We endeavored to investigate the effects of memantine pretreatment on lipid depletion and glycogen depletion in adrenal gland and liver cells, respectively, in rats acutely exposed to cold stress. It was observed that cold stress exposure increased lipid depletion in adrenal gland and glycogen depletion in hepatocytes, which supports previous studies [5, 6]. We noted that this NMDA antagonist, currently used to treat subjects with moderate to severe Alzheimer's disease [4, 5], significantly attenuated glycogen and lipid depletion in liver and adrenal gland, respectively, caused by cold stress in health Wistar rats.

The behavioral analysis allowed us to observe stress manifestation in rats after they were exposed to -8°C. Their behavior was similar to the initial reaction proposed by Selye et al [1]. Murad et al [21] noticed similar reactions. In addition, our histological analysis of liver tissue showed lower concentration of glycogen on hepatocytes of rats exposed to cold stress. This is explained by the fact that oxidative phosphorylation promotes glycogenolysis acceleration in response to catecholamine release caused by a stress condition, which lead to a lower concentration of glycogen on the cortical area of liver cells [22], such as we found in our study. The histological analysis also demonstrated that the stress group presented higher depletion of lipids on the cortical area of adrenal gland cells. This fact is explained by catecholamine release, which stimulates lipolysis in adrenal gland cells [22].

The effect of memantine on glycogen depletion observed in our findings could be explained by its antioxidants properties. A recent study [14] cited the importance of the various treatments based on NMDA-receptor antagonists including those targeted towards oxidative stress and excitotoxicity regarding Ca2+ homeostasis. Furthermore, a previous investigation noticed that various NMDA-receptor antagonists (memantine was one of them) concentration-dependently diminished all oxidase model reactions in rat liver [23]. This research supports our data that memantine possibly reduces the effects of cold stress on liver cells through its antioxidant property.

Other explanation for our results is the fact that in animals glutamatergic NMDA signaling has been shown not only to be essential for synaptic plasticity underlying memory formation, but also for the regulation of neuroendocrine secretion [24]. Glutamatergic signaling is involved in the control of the hypothalamic-pituitary-adrenocortical (HPA) axis such that intraventricular administration of glutamate increases activity of the HPA system [25] and contributes to stress induced hormone release [26, 27]. Our study supports those data, although we did not measure plasmatic catecholamines, the histological analysis provides evidence that glutamate blocker treatment with memantine reduced the physiological stress responses to cold exposure in adrenal gland and hepatocytes of rats due attenuated lipid and glycogen depletion, respectively.

Bähr et al [27] commented the need for antioxidants to protect the function of the adrenal cortex against reactive oxygen species generated by lipid peroxydation in the adrenal cortex, however, to our knowledge, no study evaluating direct effects of memantine on adrenal gland was observed. A previous research reported an inhibitory effect of antidepressant drugs on the corticosterone-induced promoter gene activity and suggested that the decrease in the glucocorticoid receptor-mediated gene transcription produced by antidepressants may be a mechanism by which these drugs block some effects induced by stress or corticosterone administration [28]. This investigation supports our data, since the reduction in the glucocorticoid receptor-mediated gene transcription induced by glutamate antagonist prevents the effects of stress [28].

Our study provides relevant information to the literature, since previous investigations have already indicated the importance of liver [29–31] and adrenal gland [32] for survivor. Other mechanism that could explain memantine effects on glycogen depletion in liver and lipid depletion in adrenal gland is its role on autonomic function. The possibly reduction of sympathetic activity caused by this drug decrease catecholamine release, which lead to a higher concentration of glycogen on the cortical area of liver and also a higher concentration of lipids on the cortical area of adrenal gland cells [22]. Moreover, Drever et al [33] suggested actions of memantine beyond NMDA receptor antagonism, including stimulating effects on cholinergic signalling via muscarinic receptors, therefore, reducing catecholamine levels.

In conclusion, our findings showed that memantine significantly reduced glycogen depletion in liver and lipid depletion in adrenal gland under an acute cold stress condition. Thus, we suggest that memantine prevents liver and adrenal gland from an acute cold stress exposure in rats.