Involvement of brain-derived neurotrophic factor in cannabinoid receptor-dependent protection against excitotoxicity.
Eur J Neurosci. 2004-04-01; 19(7): 1691-1698
DOI: 10.1111/j.1460-9568.2004.03285.x
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1. Eur J Neurosci. 2004 Apr;19(7):1691-8.
Involvement of brain-derived neurotrophic factor in cannabinoid
receptor-dependent protection against excitotoxicity.
Khaspekov LG(1), Brenz Verca MS, Frumkina LE, Hermann H, Marsicano G, Lutz B.
Author information:
(1)Molecular Genetics of Behaviour, Max-Planck-Institute of Psychiatry,
Kraepelinstrasse 2-10, 80804 Munich, Germany.
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.
DOI: 10.1111/j.1460-9568.2004.03285.x
PMID: 15078543 [Indexed for MEDLINE]