Introduction

Over the last two decades, since the endocannabinoid (eCB) system was discovered, our knowledge of its structure and functions has significantly expanded. This system consists of ligands, such as anandamide and 2‐arachidonoyl‐glycerol (2‐AG), receptors (CB1, CB2, possibly also TRPV1 and GPR55), transporters and enzymes, which are responsible for the synthesis [N‐acyl‐phosphatidylethanolamine‐phospholipase D, diacylglycerol lipase (DGL)] and degradation of these lipid mediators [fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase] (Piomelli, 2003; Mackie, 2006).

There is a multiplicity of eCB actions, mainly in the brain, under both physiological and pathological conditions. Unlike ‘classical’ neurotransmitters, the eCBs are not stored in presynaptic vesicles, rather, they are produced ‘on demand’ when increased intracellular Ca++ is the major intracellular trigger for synthesis. The primary ligands produced in the brain are anandamide (Devane et al., 1992) and 2‐AG (Mechoulam et al., 1995; Sugiura et al., 1995), which activate both the CB1 and CB2 receptors. Brain tissue concentrations of 2‐AG are approximately 200‐fold higher than those of anandamide (Bisogno et al., 1999) and the rank order for the distribution of both eCB in different areas is similar: highest in brainstem, striatum and hippocampus and lower in cortex, diencephalon and cerebellum. There is a large body of evidence showing that eCB are markedly increased in response to pathogenic events such as kainic acid‐induced seizures, 6‐hydroxydopamine or glutamate toxicity, shock‐induced stress and trauma. The fact that the eCB system is activated in response to such events suggests that it is part of the brain's compensatory repair mechanism, mediated via CB receptors signalling (for review: Bahr et al., 2006).

The CB receptors belong to the large superfamily of G protein‐coupled receptors (GPCR) (Piomelli, 2003; for a recent review see Basavarajappa, 2007), whereas TRPV1 is a ligand‐operated cation channel, which is related to the transient potential receptor family of unselective ion channels (Caterina et al., 1997). The neuronal CB1 is the more abundant CB receptor in the brain and is responsible for the psychoactive effects of the cannabinoids. These receptors have been shown to be localized presynaptically on GABAergic interneurons and glutamatergic neurons (Hajos et al., 2000; Hajos et al., 2001; Katona et al., 2001). Further studies have indeed corroborated the role of the eCB compounds in the control of excessive neuronal activity in the brain and in the modulation of neurotransmission (Marsicano et al., 2003) via retrograde signalling associated with inhibition of neurotransmitter release (for review: Onaivi, 2009).

CB2 are expressed predominantly in non‐neuronal cells as well as on subpopulations of neurons, yet, they exert no psychoactivity. Although considered to be located mostly in the immune system CB2R are now well recognized on resident inflammatory cells within the CNS, on microglial and dendritic cells (Maresz et al., 2005; Pertwee, 2008) and on brain endothelial cells (Golech et al., 2004). Activation of these receptors attenuates the inflammatory response by inhibiting the release of pro‐inflammatory mediators and by diminishing leukocyte chemotaxis and extravasation into the brain parenchyma (Pacher and Hasko, 2008). CB2 agonists were also found to decrease cytocrome‐C release, inhibit apoptosis and to exert anti‐inflammatory effects in a diverse range of animal models (Ashton and Glass, 2007; Benito et al., 2008).

Vanilloid type 1 (TRPV1) receptors are found not only on sensory neurons, where they are partly co‐expressed with CB1 receptors (Ahluwalia et al., 2000) but also in several central nuclei including hypothalamus, basal ganglia, hippocampus and cerebellum (Mezey et al., 2000; Di Marzo et al., 2001). They are also co‐expressed with CB1 and CB2 receptors on the cerebromicrovascular endothelial cells, which represent the main component of the blood–brain barrier and are involved in eCB‐mediated vasodilation (Golech et al., 2004).

Summing up, there is ample evidence suggesting that the eCBs interact with at least three types of receptors at binding sites located at a variety of cell types in the brain. The specific dominant interaction depends on a number of factors, including the levels of eCBs, tissue receptor distribution and accessibility to the receptors.

Is the eCB system a potential ‘self‐neuroprotective’ entity The expression and function of the eCBs and their respective receptors in the brain, on neurons, astrocytes, microglia and the cerebrovasculature point to their role in multiple (patho)physiological functions. To explore the role of anandamide signalling in vivo, several investigators have targeted its degrading enzyme in order to augment and extend its brain activities. Thus, the role of anandamide in setting an endogenous cannabinoid tone was shown in mice lacking the enzyme FAAH2/2. Upon administration of exogenous anandamide, its brain levels were augmented 15‐fold and the mice exhibited robust, CB1‐dependent behavioural responses such as hypomotility, analgesia, catalepsy and hypothermia (Cravatt et al., 2001). These findings attest to the role of FAAH as a key regulator of anandamide signalling in vivo. Anandamide also modulates emotional states as described by Kathuria et al. (2003). A class of potent, selective and systemically active inhibitors of FAAH, which augment brain levels of anandamide, exhibit benzodiazepine‐like properties in stressful situations. These effects are prevented by CB1 receptor blockade, pointing to the eCB as potential mediators of novel anti‐anxiety therapy. In a recent review Hwang et al. (2010) provide data supporting the notion that selective FAAH inhibitors have therapeutic potential against neuropathological states including traumatic brain injury (TBI) and stroke as well as neurodegenrerative diseases such as Alzheimer's, Huntington's and Parkinson's diseases. The accumulating data demonstrate that neuronal injury activates eCB signalling as an intrinsic neuroprotective response via activating signalling pathways downstream from CB receptors and promote neuronal maintenance and function. Ischemic and traumatic brain injuries are CNS pathologies in which high intracellular calcium accumulation are among the earliest events. They share a secondary complex of harmful pathways that include excitotoxicity, oxidative stress and acute inflammatory response (Leker and Shohami, 2002). It is now well accepted that the complex response to ischaemia and trauma need to be targeted by drug(s) that can modulate a number of independent injury factors simultaneously (Vink and Nimmo, 2009). The formation and accumulation of eCBs in response to injury, along with their multipotent properties as anti‐oxidants, vasodilators, anti‐inflammatory agents, inhibitors of excitotoxicity, as well as their role in neurogenesis, suggest that the formation of eCBs may represent a ‘self‐neuroprotective’ and neuroregenerative response. As ischaemia and TBI induce the release of numerous mediators, many of which are harmful [e.g. glutamate, reactive oxygen species (ROS), pro‐inflammatory cytokines, etc.], the eCBs stand out as neuroprotectants. Thus, to distinguish them from the endogenous harmful mediators, on one hand, and from exogenous neuroprotective synthetic drugs, on the other, the term ‘self‐neuroprotective’ response describes their ‘on‐demand’ synthesis and accumulation after injury. Thus, the lesson learned from the endogenous, multifactorial neuroprotecitve role of the eCBs can set the ground for the development of novel compounds targeting either receptors, enzymes or transporters involved in the eCB system. This review is focused on the role the eCB system plays as a self‐neuroprotective mechanism and its potential as a basis for the development of novel therapeutic modality for the treatment of CNS pathologies such as TBI and stroke.