Combined Neuroprotective Action of JWH-015 and AM251 in the CA1 Hippocampal Area of Rat Model of Transient Global Cerebral Ischemia

Abstract

Objectives: Transient global cerebral ischemia (TGCI) is induced by occlusion of the bilateral common carotid artery occlusion (BCCAO), and it mediates neuronal cell death in the CA1 hippocampal area. AM251 is a cannabinoid receptor type 1 (CB1) blocker that has been known to be protective against transient focal cerebral ischemia. JWH-015 is a selective agonist of CB2 and activator of CB1 that is involved in the promotion of neuronal recovery and survival. The aim of this study was to investigate the role of combined application of JWH-015 and AM251 in the rat model of GCI. Materials and Methods: Male Wistar rats underwent 20 minutes of ischemia followed by reperfusion. Then, 1 mg/kg JWH-015 and 2 mg/kg AM251 were administered through the caudal vein. The groups were control, sham, ischemia, vehicle, AM251, JWH-015 and AM251 + JWH-015. Animals were sacrificed 1 week after BCCAO. Results: The AM251 + JWH-015 group indicated a significant increase in the protein expressions of AKT1, Bcl-XL, Bcl-2 and Bad 14-3-3, but it showed a considerable decrease in the protein expressions of Bad and JNK1/2 (P ≤ 0.05 vs. AM251, and JWH-015 groups). The AM251 + JWH-015 group had a significantly higher number of alive cells and lower number of apoptotic cells in the CA1 hippocampal area and it also had a considerable improvement in spatial memory (P ≤ 0.05 vs. AM251, and JWH-015 groups). Conclusions: The results of this study indicated that combined application of AM251 and JWH-015 could be neuroprotective against detrimental effects of ischemia probably via suppression of neuronal apoptosis and maintenance of their survival.

Keywords

• CA1
• Survival
• Apoptosis
• Global cerebral ischemia