in focal and global ischemia in the rat. However, their mechanism of action is still unclear. We have studied the neuroprotective effects of imidazolines against NMDA-induced neuronal death and hypoxic insult in cerebellar and striatal neuronal cultures. All of the imidazolines tested decreased the NMDA-mediated neurotoxicity in a non-competitive manner. Antazoline was the most effective (IC(50) of 5 microM, maximal neuroprotection reaching 90% at 100 microM). The neuroprotective effects were still present when the imidazolines were applied during the post-insult period. Antazoline, idazoxan and guanabenz also showed neuroprotective effects against hypoxia-induced neuronal death (neuroprotection reaching 95% for antazoline at 100 microM). Antazoline was still active if applied during the reoxygenation period (15% neuroprotection). To determine the mechanism of the neuroprotective effects, the possible interaction of imidazolines with NMDA receptors was studied. Imidazolines dose-dependently and non-competitively inhibited NMDA currents. As found for the neuroprotective effects, antazoline was the most effective imidazoline, with an IC(50) of 4 microM and a maximal inhibition of 90% at 100 microM. This blockade was rapid, reversible and voltage-dependent. We compared these effects to those of the classical non-competitive antagonist of NMDA channels, MK-801. In contrast to imidazolines, blockade of the NMDA current by MK-801 was voltage-independent and reversible only at positive potentials. When co-applied with MK-801, antazoline prevented the long lasting blockade of the NMDA current by MK-801. These results are consistent with the existence of overlapping binding sites for these drugs on the NMDA receptor channel. They indicate that imidazolines exert a strong neuroprotective effect against excitotoxicity and hypoxia in cerebellar and striatal primary neuronal cultures by inhibiting NMDA receptors. Since these effects were non-competitive, imidazolines appear to be interesting new drugs with therapeutic potential." [Abstract] Otake K, Ruggiero DA, Regunathan S, Wang H, Milner TA, Reis DJ.

Regional localization of agmatine in the rat brain: an immunocytochemical study.

Brain Res. 1998 Mar 16;787(1):1-14.

"The distribution of agmatine (decarboxylated arginine) was mapped in the central nervous system (CNS) in the rat. Agmatine-like immunoreactivity was identified by light microscopy, exclusively in the cytoplasm of neuronal perikarya. Immunoreactive neurons were present in the cerebral cortex, predominantly within laminae VI and V and, to a lesser extent, III and mainly in retrosplenial, cingulate, primary somatosensory and auditory cortices, and the subiculum. In the lower brainstem, immunoreactivity was selectively localized to visceral relay nuclei: the nucleus tractus solitarii and pontine parabrachial complex, and periventricular areas including the laterodorsal nucleus, locus coeruleus and dorsal raphe. In the midbrain, immunolabeled cells were concentrated in the ventral tegmental area and periaqueductal gray. In the forebrain, subcortical neurons were labeled predominantly in the preoptic area, amygdala, septum, bed nucleus of the stria terminalis, midline thalamus, and the hypothalamus. Ultrastructural analysis of layer V of the somatosensory cortex demonstrated agmatine-immunoreactivity in neurons, primarily in large dense-core vesicles located in the cytoplasm. Agmatine immunoreactivity was also affiliated with endoplasmic reticulum and the plasmalemma. Cortical neurons and the subiculum were labeled in animals not administered the axonal transport inhibitor, colchicine; thus, may normally contain higher concentrations of the amine than other brain regions. The central distribution of agmatine is consistent with the hypothesis that the amine may be a novel neurotransmitter of neurons involved in behavioral and visceral control." [Abstract] ARICIOGLU, FEYZA, REGUNATHAN, SOUNDAR, PILETZ, JOHN E.

Is Agmatine an Endogenous Factor Against Stress?

Ann NY Acad Sci 2003 1009: 127-132

"Agmatine is an endogenous amine synthesized from the decarboxylation of arginine. A proposed intracellular role of agmatine is to balance the production of polyamines (a promitotic process) and nitric oxide (an inflammatory process). Agmatine is also released from neurons upon depolarization. We previously reported that agmatine concentrations are increased in rat pups' brains shortly after hypoxic-ischemia and in the plasma of depressed patients. Herein, male rats (270-290 g) were divided into four groups receiving different degrees of known stress: 2-hour restraint at 21 degrees C, 4-hour restraint at 21 degrees C, 4-hour restraint at 4 degrees C, and control rats only handled at 21 degrees C. Cortex, cerebellum, medulla, hippocampus, hypothalamus, and blood plasma samples were collected for determination of endogenous agmatine levels. No changes in agmatine levels were detected after 2-hour and 4-hour restraint at room temperature, but concentrations of agmatine were increased in all brain regions except cerebellum after 4-hour restraint in the cold. Plasma agmatine levels (ng/mL) were 6.8 +/- 0.6 in controls versus 58.1 +/- 12.8 in the 4-hour restraint-plus-cold group. Cortical agmatine levels (ng/g wet tissue) were 15.3 +/- 2.4 in controls versus 57.4 +/- 19.6 in the 4-hour restraint-plus-cold group. Therefore, endogenous agmatine was increased in response to cold-restraint stress, possibly as a neuroprotective agent." [Abstract] Greyson B.

Dissociation in people who have near-death experiences: out of their bodies or out of their minds?

Lancet. 2000 Feb 5;355(9202):460-3.

"BACKGROUND: Some people who come close to death report having experiences in which they transcend the boundaries of the ego and the confines of time and space. Such near-death experiences (NDEs) share some features with the phenomenon of dissociation, in which a person's self identity becomes detached from bodily sensation. This study explored the frequency of dissociative symptoms in people who had come close to death. METHODS: 96 individuals who had had self-reported NDEs, and 38 individuals who had come close to death but who had not had NDEs completed a mailed questionnaire that included a measure of "depth" of near-death experience (the NDE scale) and a measure of dissociative symptoms (the Dissociative Experiences Scale). Median scores in the two groups were compared with Mann-Whitney U tests. The association between depth of NDE and dissociative symptoms was tested by Spearman's rank-order correlation between scores on the NDE scale and the dissociative experiences scale. FINDINGS: People who reported NDEs also reported significantly more dissociative symptoms than did the comparison group. Among those who reported NDEs, the depth of the experience was positively correlated with dissociative symptoms, although the level of symptoms was substantially lower than that of patients with pathological dissociative disorders. INTERPRETATION: The pattern of dissociative symptoms reported by people who have had NDEs is consistent with a non-pathological dissociative response to stress, and not with a psychiatric disorder. A greater understanding of the mechanism of dissociation may shed further light on near-death and other mystical or transcendental experiences." [Abstract]



Li YF, Gong ZH, Cao JB, Wang HL, Luo ZP, Li J.

Antidepressant-like effect of agmatine and its possible mechanism.

Eur J Pharmacol. 2003 May 23;469(1-3):81-8.

"In mammalian brain, agmatine is an endogenous neurotransmitter and/or neuromodulator, which is considered as an endogenous ligand for imidazoline receptors. In this study, the antidepressant-like action of agmatine administered p.o. or s.c. was evaluated in three behavioral models in mice or rats. Agmatine at doses 40 and 80 mg/kg (p.o.) reduced immobility time in the tail suspension test and forced swim test in mice or at dose 20 mg/kg (s.c.) in the forced swim test. Agmatine also reduced immobility time at 10 mg/kg (p.o.) or at 1.25, 2.5 and 5 mg/kg (s.c.) in the forced swim test in rats. These results firstly indicated that agmatine possessed an antidepressant-like action. With 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and lactic dehydrogenase (LDH) assay, 1, 10 and 100 microM agmatine or a classical antidepressant, 2.5 and 10 microM desipramine, protected PC12 cells from the lesion induced by 300 microM N-methyl-D-aspartate (NMDA) treatment for 24 h. Using high-performance liquid chromatography with electrochemical detection (HPLC-ECD), it was found that the levels of monoamines including norepinephrine, epinephrine, dopamine or 5-hydroxytryptamine (5-HT) in PC12 cells decreased after the treatment with 200 microM NMDA for 24 h, while in the presence of 1 and 10 microM agmatine or 1 and 5 microM desipramine, the levels of norepinephrine, epinephrine or dopamine were elevated significantly while 5-HT did not change. Moreover, norepinephrine, 5-HT or dopamine had the same cytoprotective effect as agmatine at doses 0.1, 1 and 10 microM. In the fura-2/AM (acetoxymethyl ester) labeling assay, 1 and 10 microM agmatine, 1 and 5 microM desipramine or monoamines norepinephrine, 5-HT at doses 0.1 and 1 microM attenuated the intracellular Ca(2+) overloading induced by 200 microM NMDA treatment for 24 h in PC12 cells. In summary, we firstly demonstrated that agmatine has an antidepressant-like effect in mice and rats. A classical antidepressant, desipramine, as well as agmatine or monoamines protect the PC12 cells from the lesion induced by NMDA treatment. Agmatine reverses the NMDA-induced intracellular Ca(2+) overloading and the decrease of monoamines (including norepinephrine, epinephrine or dopamine) contents in PC12 cells, indicating that agmatine's antidepressant-like action may be related to its modulation of NMDA receptor activity and/or reversal of the decrease of monoamine contents and Ca(2+) overloading induced by NMDA." [Abstract] Lavinsky D, Arteni NS, Netto CA.

Agmatine induces anxiolysis in the elevated plus maze task in adult rats.

Behav Brain Res. 2003 Apr 17;141(1):19-24. [Abstract] Halaris A, Zhu H, Feng Y, Piletz JE.

Plasma agmatine and platelet imidazoline receptors in depression.

Ann N Y Acad Sci. 1999 Jun 21;881:445-51.

"Plasma agmatine concentrations are elevated significantly in depressed patients compared to healthy controls. Treatment with the antidepressant bupropion normalized plasma agmatine levels. Correlational evidence is presented that a change in plasma agmatine levels may lead to similar changes in platelet I1 imidazoline receptors." [Abstract] Greyson B.

Incidence of near-death experiences following attempted suicide.

Suicide Life Threat Behav. 1986 Spring;16(1):40-5.

"Near-death experiences (NDEs), profound subjective experiences occurring during a close brush with death and containing transcendental or mystical elements, have been reported to reduce suicidal ideation, despite their "romanticization" of death. Among 61 consecutive hospital admissions for attempted suicide, 16 patients (26.2%) reported NDEs precipitated by the attempt. NDEs were not significantly associated with any demographic factors. In light of the frequency of NDEs following attempted suicide, further studies are indicated in regard to the effect of those experiences on subsequent suicidal behavior." [Abstract] Gorbatyuk OS, Milner TA, Wang G, Regunathan S, Reis DJ.

Localization of agmatine in vasopressin and oxytocin neurons of the rat hypothalamic paraventricular and supraoptic nuclei.

Exp Neurol. 2001 Oct;171(2):235-45.

"Agmatine (decarboxylated l-arginine), an endogenous ligand of imidazoline and alpha(2) adrenoreceptors, is particularly enriched in the rat hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. The present study utilized light and electron microscopic immunocytochemical methods to determine the distribution and extent of colocalization of agmatine relative to subpopulations of vasopressin- (VP) and oxytocin- (OT) producing neurons in PVN and SON nuclei. By light microscopy, agmatine-immunoreactive perikarya were found in both the magnocellular and the parvocellular neuronal subdivisions of PVN and SON. Confocal and electron microscopy revealed that agmatine-immunoreactivity (I) within neuronal perikarya was associated with the nuclear membrane as well as mitochondria, Golgi complexes, endoplasmic reticula, and plasmalemma. Additionally, agmatine-I was identified in both axons and axonal terminals, which were enriched in large dense-core vesicles. Dual and triple immunocytochemical labeling experiments also demonstrated that agmatine coexists with VP or OT in most PVN and SON magnocellular neurons. Combinations of iontophoretic injections of Fluorogold into the dorsomedullary complex with immunocytochemical labeling revealed that many retrogradely labeled neurons in the parvocellular region of the PVN contained agmatine-I and either VP or OT. These findings provide evidence that agmatine may function as a modulator of both hypothalamically mediated neuroendocrine and autonomic responses." [Abstract] Reis DJ, Yang XC, Milner TA.

Agmatine containing axon terminals in rat hippocampus form synapses on pyramidal cells.

Neurosci Lett. 1998 Jul 10;250(3):185-8.

"We examined the cellular and subcellular localization of agmatine in the hippocampal CA1 region by immunocytochemistry. By light microscopy, agmatine-like immunoreactivity (agmatine-LI) was found primarily in the perikarya and dendritic profiles of pyramidal cells and in punctate processes preponderantly in stratum radiatum. Electron microscopy revealed that agmatine-LI was cytoplasmic and concentrated in 'clusters' associated with mitochondria and tubular vesicles. In stratum radiatum, agmatine-LI was primarily in axons and axon terminals associated with small, synaptic vesicles. The terminals almost exclusively formed asymmetric synapses on the spines of dendrites, many of which originated from pyramidal cells. Some agmatine-LI also was present in shafts and spines of pyramidal cell dendrites and in astrocytic processes. The results demonstrate that agmatine in the hippocampus is found primarily in terminals forming excitatory (asymmetric) synapses on pyramidal cells, some of which contain agmatine-LI. These findings further implicate agmatine as an endogenous neurotransmitter which may be co-stored with L-glutamate and may act in part in the rat hippocampus as a blocker of the N-methyl-D-aspartate receptor and nitric oxide synthase." [Abstract] Yu CG, Marcillo AE, Fairbanks CA, Wilcox GL, Yezierski RP.

Agmatine improves locomotor function and reduces tissue damage following spinal cord injury.

Neuroreport. 2000 Sep 28;11(14):3203-7.

"Clinically effective drug treatments for spinal cord injury (SCI) remain unavailable. Agmatine, an NMDA receptor antagonist and inhibitor of nitric oxide synthase (NOS), is an endogenous neuromodulator found in the brain and spinal cord. Evidence is presented that agmatine significantly improves locomotor function and reduces tissue damage following traumatic SCI in rats. The results suggest the importance of future therapeutic strategies encompassing the use of single drugs with multiple targets for the treatment of acute SCI. The therapeutic targets of agmatine (NMDA receptor and NOS) have been shown to be critically linked to the pathophysiological sequelae of CNS injury and this, combined with the non-toxic profile, lends support to agmatine being considered as a potential candidate for future clinical applications." [Abstract] Carolyn A. Fairbanks, Kristin L. Schreiber, Kori L. Brewer, Chen-Guang Yu, Laura S. Stone, Kelley F. Kitto, H. Oanh Nguyen, Brent M. Grocholski, Don W. Shoeman, Lois J. Kehl, Soundararajan Regunathan, Donald J. Reis, Robert P. Yezierski, and George L. Wilcox

Agmatine reverses pain induced by inflammation, neuropathy, and spinal cord injury

PNAS 97: 10584-10589. 2000.

"Antagonists of glutamate receptors of the N-methyl-d-aspartate subclass (NMDAR) or inhibitors of nitric oxide synthase (NOS) prevent nervous system plasticity. Inflammatory and neuropathic pain rely on plasticity, presenting a clinical opportunity for the use of NMDAR antagonists and NOS inhibitors in chronic pain. Agmatine (AG), an endogenous neuromodulator present in brain and spinal cord, has both NMDAR antagonist and NOS inhibitor activities. We report here that AG, exogenously administered to rodents, decreased hyperalgesia accompanying inflammation, normalized the mechanical hypersensitivity (allodynia/hyperalgesia) produced by chemical or mechanical nerve injury, and reduced autotomy-like behavior and lesion size after excitotoxic spinal cord injury. AG produced these effects in the absence of antinociceptive effects in acute pain tests. Endogenous AG also was detected in rodent lumbosacral spinal cord in concentrations similar to those previously detected in brain. The evidence suggests a unique antiplasticity and neuroprotective role for AG in processes underlying persistent pain and neuronal injury." [Full Text] Aricioglu F, Korcegez E, Bozkurt A, Ozyalcin S.

Effect of agmatine on acute and mononeuropathic pain.

Ann N Y Acad Sci. 2003 Dec;1009:106-15.

"Agmatine is a polycationic amine synthesized from L-arginine by arginine decarboxylase in brain and several tissues. It binds to N-methyl-D-aspartate (NMDA) subtype of glutamatergic, alpha(2)-adrenergic and imidazoline (I) receptors. The present study was designed to investigate effect of agmatine on acute and mononeuropathic pain after chronic constriction injury (CCI). CCI was created by four loose ligations around the right sciatic nerve. The analgesic threshold in rats was evaluated by using thermal hyperalgesia/allodynia (THA) at 4 degrees C. The evaluations were made preoperatively, on postoperative day 15, and after drug administration. Agmatine (10, 20, 40, 80, and 100 mg/kg) was administered intraperitoneally for 5 days beginning on postoperative day 15. Agmatine significantly reduced the hyperalgesia in all doses applied. When agmatine was injected intraperitoneally (10, 20, 40, 80, and 100 mg/kg), it increased the nociceptive threshold in the tail-immersion test in a dose-dependent manner, but it had no effect in the hot-plate test. This effect of agmatine in the tail-immersion test was blocked by both yohimbine (1 mg/kg) and idazoxan (0.5 mg/kg). When agmatine was administered intracerebroventricularly (25-200 microg/10 microL), it increased the nociceptive threshold in the hot-plate but not in the tail-immersion test. We conclude that agmatine, an endogenous substance derived from arginine, can modulate both acute and chronic pain." [Abstract] Onal A, Soykan N.

Agmatine produces antinociception in tonic pain in mice.

Pharmacol Biochem Behav. 2001 May-Jun;69(1-2):93-7.

"Agmatine is an endogenous polyamine metabolite formed by decarboxylation of L-arginine. In this study, the effect of agmatine on tonic pain was compared to its effect on phasic pain by using the formalin and tail-flick (TF) tests in mice. When administered intraperitoneally (ip), agmatine (37.5-300 mg/kg) exhibited a decrease in nociceptive behaviours in the first and second phase of the formalin test, which is a tonic pain model. The alpha(2) adrenoceptor antagonist yohimbine blocked the effect of agmatine in Phase 2 but did not change its effect in Phase 1. In the TF test, there was no significant change in the behaviour of agmatine-administered (75-300 mg/kg) animals. As a result, agmatine appears to have an analgesic effect on tonic rather than phasic pain, and alpha(2) receptors seem partly to have a role in the antinociceptive effect of agmatine on tonic pain." [Abstract] Li J, Li X, Pei G, Qin BY.

Influence of agmatine in adaptation of cAMP signal transduction system of opiate receptors.

Zhongguo Yao Li Xue Bao. 1999 Jul;20(7):592-6.

"AIM: To observe attenuative effects of agmatine on opiate desensitization and substance dependence. METHODS: Guanosine 5'-O-(3-[35S] thiotriphosphate) ([35S]GTTP) binding and cellular cyclic AMP (cAMP) level were determined by radioligand binding assay and radioimmunoassay in NG108-15 cells, respectively. RESULTS: Agmatine increased stimulative action of opioids on [35S]GTTP binding by about 35% and inhibitory effects of opioids on cellular cAMP concentration by about 114.3% in NG108-15 cells pretreated with opioids. On the other hand, it also inhibited cAMP over-shooting by 214.9% of morphine substance dependent cells precipitated by naloxone compared with that of control. These effects of agmatine were antagonized by idazoxan in a concentration-dependent manner. CONCLUSION: Agmatine reversed the formative process of adaptation in cAMP signal transduction cascade." [Abstract] Aricioglu F, Kan B, Yillar O, Korcegez E, Berkman K.

Effect of agmatine on electrically and chemically induced seizures in mice.

Ann N Y Acad Sci. 2003 Dec;1009:141-6.

"Agmatine, an amine and organic cation, is formed by the decarboxylation of L-arginine by arginine decarboxylase. It binds to alpha(2)-adrenergic and imidazoline receptors. It blocks N-methyl-D-aspartate (NMDA) subtype of glutamate receptors and inhibits nitric oxide (NO) synthase. Because the importance of NMDA receptors and the NO system are well known in seizure activity, this study was designed to investigate the effect of agmatine on electrically and chemically induced seizures by using maximal electroshock (MES) and pentilentetrazole (PTZ) models in mice. Initial studies established convulsive current 50 (CC(50)) for MES and effective dose 50 (ED(50)) for PTZ to produce seizures. Agmatine (20, 40, 80, and 100 mg/kg intraperitoneally) increased the threshold of seizures in MES dose dependently. In PTZ-induced convulsions, the highest dose of agmatine (100 mg/kg) increased the seizure onset time and decreased percent survival. The percentage of grade V seizures was found to be increased by agmatine doses greater than 20 mg/kg." [Abstract] Demehri S, Homayoun H, Honar H, Riazi K, Vafaie K, Roushanzamir F, Dehpour AR.

Agmatine exerts anticonvulsant effect in mice: modulation by alpha 2-adrenoceptors and nitric oxide.

Neuropharmacology. 2003 Sep;45(4):534-42.

"The effect of agmatine, an endogenous polyamine metabolite, on seizure susceptibility was investigated in mice. Acute intraperitoneal administration of agmatine (5, 10, 20, 40 mg/kg) had a significant and dose-dependent inhibitory effect on pentylenetetrazole (PTZ)-induced seizures. The peak of this anticonvulsant effect was 45 min after agmatine administration. We further investigated the possible involvement of the alpha(2)-adrenoceptors and L-arginine/NO pathway in this effect of agmatine. The alpha(2)-adrenoceptor antagonist, yohimbine (0.5-2 mg/kg), induced a dose-dependent blockade of the anticonvulsant effect of agmatine. The nitric oxide synthase (NOS) substrate, L-arginine (60 mg/kg), inhibited the anticonvulsant property of agmatine and this effect was significantly reversed by NOS inhibitor N(G)-nitro-L-arginine (L-NAME, 30 mg/kg), implying an NO-dependent mechanism for L-arginine effect. We further examined a possible additive effect between agmatine (1 or 5 mg/kg) and L-NAME (10 mg/kg). The combination of L-NAME (10 mg/kg) with agmatine (5 but not 1 mg/kg) induced a significantly higher level of seizure protection as compared with each drug alone. Moreover, a combination of lower doses of yohimbine (0.5 mg/kg) and L-arginine (30 mg/kg) also significantly decreased the anticonvulsant effect of agmatine. In conclusion, the present data suggest that agmatine may be of potential use in seizure treatment." [Abstract] Bence AK, Worthen DR, Stables JP, Crooks PA.

An in vivo evaluation of the antiseizure activity and acute neurotoxicity of agmatine.

Pharmacol Biochem Behav. 2003 Feb;74(3):771-5.

"Agmatine, an endogenous cationic amine, exerts a wide range of biological effects, including modulation of glutamate-activated N-methyl-D-aspartate (NMDA) receptor function in the central nervous system (CNS). Since glutamate and the NMDA receptor have been implicated in the initiation and spread of seizure activity, the capacity of agmatine to inhibit seizure spread was evaluated in vivo. Orally administered agmatine (30 mg/kg) protected against maximal electroshock seizure (MES)-induced seizure spread in rats as rapidly as 15 min and for as long as 6 h after administration. Inhibition of MES-induced seizure spread was also observed when agmatine was administered intraperitoneally. Agmatine's antiseizure activity did not appear to be dose-dependent. An in vivo neurotoxicity screen indicated that agmatine was devoid of any acute neurological toxicity at the doses tested. These preliminary data suggest that agmatine has promising anticonvulsant activity." [Abstract] Vuilleumier P, Despland PA, Assal G, Regli F.

[Astral and out-of-body voyages. Heautoscopy, ecstasis and experimental hallucinations of epileptic origin]

Rev Neurol (Paris). 1997 Mar;153(2):115-9.

"We report a 38 year-old patient who had temporoparietal epilepsy and unusual ictal "out of body" experiences that remained undiagnosed for more than ten years, until her admission for a motor seizure of the left hemibody. Out of body episodes were experienced as intense and ecstatic astral journeys. EEG showed a bilateral extension of epileptiform abnormalities to the parietal regions, predominantly on the right side. We discuss the various forms of heautoscopy and their putative mechanisms. We suggest that a disturbance in representing space in independent extrapersonal and personal coordinates might be as crucial as the elusive hypothesis of a body schema disorder. Combined involvement of the parietal neocortex and temporolimbic structures might allow those experiences to gain a subjective vividness which appears to be indissociable from normal conscious experiences." [Abstract] Britton WB, Bootzin RR.

Near-death experiences and the temporal lobe.

Psychol Sci. 2004 Apr;15(4):254-8.

"Many studies in humans suggest that altered temporal lobe functioning, especially functioning in the right temporal lobe, is involved in mystical and religious experiences. We investigated temporal lobe functioning in individuals who reported having transcendental "near-death experiences" during life-threatening events. These individuals were found to have more temporal lobe epileptiform electroencephalographic activity than control subjects and also reported significantly more temporal lobe epileptic symptoms. Contrary to predictions, epileptiform activity was nearly completely lateralized to the left hemisphere. The near-death experience was not associated with dysfunctional stress reactions such as dissociation, posttraumatic stress disorder, and substance abuse, but rather was associated with positive coping styles. Additional analyses revealed that near-death experiencers had altered sleep patterns, specifically, a shorter duration of sleep and delayed REM sleep relative to the control group. These results suggest that altered temporal lobe functioning may be involved in the near-death experience and that individuals who have had such experiences are physiologically distinct from the general population." [Abstract] Podoll K, Robinson D.

Out-of-body experiences and related phenomena in migraine art.

Cephalalgia. 1999 Dec;19(10):886-96.

"In a collection of 562 migraine art pictures, seven pieces illustrate various elements of out-of-body experiences (OBEs) and related phenomena, including the somesthetic sensations of a duplicate or parasomatic body and the visual experiences of perceiving the own body, i.e. autoscopy, and its environment from a vantage point out of the body. Phenomenological features of the OBEs depicted are compared with 17 similar case reports reviewed from the literature. It is concluded that OBEs can occur as migraine aura symptom, which supports the notion that OBEs represent a preformed functional response of the brain. This neuropsychological theory supplements existing psychological theories of OBEs, which consider the said phenomena as representing hallucinatory experiences based on imagination and memory." [Abstract] Lawrence M.

The unconscious experience.

Am J Crit Care. 1995 May;4(3):227-32.

"BACKGROUND: Although considerable research has been done on pathophysiology, metabolic and physical causes, and prognostic indicators, little is known about unconsciousness or coma from the perspective of the patient. OBJECTIVE: To describe the experiences of patients who were once documented as being unconscious. METHODS: Phenomenologic interviews were conducted with 100 patients whose records indicated that they had been unconscious during hospitalization. Interviews were also attempted with primary family members, significant others, or other external observers. Chart audits documenting the unconscious episode, medications, and diagnoses were also carried out. Data were compared, using van Kaam's method, and contrasted. RESULTS: Patients experienced one or more of five states: unconsciousness, inner consciousness, perceived unconsciousness, distorted consciousness, and paranormal experiences. They described hearing, understanding, and responding emotionally to what was being said when it was assumed they were not aware. In addition, 23 subjects reported near-death experiences or visits, out-of-body experiences, or some other paranormal experience. CONCLUSION: Patients' unconscious experiences can cause long-term effects. Patients often need reassurance that other patients subjected to similar conditions also have these experiences." [Abstract] Morse M, Conner D, Tyler D.

Near-death experiences in a pediatric population. A preliminary report.

Am J Dis Child. 1985 Jun;139(6):595-600.

"Numerous accounts of a unique psychological state associated with near-fatal events have been described in adults; however, we know of no studies in the medical literature of the nature or incidence of such experiences in children. Four of seven children who survived cardiopulmonary arrests or coma associated with trauma, drownings, or hyperosmolar states reported near-death experiences. Their subjective accounts of their experiences included a sense of being out of the body, traveling in a tunnel or staircase, seeing beings dressed in white, and a decisional return to the body. Six patients hospitalized in the intensive care unit for epiglottitis, heart surgery, or Guillain-Barre syndrome, all of whom had mechanical ventilatory support and were treated with anesthetic agents and narcotics, had no memories of the time they were unconscious. Clearly, children report near-death experiences similar to ones previously described in adults. Further systematic study of this phenomenon is indicated." [Abstract] Bressloff PC, Cowan JD, Golubitsky M, Thomas PJ, Wiener MC.

What geometric visual hallucinations tell us about the visual cortex.

Neural Comput. 2002 Mar;14(3):473-91.

"Many observers see geometric visual hallucinations after taking hallucinogens such as LSD, cannabis, mescaline or psilocybin; on viewing bright flickering lights; on waking up or falling asleep; in "near-death" experiences; and in many other syndromes. Kluver organized the images into four groups called form constants: (I) tunnels and funnels, (II) spirals, (III) lattices, including honeycombs and triangles, and (IV) cobwebs. In most cases, the images are seen in both eyes and move with them. We interpret this to mean that they are generated in the brain. Here, we summarize a theory of their origin in visual cortex (area V1), based on the assumption that the form of the retino-cortical map and the architecture of V1 determine their geometry. (A much longer and more detailed mathematical version has been published in Philosophical Transactions of the Royal Society B, 356 [2001].) We model V1 as the continuum limit of a lattice of interconnected hypercolumns, each comprising a number of interconnected iso-orientation columns. Based on anatomical evidence, we assume that the lateral connectivity between hypercolumns exhibits symmetries, rendering it invariant under the action of the Euclidean group E(2), composed of reflections and translations in the plane, and a (novel) shift-twist action. Using this symmetry, we show that the various patterns of activity that spontaneously emerge when V1's spatially uniform resting state becomes unstable correspond to the form constants when transformed to the visual field using the retino-cortical map. The results are sensitive to the detailed specification of the lateral connectivity and suggest that the cortical mechanisms that generate geometric visual hallucinations are closely related to those used to process edges, contours, surfaces, and textures." [Abstract] Hollmann, Markus W., Liu, Hong-Tao, Hoenemann, Christian W., Liu, Wei-Hua, Durieux, Marcel E.

Modulation of NMDA Receptor Function by Ketamine and Magnesium. Part II: Interactions with Volatile Anesthetics

Anesth Analg 2001 92: 1182-1191

"Mg2+ and ketamine interact superadditively at N- methyl-D-aspartate (NMDA) receptors, which may explain the clinical efficacy of the combination. Because patients are usually exposed concomitantly to volatile anesthetics, we tested the hypothesis that volatile anesthetics interact with ketamine and/or Mg2+ at recombinantly expressed NMDA receptors. NR1/NR2A or NR1/NR2B receptors were expressed in Xenopus oocytes. We determined the effects of isoflurane, sevoflurane, and desflurane on NMDA receptor signaling, alone and in combination with S(+)-ketamine (4.1 microM on NR1/NR2A, 3.0 microM on NR2/NR2B) and/or Mg2+ (416 microM on NR1/NR2A, 629 microM on NR1/NR2B). Volatile anesthetics inhibited NR1/NR2A and NR1/NR2B glutamate receptor function in a reversible, concentration-dependent, voltage-insensitive and noncompetitive manner (half-maximal inhibitory concentration at NR1/NR2A receptors: 1.30 +/- 0.02 minimum alveolar anesthetic concentration [MAC] for isoflurane, 1.18 +/- 0.03 MAC for desflurane, 1.24 +/- 0.06 MAC for sevoflurane; at NR1/NR2B receptors: 1.33 +/- 0.12 MAC for isoflurane, 1.22 +/- 0.08 MAC for desflurane, and 1.28 +/- 0.08 MAC for sevoflurane). On both NR1/NR2A and NR1/NR2B receptors, 50% inhibitory concentration for volatile anesthetics was reduced approximately 20% by Mg2+, approximately 30% by S(+)-ketamine, and approximately 50% by the compounds in combination. Volatile anesthetic effects on NMDA receptors can be potentiated significantly by Mg2+, S(+)-ketamine, or-most profoundly-both. Therefore, the analgesic effects of ketamine and Mg2+, are likely to be enhanced in the presence of volatile anesthetics. IMPLICATIONS: Clinically relevant concentrations of volatile anesthetics inhibit functioning of N-methyl-D-aspartate receptors expressed recombinantly in Xenopus oocytes. This inhibition is reversible, concentration-dependent and voltage-insensitive, and results from noncompetitive antagonism of glutamate/glycine signaling. In addition, these effects can be potentiated significantly by co-application of either Mg2+, S(+)-ketamine, or--most profoundly--both." [Abstract] Losi G, Vicini S, Neale J.

NAAG fails to antagonize synaptic and extrasynaptic NMDA receptors in cerebellar granule neurons.

Neuropharmacology. 2004 Mar;46(4):490-6.

"The peptide transmitter N-acetylaspartylglutamate (NAAG) selectively activates the group II metabotropic glutamate receptors. Several reports also suggest that this peptide acts as a partial agonist at N-methyl-D-aspartate (NMDA) receptors but its putative antagonist effects have not been directly tested. To do this, we used whole cell recordings from cerebellar granule cells (CGC) in culture that allow the highest possible resolution of NMDA channel activation. When CGC were activated with equimolar concentrations of NMDA and NAAG, the peptide failed to alter the peak current elicited by NMDA. Very high concentrations of NAAG (100-200 microM) did not significantly reduce the current elicited by 10 microM NMDA or 0.1 microM glutamate, while 400 microM NAAG produced only a very small (less than 15%) reduction in these whole cell currents. Similarly, NAAG (400 microM) failed to significantly alter the average decay time constant or the peak amplitude of NMDA receptor-mediated miniature excitatory post-synaptic currents (mEPSCs). We conclude that high concentrations of the peptide do not exert physiologically relevant antagonist actions on synaptic NMDA receptor activation following vesicular release of glutamate. As an agonist, purified NAAG was found to be at least 10,000-fold less potent than glutamate in increasing "background" current via NMDA receptors on CGC. Inasmuch as it is difficult to confirm that NAAG preparations are completely free from contamination with glutamate at the 0.01% level, the peptide itself appears unlikely to have a direct agonist activity at the NMDA receptor subtypes found in CGC. Recent reports indicate that enhancing the activity of endogenous NAAG may be an important therapeutic approach to excitotoxicity and chronic pain perception. These effects are likely mediated by group II mGluRs, not NMDA receptors." [Abstract] Valivullah HM, Lancaster J, Sweetnam PM, Neale JH.

Interactions between N-acetylaspartylglutamate and AMPA, kainate, and NMDA binding sites.

J Neurochem. 1994 Nov;63(5):1714-9.

"The structure of N-acetylaspartylglutamate (NAAG) suggests this neuronal dipeptide as a candidate for interaction with discrete subclasses of ionotropic and metabotropic acidic amino acid receptors. A substantial difficulty in the assay of these interactions is posed by membrane-bound peptidase activity that converts the dipeptide to glutamate and N-acetylaspartate, molecules that will interfere with receptor assays. We have developed two sets of unique receptor assay conditions and applied one standard assay to measure the interactions, under equilibrium binding conditions, of [3H]kainate, [3H]amino-3-hydroxy-5-methylisoxazole-4-propionic acid ([3H]AMPA), and [3H]CGS-19755 with the three classes (kainate, quisqualate, and N-methyl-D-aspartate) of ionotropic glutamate receptors, while inhibiting peptidase activity against NAAG. Under these conditions, NAAG exhibits apparent inhibition constants (IC50) of 500, 790, and 8.8 microM in the kainate, AMPA, and CGS-19755 receptor binding assays, respectively. Glutamate was substantially more effective and less specific in these competition assays, with inhibition constants of 0.36, 1.1, and 0.37 microM. These data support the hypothesis that, relative to glutamate, NAAG functions as a specific, low potency agonist at N-methyl-D-aspartate subclass of ionotropic acidic amino acid receptors, but the peptide is not likely to activate directly the kainate or quisqualate subclasses of excitatory ionotropic receptors under physiologic conditions." [Abstract] Harsing LG Jr, Solyom S, Salamon C.

The role of glycineB binding site and glycine transporter (GlyT1) in the regulation of [3H]GABA and [3H]glycine release in the rat brain.

Neurochem Res. 2001 Sep;26(8-9):915-23.

"The effect of N-methyl-D-aspartic acid (NMDA), a selective glutamate receptor agonist, on the release of previously incorporated [3H]gamma-aminobutyric acid(GABA) was examined in superfused striatal slices of the rat. NMDA (0.01 to 1.0 mM) increased [3H]GABA overflow with an EC50 value of 0.09 mM. The [3H]GABA releasing effect of NMDA was an external Ca2+-dependent process and the GABA uptake inhibitor nipecotic acid (0.1 mM) potentiated this effect. These findings support the view that NMDA evokes GABA release from vesicular pool in striatal GABAergic neurons. Addition of glycine (1 mM), a cotransmitter for NMDA receptor, did not influence the NMDA-induced [3H]GABA overflow. Kynurenic acid (1 mM), an antagonist of glycineB site, decreased the [3H]GABA-releasing effect of NMDA and this reduction was suspended by addition of 1 mM glycine. Neither glycine nor kynurenic acid exerted effects on resting [3H]GABA outflow. These data suggest that glycineB binding site at NMDA receptor may be saturated by glycine released from neighboring cells. Glycyldodecylamide (GDA) and N-dodecylsarcosine, inhibitors of glycineT1 transporter, inhibited the uptake of [3H]glycine (IC50 33 and 16 microM) in synaptosomes prepared from rat hippocampus. When hippocampal slices were loaded with [3H]glycine, resting efflux was detected whereas electrical stimulation failed to evoke [3H]glycine overflow. Neither GDA (0.1 mM) nor N-dodecylsarcosine (0.3 mM) influenced [3H]glycine efflux. Using Krebs-bicarbonate buffer with reduced Na+ for superfusion of hippocampal slices produced an increased [3H]glycine outflow and electrical stimulation further enhanced this release. These experiments speak for glial and neuronal [3H]glycine release in hippocampus with a dominant role of the former one. GDA, however, did not influence resting or stimulated [3H]glycine efflux even when buffer with low Na+ concentration was applied." [Abstract] Karcz-Kubicha M, Wedzony K, Zajaczkowski W, Danysz W.

NMDA receptor antagonists acting at the glycineB site in rat models for antipsychotic-like activity.

J Neural Transm. 1999;106(11-12):1189-204.

"Several partial agonist and full antagonists acting at the glycine site of the NMDA receptors were tested for potential antipsychotic-like properties in rats. As models, amphetamine- and phencyclidine (PCP)-induced locomotor activation in the open field and PCP-induced impairment of prepulse inhibition of the acoustic startle response were employed. In the open field test, partial agonists, D-cycloserine failed to show any effect, aminocyclopropane carboxylic acid (ACPC) enhanced the action of PCP (but not that of amphetamine) and R(+)HA-966 attenuated the locomotor activation produced by both amphetamine and PCP. Both full glycineB antagonists, L-701,324 and MRZ 2/576 attenuated the action of amphetamine and PCP but at the doses that also produce transient behavioural inhibition in naive animals. A competitive NMDA receptor antagonist CGP 39551 was ineffective. In the prepulse inhibition test neither L-701,324 nor MRZ 2/576 changed sensorimotor gating in naive animals nor attenuated the disrupting effects of PCP. The present data do not support antipsychotic profile of glycineB full antagonists. However, psychotomimetic potential of glycineB antagonists seems to be low." [Abstract]

