Δ 9 ‐Tetrahydrocannabinol (THC) and AM 404 protect against cerebral ischaemia in gerbils through a mechanism involving cannabinoid and opioid receptors

Background and purpose: It has been suggested that the endocannabinoid system elicits neuroprotection against excitotoxic brain damage. In the present study the therapeutic potential of AM 404 on ischaemia‐induced neuronal injury was investigated in vivo and compared with that of the classical cannabinoid receptor type 1 (CB 1 ) agonist, Δ 9 ‐tetraydrocannabinol (THC), using a model of transient global cerebral ischaemia in the gerbil. Experimental approach: The effects of AM 404 (0.015–2 mg kg −1 ) and THC (0.05–2 mg kg −1 ), given 5 min after ischaemia, were measured from 1 h to 7 days in terms of electroencephalographic (EEG) total spectral power, spontaneous motor activity, memory function, rectal temperature and hippocampal CA 1 neuronal count. Key results: Over the dose range tested, AM 404 (2 mg kg −1 ) and THC (1 mg kg −1 ) completely reversed the ischaemia‐induced behavioural, EEG and histological damage. Only THC (1 and 2 mg kg −1 ) induced a decrease of body temperature. Pretreatment with the selective CB 1 receptor antagonist, AM 251 (1 mg kg −1 ) and the opioid antagonist, naloxone (2 mg kg −1 ) reversed the protective effect induced by both AM 404 and THC while the TRPV 1 vanilloid antagonist, capsazepine (0.01 mg kg −1 ), was ineffective. Conclusions and implications: Our findings demonstrate that AM 404 and THC reduce neuronal damage caused by bilateral carotid occlusion in gerbils and that this protection is mediated through an interaction with CB 1 and opioid receptors. Endocannabinoids might form the basis for the development of new neuroprotective drugs useful for the treatment of stroke and other neurodegenerative pathologies. British Journal of Pharmacology (2007) 152 , 1301–1311; doi: 10.1038/sj.bjp.0707514 ; published online 29 October 2007