arachidonyl-2-chloroethylamide and Stroke

One of the most common psychological consequences of stroke is post-stroke depression (PSD). While more than 30 percent of stroke patients eventually develop PSD, the neurobiological mechanisms underlying such a phenomenon have not been well investigated. Given the critical involvement of hypothalamic-pituitary-adrenal axis and endocannabinoid system in response to stressful stimuli, we evaluated the hypothesis that cannabinoid receptors in the hypothalamus are critical for modulation of post-stroke depression-like behaviors in rats. To this end, rats were treated with middle cerebral artery occlusion (MCAO) followed by chronic unpredictable mild stress (CUMS) treatment procedure. We then assessed the expression of CB1 and CB2 receptors in the hypothalamus, and evaluated the effects of pharmacological stimulations of CB1 or CB2 receptors on the expression and development of depression-like behaviors in PSD rats. We found that PSD rats exhibited decreased the expression of CB1 receptor, but not CB2 receptor, in the ventral medial hypothalamus (VMH). Such an effect was not observed in the dorsally adjacent brain regions. Furthermore, intra-VMH injections of CB2 receptor agonist, but not CB1 receptor agonist, attenuated the expression of depression-like behaviors in PSD rats. Finally, repeated intraperitoneal injections of CB1 or CB2 receptor agonists during CUMS treatment inhibited the development of depression-like behaviors in PSD rats. Taken together, these results suggest that decreased CB1 receptor expression is likely associated with the development of post-stroke depression, and CB2 receptor may be a potential therapeutic target for the treatment post-stroke depressive disorders.

Topics: Animals; Arachidonic Acids; Cannabinoid Receptor Agonists; Cannabinoids; Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Exploratory Behavior; Food Preferences; Hypothalamus; Infarction, Middle Cerebral Artery; Male; Microinjections; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Stroke

Brain ischemia produces neuronal cell death and the recruitment of pro-inflammatory cells. In turn, the search for neuroprotection against this type of insult has rendered results involving a beneficial role of endocannabinoid receptor agonists in the Central Nervous System. In this work, to further elucidate the mechanisms associated to this neuroprotective effect, focal brain ischemia was generated by middle cerebral artery occlusion (MCAo) in C57Bl/6 mice. Three, 24 and 48 h after MCAo, animals received CB1R agonist ACEA (1 mg/kg), CB1R antagonist AM251 (1 mg/kg) or vehicle. To assess motor activity, neural deficit scores and motor tests were performed 1 day before and 3, 7, 14, 21, and 28 days after MCAo. At 7 and 28 days post lesion, cytoskeleton structure, astroglial and microglial reaction, and alterations in synapsis were studied in the cerebral cortex. ACEA treatment reduced astrocytic reaction, neuronal death, and dendritic loss. In contrast, AM251 treatment increased these parameters. Motor tests showed a progressive deterioration in motor activity in ischemic animals, which only ACEA treatment was able to counteract. Our results suggest that CB1R may be involved in neuronal survival and in the regulation of neuroprotection during focal cerebral ischemia in mice.

Topics: Animals; Arachidonic Acids; Brain Ischemia; Male; Mice; Mice, Inbred C57BL; Motor Skills; Neurons; Neuroprotective Agents; Receptor, Cannabinoid, CB1; Recovery of Function; Stroke