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Molecular Pharmacology

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Research ArticleArticle

Molecular Mechanisms of Cannabinoid Protection from Neuronal Excitotoxicity

Sun Hee Kim, Seok Joon Won, Xiao Ou Mao, Kunlin Jin and David A. Greenberg
Molecular Pharmacology March 2006, 69 (3) 691-696; DOI: https://doi.org/10.1124/mol.105.016428
Sun Hee Kim
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Seok Joon Won
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Xiao Ou Mao
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Kunlin Jin
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David A. Greenberg
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Abstract

Cannabinoids protect neurons from excitotoxic injury. We investigated the mechanisms involved by studying N-methyl-d-aspartate (NMDA) toxicity in cultured murine cerebrocortical neurons in vitro and mouse cerebral cortex in vivo. The cannabinoid agonist R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)-methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl)-methanone mesylate [R(+)-Win 55212] reduced neuronal death in murine cortical cultures treated with 20 μM NMDA, and its protective effect was attenuated by the CB1 cannabinoid receptor (CB1R) antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-cichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A). Cultures from CB1R-knockout mice were more sensitive to NMDA toxicity than were cultures from wild-type mice. The in vitro protective effect of R(+)-Win 55212 was reduced by pertussis toxin, consistent with signaling through CB1R-coupled G-proteins. The nitric-oxide synthase (NOS) inhibitors 7-nitroindazole (7-NI) and N-ω-nitro-l-arginine methyl ester also reduced NMDA toxicity. In addition, CB1R and neuronal NOS were coexpressed in cultured cortical neurons, suggesting that cannabinoids might reduce NMDA toxicity by interfering with the generation of NO. NOS activity in cerebral cortex was higher in CB1R-knockouts than in wildtype mice, and 7-NI reduced NMDA lesion size. R(+)-Win 55212 inhibited NO production after NMDA treatment of wild-type cortical neuron cultures, measured with 4-amino-5-methylamino-2′,7′-difluorofluorescein diacetate, and this effect was reversed by SR141716A. In contrast, R(+)-Win 55212 failed to inhibit NO production in cultures from CB1R knockouts. Dibutyryl-cAMP blocked the protective effect of R(+)-Win 55212, and this was reversed by the protein kinase A (PKA) inhibitor N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide (H89). Cannabinoids seem to protect neurons against NMDA toxicity at least in part by activation of CB1R and downstream inhibition of PKA signaling and NO generation.

  • Received July 1, 2005.
  • Accepted November 18, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 69 (3)
Molecular Pharmacology
Vol. 69, Issue 3
1 Mar 2006
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Research ArticleArticle

Molecular Mechanisms of Cannabinoid Protection from Neuronal Excitotoxicity

Sun Hee Kim, Seok Joon Won, Xiao Ou Mao, Kunlin Jin and David A. Greenberg
Molecular Pharmacology March 1, 2006, 69 (3) 691-696; DOI: https://doi.org/10.1124/mol.105.016428

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Research ArticleArticle

Molecular Mechanisms of Cannabinoid Protection from Neuronal Excitotoxicity

Sun Hee Kim, Seok Joon Won, Xiao Ou Mao, Kunlin Jin and David A. Greenberg
Molecular Pharmacology March 1, 2006, 69 (3) 691-696; DOI: https://doi.org/10.1124/mol.105.016428
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