Involvement of brain‐derived neurotrophic factor in cannabinoid receptor‐dependent protection against excitotoxicity

Abstract

Cannabinoid type 1 (CB1) receptors play a central role in the protection against excitotoxicity induced by treatment of mice with kainic acid (KA). As inactivation of CB1 receptor function in mice blocks KA-induced increase of brain-derived neurotrophic factor (BDNF) mRNA levels in hippocampus, the notion was put forward that BDNF might be a mediator, at least in part, of CB1 receptor-dependent neuroprotection [Marsicano et al. (2003) Science, 302, 84-88]. To assess this signalling cascade in more detail, organotypic hippocampal slice cultures were used, as this in vitro system conserves morphological and functional properties of the hippocampus. Here, we show that both genetic ablation of CB1 receptors and pharmacological blockade with the specific CB1 receptor antagonist SR141716A increased the susceptibility of the in vitro cultures to KA-induced excitotoxicity, leading to extensive neuronal death. Next, we found that the application of SR141716A to hippocampal cultures from wild-type mice abolished the KA-induced increase in BDNF protein levels. Therefore, we tried to rescue these organotypic cultures from neuronal death by exogenously applied BDNF. Indeed, BDNF was sufficient to prevent KA-induced neuronal death after blockade of CB1 receptor signalling. In conclusion, our results strongly suggest that BDNF is a key mediator in CB1 receptor-dependent protection against excitotoxicity, and further underline the physiological importance of the endogenous cannabinoid system in neuroprotection.

Dual Modulation of Endocannabinoid Transport and Fatty Acid Amide Hydrolase Protects against Excitotoxicity

“…The cultured slices express compensatory responses to injury and survival signaling pathways that are similar to those found in the adult brain Khaspekov et al, 2004;Karanian et al, 2005). As shown in Figure 1, A and B, stimulation of CB 1 receptors with the stable agonist AM356 results in the activation of ERK as well as FAK, a signaling event upstream of the ERK/ MAPK pathway (Derkinderen et al, 1998;Karanian et al, 2005).…”

“…Selective inhibitors of the transporter and FAAH caused additive augmentation of endogenous signaling events mediated by the cannabinoid CB 1 receptor. Disruption of such signals has been shown to prevent neuronal maintenance processes and increase vulnerability to brain damage (Parmentier-Batteur et al, 2002;Marsicano et al, 2003;Khaspekov et al, 2004;Karanian et al, 2005). Here, blocking endocannabinoid inactivation enhanced cannabinergic activity and ameliorated cellular disturbances associated with excitotoxicity.…”

“…The protective effects may involve signal transduction pathways linked to cannabinoid CB 1 receptors that recognize the endocannabinoids anandamide and 2-arachidonylglycerol (Bouaboula et al, 1995;Derkinderen et al, 1998Derkinderen et al, , 2003Galve-Roperh et al, 2002;Karanian et al, 2005). Blocking CB 1 receptors pharmacologically was found to disrupt neuronal maintenance and increase excitotoxic vulnerability (Khaspekov et al, 2004;Karanian et al, 2005), and mice that lack the receptors were more susceptible to ischemia (ParmentierBatteur et al, 2002) and seizure induction (Marsicano et al, 2003). The findings indicate that CB 1 signaling is important for neuronal survival.…”

Impaired cannabinoid receptor type 1 signaling interferes with stress-coping behavior in mice

“…49 A downregulation of BDNF in the hippocampus, for example, is believed to correlate with depression-like behavior, and injections of BDNF into the hippocampus have been demonstrated to lead to decreased floating in the FST. 37 As we could recently demonstrate that endocannabinoid signaling via CB1 receptors regulates BDNF expression, 2,43 we investigated BDNF mRNA expression in the hippocampus of CB1 À/À and CB1 þ / þ mice. In situ hybridization revealed a specific downregulation of BDNF mRNA in the CA3 region of the hippocampus of CB1 À/À mice (Figure 7), which might, thus, be related to the depression-like FST phenotype in CB1 À/À mice.…”

Aplicaciones de los cannabinoides en glaucoma

“…Así, la activación de los receptores CB1 presinápticos inhibe retrógradamente la liberación de glutamato, mejora el control de la excitabilidad neuronal y regula la plasticidad sináptica 42,43 . Su activación también induce un aumento de la expresión de Brain-derived neurotrophic factor (BDNF), aumentando también la supervivencia neuronal a través de mecanismos de neuromodulación en las células oligodendrogliales 44,45 . Por su parte, la activación de los receptores CB2 ejerce su efecto neuroprotector mediante la modulación de la neuroinflamación a través de la microglía, macrófagos y células dendríticas, aumentándose a su vez, de forma autocrina, la producción de endocannabinoides (AEA, 2-AG), como se ha demostrado en pacientes con esclerosis múltiple 46 .…”