Tetrahydrocannabinol-induced neurotoxicity depends on CB1 receptor-mediated c-Jun N-terminal kinase activation in cultured cortical neurons.
Delta9-Tetrahydrocannabinol (THC), the main psychoactive ingredient of marijuana, induces apoptosis in cultured cortical neurons. THC exerts its apoptotic effects in cortical neurons by binding to the CB1 cannabinoid receptor. The CB1 receptor has been shown to couple to the stress-activated protein kinase, c-Jun N-terminal kinase (JNK). However, the involvement of specific JNK isoforms in the neurotoxic properties of THC remains to be established. The present study involved treatment of rat cultured cortical neurons with THC (0.005-50 microM), and combinations of THC with the CB1 receptor antagonist, AM 251 (10 microM) and pertussis toxin (PTX; 200 ng ml-1). Antisense oligonucleotides (AS) were used to deplete neurons of JNK1 and JNK2 in order to elucidate their respective roles in THC signalling. Here we report that THC induces the activation of JNK via the CB1 receptor and its associated G-protein, Gi/o. Treatment of cultured cortical neurons with THC resulted in a differential timeframe of activation of the JNK1 and JNK2 isoforms. Use of specific JNK1 and JNK2 AS identified activation of caspase-3 and DNA fragmentation as downstream consequences of JNK1 and JNK2 activation. The results from this study demonstrate that activation of the CB1 receptor induces JNK and caspase-3 activation, an increase in Bax expression and DNA fragmentation. The data demonstrate that the activation of both JNK1 and JNK2 isoforms is central to the THC-induced activation of the apoptotic pathway in cortical neurons.
Downer
Eric J
EJ
Department of Physiology, Trinity College, Trinity College Institute of Neuroscience, Dublin 2, Ireland.
Fogarty
Marie P
MP
Campbell
Veronica A
VA
D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D013759:Dronabinol / Q000633:toxicity*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000502:physiology*
D043884:Receptor, Cannabinoid, CB1; D013759:Dronabinol; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases