Involvement of brain-derived neurotrophic factor in cannabinoid receptor-dependent protection against excitotoxicity.
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.
Khaspekov
Leonid G
LG
Molecular Genetics of Behaviour, Max-Planck-Institute of Psychiatry, Kraepelinstrasse 2-10, 80804 Munich, Germany.
Brenz Verca
Maria S
MS
Frumkina
Lidia E
LE
Hermann
Heike
H
Marsicano
Giovanni
G
Lutz
Beat
B
D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism* / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists; D016923:Cell Death / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D007608:Kainic Acid / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology; D009924:Organ Culture Techniques; D010880:Piperidines / Q000494:pharmacology; D011419:Propidium / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D043882:Receptors, Cannabinoid / Q000235:genetics / Q000378:metabolism*; D000077285:Rimonabant; D013997:Time Factors
D019208:Brain-Derived Neurotrophic Factor; D063387:Cannabinoid Receptor Antagonists; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011419:Propidium; D000077285:Rimonabant; D007608:Kainic Acid