Vanilloid VR 1 receptor is involved in rimonabant-induced neuroprotection

Recently, a potential neuroprotective effect of rimonabant, independent of the CB ₁ receptor interaction, has been proposed. In the present study, the role of transient receptor potential channel vanilloid subfamily member 1, named VR ₁, on neuroprotective effect of rimonabant, on global cerebral ischemia in gerbils, was investigated. Rimonabant (0.05-3 mg kg ^-1), given i.p. 5 min after recirculation, dose dependently antagonized the ischemia-induced decrease in electroencephalographic (EEG) total spectral power and restored relative frequency band distribution 7 days after ischemia. Rimonabant (0.125-0.5 mg kg ^-1) fully prevented ischemia-induced hyperlocomotion 1 day after ischemia and memory impairment evaluated in a passive avoidance task, 3 days after ischemia. At 7 days after ischemia, the survival of pyramidal cells, in the CA ₁ subfield, was respectively 91 and 96%, in the animals given rimonabant 0.25 and 0.5 mg kg ^-1, compared to the vehicle group. Higher doses were not protective. The protection induced by rimonabant followed a bell-shaped curve, the maximal active doses being 0.25 and 0.5 mg kg ^-1. Capsazepine (0.01 mg kg ^-1), a selective VR ₁ vanilloid receptor antagonist, completely reversed rimonabant-induced neuroprotective effects against EEG flattening, memory impairment and CA ₁ hippocampal neuronal loss. These findings suggest that VR ₁ vanilloid receptors are involved in rimonabant's neuroprotection even if other mechanisms can contribute to this effect.