Endovanilloid and endocannabinoid mechanism in neuroprotection

Exogenous and endogenous cannabinoids exert neuroprotection either in vitro or in vivo under different experimental conditions. Thus, cannabinoid receptor activation protects hippocampal or granule cerebellar neurons from excitotoxicity (Skaper et al., 1996; Shen and Thayer,1998; Hampson and Grimaldi, 2001), from hypoxia and glucose deprivation (Nagayama et al., 1999), from acute brain trauma (Panikashvili et al., 2001), ouabain-induced neurotoxicity (van der Stelt et al., 2001) and oxidative cell death (Kim et al., 2005). The size of cerebral infarcts after middle cerebral artery occlusion is increased in CB1-knockout mice (Parmentier-Batteur et al., 2002).The protective effect has been ascribed to inhibition of glutamate transmission, reduction of Ca++ influx and subsequent inhibition of noxious cascades, such as tumor necrosis factor-a (TNF-a) generation and oxidative stress (van der Stelt et al., 2002). More recently, exogenous 2-arachidonoylglycerol (2-AG) has been found to reduce brain edema, infarct volume and hippocampal death after closed head injury (Panikashvili et al., 2005), in part via CB1 receptor–mediated mechanism. However, cannabinoid CB1 receptor activation does not prevent the toxicity of glutamate towards embryonic chick telencephalon primary cultures (Nilsson et al., 2003). Increased production of endocannabinoid-related compounds modulate the inflammatory response to ischemia (Franklin et al., 2003). Therefore, endogenous cannabinoid signaling mechanisms may represent a key component of protection and repair programs mobilized in the injured brain. On the other hand, in addition to the CB1 receptor, the endocannabinoid N-arachidonoylethanolamine (AEA) or its metabolites may convey neuroprotection via other molecular targets (Grotenhermen, 2004). AEA is also a full agonist at the transient receptor potential channel vanilloid subfamily member 1 (VR1), recently reported to be involved in neurodegeneration. It is present in regions highly susceptible to neurodegenerative insults and it is influenced by temperature and pH changes (Mezey et al., 2000; Marinelli et al., 2002). In addition, during brain injury, AEA and lipoxigenase products accumulate in the brain (Marinelli et al., 2000, Muthian et al., 2004). Capsazepine, the selective VR1 vanilloid antagonist, has been shown to protect against neuronal injury caused by oxygen glucose deprivation by inhibiting I (h) (Veldhuis et al., 2003). A role of vanilloid receptors and lipoxygenases in neuroprotection by AEA and arvanil against in vivo excitotoxicity in the rat, has been reported (Ray et al., 2003) and a protective role of cannabinoid receptors against apoptosis induced by AEA vai vanilloid receptors(Maccarrone et al., 2000). Here we report the results recently obtained after acute post-ischemic treatment of different exogenous cannabinods agonists (CP 55,940, Cannabidiol, D9-tetrahydrocannabidiol (D9-THC), CB1 cannabinoid receptor antagonists (SR 141716), VR1 vanilloid receptor agonists (Capsaicin) or antagonists (Capsazepine) in a model of transient global cerebral ischemia in Mongolian gerbils. The neuroprotection was quantified in terms of complete recovery of EEG total and relative spectral power, spontaneous motor activity, memory function and hippocampal CA1 neuronal density, starting from 1 to 7 days. All the compounds protected against ischemia-induced EEG flattening, hyperlocomotion and memory impairment with a dose-dependent bell-shaped curve. In addition, a survival of hippocampal neurons was obtained. From the present lecture it can be concluded that there is a considerable experimental evidence for a neuroprotective role of both CB1 and VR1 cannabinoid and vanilloid receptors. However, the activation of both receptors does not completely explain the neuroprotective effect observed during brain injury. The data are critically reviewed and possible explanations are given