Vanilloid VR₁ receptor is involved in rimonabant‐induced neuroprotection

Abstract

1 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. 2 Rimonabant (0.05-3 mg kg À1 ), 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. 3 Rimonabant (0.125-0.5 mg kg À1 ) fully prevented ischemia-induced hyperlocomotion 1 day after ischemia and memory impairment evaluated in a passive avoidance task, 3 days after ischemia. 4 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 À1 , compared to the vehicle group. Higher doses were not protective. 5 The protection induced by rimonabant followed a bell-shaped curve, the maximal active doses being 0.25 and 0.5 mg kg À1 . 6 Capsazepine (0.01 mg kg À1 ), a selective VR 1 vanilloid receptor antagonist, completely reversed rimonabant-induced neuroprotective effects against EEG flattening, memory impairment and CA 1 hippocampal neuronal loss. 7 These findings suggest that VR 1 vanilloid receptors are involved in rimonabant's neuroprotection even if other mechanisms can contribute to this effect.

Cannabinoid Type 2 Receptor Activation Downregulates Stroke-Induced Classic and Alternative Brain Macrophage/Microglial Activation Concomitant to Neuroprotection

“…Although the exact mechanisms of the bell-shaped doseresponse curves remain to be elucidated, it could be speculated that interactions with other cannabinoid receptors might be involved. 17,20,27,28 As previously reported, 17 lack of CB2R expression did not affect infarct outcome. It has been reported that no significant changes in N-arachidonoylethanolamine, one of the main endogenous cannabinoid agonists, was seen after 4, 12, or 24 hours of pMCAO in mice (reviewed in 6 ).…”

Role of Cannabinoids and Endocannabinoids in Cerebral Ischemia

“…TRPV1 receptors are activated by changes in temperature and pH as well as AEA and lipoxygenase products that accumulate during ischemia and can contribute to excitotoxicity [103]. Although the mechanism of this effect of rimonabant is unclear (see discussion section of [102] for a thorough discussion of the possibilities), this study provides strong support for a neuroprotective effect of the drug against ischemic/reperfusion injury.…”

“…In one of these studies [30], a second, structurally unrelated CB1 receptor antagonist, LY 320135 [101], was also protective. Rimonabant is also protective in male gerbils exposed to transient, global ischemia [102]. The drug, administered 5 min after reperfusion and at low doses (less than 0.5 mg/kg), protected against the development of behavioral and EEG changes; in addition, animals given rimonabant exhibited nearly complete survival of cells in the CA1 region of the hippocampus 7 days after the ischemia.…”

The Biarylpyrazole Compound AM251 Alters Mitochondrial Physiology via Proteolytic Degradation of ERRα

“…However, administration of rimonabant still stimulates neurogenesis and induces cannabinoid-like effects in mice deficient in cannabinoid 1 receptors (Jin et al, 2004;Wiley et al, 2012), indicating the involvement of additional targets. Indeed, the neuroprotective effect of rimonabant requires the vanilloid receptor VR1, independent of the CB 1 R interaction (Jin et al, 2004;Pegorini et al, 2006). These biarylpyrazole compounds also appear to have targets other than CB 1 R, CB 2 R, and VR1 (Raffa and Ward, 2012); for example, AM251 and rimonabant are agonists of GPR55, a recently deorphanized G protein-coupled receptor that is expressed in peripheral tissues and is positively associated with obesity in human (Moreno-Navarrete et al, 2012).…”