Interactions between CB(1) receptors and TRPV1 channels mediated by 12-HPETE are cytotoxic to mesencephalic dopaminergic neurons. Export

@article{citeulike:3380801, abstract = {BACKGROUND AND PURPOSES: We recently proposed the existence of neurotoxic interactions between the cannabinoid type 1 (CB(1)) receptor and transient receptor potential vanilloid 1 (TRPV1) channels in rat mesencephalic cultures. This study seeks evidence for the mediator(s) and mechanisms underlying the neurotoxic interactions between CB(1) receptors and TRPV1 in vitro and in vivo. EXPERIMENTAL APPROACH: The mediator(s) and mechanism(s) for the interactions between CB(1) receptors and TRPV1 were evaluated by cell viability assays, immunocytochemistry, Fura-2 calcium imaging, mitochondrial morphology assay, ELISA and Western blot assay in vitro in neuron-enriched mesencephalic cultures. Injections into the substantia nigra and subsequent cell counts were also used to confirm these interactions in vivo.KEY RESULTS: The neurotoxic interactions were mediated by 12(S)-hydroperoxyeicosatetraenoic acid (12(S)-HPETE), an endogenous TRPV1 agonist. CB(1) receptor agonists (HU210 and WIN55,212-2) increased the level of 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE), a downstream metabolite of 12(S)-HPETE, which stimulates TRPV1-mediated death of mesencephalic neurons, both in vitro and in vivo. The neurotoxicity was mediated by increased intracellular Ca(2+) concentration ([Ca(2+)](i)) through TRPV1, consequently leading to mitochondrial damage and was attenuated by baicalein, a 12-lipoxygenase inhibitor. CONCLUSION AND IMPLICATIONS: Activation of CB(1) receptors in rat mesencephalic neurons was associated with biosynthesis of 12(S)-HPETE, which in turn stimulated TRPV1 activity, leading to increased [Ca(2+)](i), mitochondrial damage and neuronal death.}, author = {Kim, S. R. and Bok, E. and Chung, Y. and Chung, E. S. and Jin, B. K.}, citeulike-article-id = {3380801}, day = {9}, journal = {Br J Pharmacol (British journal of pharmacology)}, keywords = {12-hpete, cb1, dopamine, dopaminergic\_neurons, trpv1}, month = {September}, number = {2}, posted-at = {2008-10-06 23:31:14}, priority = {3}, title = {Interactions between CB(1) receptors and TRPV1 channels mediated by 12-HPETE are cytotoxic to mesencephalic dopaminergic neurons.}, volume = {155}, year = {2008} }

TY - JOUR ID - citeulike:3380801 L3 - citeulike-article-id:3380801 N2 - BACKGROUND AND PURPOSES: We recently proposed the existence of neurotoxic interactions between the cannabinoid type 1 (CB(1)) receptor and transient receptor potential vanilloid 1 (TRPV1) channels in rat mesencephalic cultures. This study seeks evidence for the mediator(s) and mechanisms underlying the neurotoxic interactions between CB(1) receptors and TRPV1 in vitro and in vivo. EXPERIMENTAL APPROACH: The mediator(s) and mechanism(s) for the interactions between CB(1) receptors and TRPV1 were evaluated by cell viability assays, immunocytochemistry, Fura-2 calcium imaging, mitochondrial morphology assay, ELISA and Western blot assay in vitro in neuron-enriched mesencephalic cultures. Injections into the substantia nigra and subsequent cell counts were also used to confirm these interactions in vivo.KEY RESULTS: The neurotoxic interactions were mediated by 12(S)-hydroperoxyeicosatetraenoic acid (12(S)-HPETE), an endogenous TRPV1 agonist. CB(1) receptor agonists (HU210 and WIN55,212-2) increased the level of 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE), a downstream metabolite of 12(S)-HPETE, which stimulates TRPV1-mediated death of mesencephalic neurons, both in vitro and in vivo. The neurotoxicity was mediated by increased intracellular Ca(2+) concentration ([Ca(2+)](i)) through TRPV1, consequently leading to mitochondrial damage and was attenuated by baicalein, a 12-lipoxygenase inhibitor. CONCLUSION AND IMPLICATIONS: Activation of CB(1) receptors in rat mesencephalic neurons was associated with biosynthesis of 12(S)-HPETE, which in turn stimulated TRPV1 activity, leading to increased [Ca(2+)](i), mitochondrial damage and neuronal death. IS - 2 JF - Br J Pharmacol (British journal of pharmacology) TI - Interactions between CB(1) receptors and TRPV1 channels mediated by 12-HPETE are cytotoxic to mesencephalic dopaminergic neurons. VL - 155 KW - 12-hpete KW - cb1 KW - dopamine KW - dopaminergic_neurons KW - trpv1 AU - Kim, SR AU - Bok, E AU - Chung, Y AU - Chung, ES AU - Jin, BK PY - 2008/09/09/ ER -