Stimulated CB1 Cannabinoid Receptor Inducing Ischemic Tolerance and Protecting Neuron from Cerebral Ischemia

Background: It is reported that endogenous cannabinoids can cause vasodilation and bradycardia. They have anti-inflammatory effect and protect endothelial cells from injury, therefore they have potential application prospect in the prevention of cardio-cerebrovascular diseases. However, the mechanisms of the neuroprotection mediated by cannabinoid 1 receptors (CB1Rs) have not been uncovered in detail.

Methods: Nearly one hundred of new publications relevant to the theme are almost selected from Pubmed. The advanced details associated with the involvement of CB1R in cerebral ischemia as well as cerebral ischemic tolerance are reviewed.

Results: Anandamide system is mainly made up of cannabinoid receptors, their endogenous ligands and some related enzymes. The activation of the system mediates various molecular events so that plays a crucial role in the neuroprotection of cerebral ischemia. Increasing evidences suggest that CB1R is one of key molecules that mediate cerebral ischemia and cerebral ischemia tolerance. It is likely to provide an appropriate antioxidant balance by increasing endogenous free radical scavengers and helpful to exert the neuroprotective effects. Moreover, MAPKs, including ERK1/2, c-Jun Nterminal kinase (JNK) and p38MAPK can be recruited and stimulated through a complex signaling networks mediated by CB1R. Considerable evidences have indicated that CB1R was a crucial regulator for ERK1/2 signaling pathway. It is known that PI3K/Akt is a classical signaling pathway and its activation exerts neuroprotective effect via significant promoting cell survival. Glycogen synthase kinase-3β (GSK-3β) is an important downstream target of p-Akt. The PI3K/Akt/GSK-3β signaling pathway mediated by CB1Rs takes an important part in cerebral ischemic injury. PKC and CB1R are found to be abundantly co-expressed in presynaptic nerve endings of brain. There are considerable reports that different PKC isozymes played vital roles respectively in cerebral ischemic injury and preconditioning. The CB1R -mediated activation of PKCε can effectively stimulate ischemic tolerance.

Conclusion: CB1R played an important part via several signaling pathways in the protection from ischemic stroke and in ischemic tolerance. The involved molecular signaling pathways include ERK1/2, PI3K/Akt/GSK-3β and the translocation and activation of PKCε. With the intimate association between CB1R and neuron injuries, to target the receptor will exert neuroprotective effects on cerebral ischemia, which provides wide foreground for a novel therapy target.