Cannabinoid receptors have been suggested as potential therapeutic targets in cerebral ischemia. In this study, cannabinoid receptor (CBR) agonists and antagonists were tested for their ability to protect against the effects of global cerebral ischemia. For this purpose, rats were intraperitoneally (i.p.) treated with N‐arachidonoyl dopamine (NADA; CBR1 agonist), Rimonabant (CBR1 antagonist), GW 405833 (CBR2 agonist), AM630 (CBR2 antagonist) at a dose of 1 mg/kg and subjected later to transient of their bilateral common carotid arteries (CCA) for 30 min. The control group received the vehicle (dimethyl sulfoxide). The brain content of the oxidative stress biomarkers malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO) was determined. In addition, paraoxonase-1 (PON-1) activity, acetylcholinesterase (AChE), and nuclear factor-B (NF-B) brain's content were measured, and histopathological study of brain tissue was done. In the ischemic group, brain tissue concentrations of malondialdehyde and nitric oxide were higher, and reduced glutathione was lower than the control animals. In addition, brain ischemia resulted in a significant decrease in PON-1 activity and increased NF-B.
On the other hand, I/R had no significance on the AchE brain's content. Brain ischemia resulted in degeneration in the cerebral cortex, hippocampus, and substantia nigra. In the ischemic brain, either NADA or AM630 produced a significant decrease in lipid peroxidation. Cannabinoids inhibited nitric oxide and increased reduced glutathione contents in the ischemic brain. The level of NF-B was decreased by either NADA or AM630 but AChE decreased significantly by cannabinoids. Moreover, NADA, GW 405833, or AM630 caused a significant decrease in PON-1 activity. AM630 markedly improved the ischemia-induced histopathological changes. In addition, protection of substantia nigra neurons was observed after treatment with NADA or GW 405833.