Neuroprotection induced by delta-9-THC in a model of transient global cerebral ischemia

There is increasing experimental evidence of a neuroprotective effect of cannabinoids in experimental models including ischemia (Nagayama et al. 1999; Braida et al. 2000, 2003; van der Stelt et al., 2001a, 2001b; Veldhuis et al., 2003; Marsicano et al., 2003) and head trauma (Panikashvli et al., 2001). D9-THC, the major and psychoactive constituent of marijuana, is known to exert protective actions either in vitro, in rat cortical neurons (Hampson et al., 1998), or in vivo, in a model of rat forebrain ischemia (Louw et al., 2000) and neurotoxicity (van der Stelt et al., 2001; El-Remessy et al., 2003). However the role of CB1 cannabinoid receptor on D9-THC -induced neuroprotection is still controversial since partial (El-Remessy et al., 2003) or any (Hampson et al., 1998; van der Stelt et al., 2001) antagonism was found. The aim of the present work was to further investigate in vivo the effect of post-ischemic treatment with D9-THC on transient global cerebral ischemia in gerbils using a wide range of doses (0.05 \u2013 2 mg/kg) and to evaluate the role of CB1 cannabinoid receptor using the selective CB1 cannabinoid antagonist SR 141716. Gerbils, previously submitted to bilateral carotid occlusion for 10 min, were treated with D9-THC 5 min after recirculation and monitored for 7 days. Electroencephalographic (EEG) mean total spectral power (on Day 7), spontaneous motor activity (on Day 1) and cognitive function (on Day 3), were evaluated as parameters known to be hardly influenced by cerebral ischemia. D9-THC protected against ischemia-induced EEG flattening and hyperlocomotion, evaluated in an activity cage, with a dose-dependent bell-shaped curve, the maximal active dose being 1 mg/kg. Ischemia-induced memory impairment, evaluated through the passive avoidance test was blocked by D9-THC from 0.5 to 2 mg/kg. Preliminary results indicate that the neuroprotection by D9-THC is in part mediated by the cannabinoid receptor CB1

Effect of the anandamide transporter inhibitor,AM404, on anxiety response in rats

There are many and contradictory reports on the interaction between cannabinoids and anxiety. Both cannabinoid agonists and antagonists have been shown to have anxiolytic- and anxiogenic-like behavioural reactions in rodents depending on the dose and the context (Onaivi et al. 1990; Crawley et al. 1993; Onaivi et al. 1995; Rodriguez de Fonseca, 1996; Navarro et al., 1997; Akinshola et al. 1999; Haller et al., 2002; Berrendero and Maldonado 2002;Valjent et al.. 2002; Haller et al. 2004). The aim of the present work was to further elucidate the role of endocannabinoid system in anxiety response. For this purpose, the anandamide transport inhibitor, AM 404 (2.5-10 mg/kg), and D9\u2013THC (0.015-1.5 mg/kg), previously evaluated in our laboratory for its reinforcing properties in a Conditioned Place Preference test (Braida et al., 2005), were studied in a plus-maze apparatus according to Pellow et al. (1985) The test length was 5 min and the total time spent in each arm and the number of arm entries were scored by trained observers in male Sprague-Dawley rats, 30 min after treatment. The role of the CB1 cannabinoid and opioid receptor was investigated pre-treating rats with SR 141716 (0.25-1 mg/kg) and naloxone (0.5-2 mg/kg), 10 min before D9\u2013THC or AM 404. Both D9\u2013THC (0.75 mg/kg) and AM 404 (10 mg/kg) significantly elevated the percentage of open arm entries and the time spent in the open arms, showing an anxiolytic activity. This effect was reversed by pre-treatment with SR 141716. An interaction with opioid system was also found. These findings further support a key role of endocannabinoid system in the regulation of emotional states

Vanilloid VR(1) receptor is involved in rimonabant-induced neuroprotection

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(−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. 3. 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. 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(−1), 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(−1). 6. 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. 7. These findings suggest that VR(1) vanilloid receptors are involved in rimonabant's neuroprotection even if other mechanisms can contribute to this effect

Capsaicin exhibits neuroprotective effects in a model of transient global cerebral ischemia in Mongolian gerbils

1. Capsaicin, the irritant principle of hot peppers, is a vanilloid agonist known to activate the transient receptor potential channel vanilloid subfamily member 1 (VR1), recently reported to be involved in neurodegeneration. The present study investigated the role of VR1 in a model of global cerebral ischemia in gerbils. 2. Over the dose range tested, capsaicin (0.01, 0.025, 0.05, 0.2 and 0.6 mg kg(−1)), given 5 min after recirculation, dose-dependently antagonized the ischemia-induced electroencephalographic total spectral power decrease and restored relative frequency band distribution evaluated 7 days after ischemia. 3. Capsaicin, at all tested doses, fully prevented ischemia-induced hyperlocomotion evaluated 1 day after ischemia. 4. Capsaicin dose-dependently antagonized ischemia-induced memory impairment evaluated in a passive avoidance task, 3 days after ischemia. 5. Capsaicin showed a dose-dependent hypothermic effect evaluated for 2 h after recirculation. 6. At 7 days after ischemia, a progressive survival of pyramidal cells in the CA1 subfield in capsaicin-treated gerbils, with a maximum of 80%, at a dose of 0.2 mg kg(−1), was obtained. 7. The selective VR1 antagonist, capsazepine (0.01 mg kg(−1)), reversed capsaicin-induced protective effects, in a competitive manner. 8. These results suggest that the neuroprotective effect of capsaicin may be attributable, at least in part, to VR1 desensitization and provide a valuable target for development of interventional pharmacological strategies