Cannabinoid Receptor Agonists Protect Cultured Rat Hippocampal Neurons from Excitotoxicity
Abstract
Cannabinoid receptor agonists act presynaptically to inhibit the release of glutamate. Because other drugs with this action are known to reduce excitotoxicity, we tested several cannabimimetics in a model of synaptically mediated neuronal death. Reduction of the extracellular Mg2+ concentration to 0.1 mm evoked a repetitive pattern of intracellular Ca2+ concentration ([Ca2+]i) spiking that, when maintained for 24 hr, resulted in significant neuronal death. The [Ca2+]i spiking and cell death in this model result from excessive activation ofN-methyl-d-aspartate receptors, as indicated by the inhibition of both [Ca2+]i spiking and neuronal death by the N-methyl-d-aspartate receptor antagonist CGS19755 (10 μm). The cannabimimetic drug Win55212–2 (100 nm) completely blocked [Ca2+]i spiking and prevented neuronal death induced by low extracellular Mg2+ concentrations. These effects on [Ca2+]i spiking and viability were stereoselective and were prevented by the CB1 receptor antagonist SR141716 (100 nm). The partial agonist CP55940 (100 nm) also afforded significant protection from excitotoxicity. Cannabimimetic drugs did not protect cells from the direct application of glutamate (30 μm). These data suggest that cannabimimetic drugs may slow the progression of neurodegenerative diseases.
Footnotes
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Send reprint requests to: Dr. S. A. Thayer, Department of Pharmacology, University of Minnesota Medical School, 3–249 Millard Hall, 435 Delaware St. SE, Minneapolis, MN 55455. E-mail:thayer{at}med.umn.edu
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This work was supported by grants from the National Institute on Drug Abuse (DA07304 and DA09293) and the National Science Foundation (IBN9723796). M.S. was supported by National Institute on Drug Abuse Training Grant DA07097.
- Abbreviations:
- [Ca2+]i
- intracellular Ca2+ concentration
- [Mg2+]o
- extracellular Mg2+concentration
- NMDA
- N-methyl-d-aspartate
- CGS19755
- (±)-2-amino-5-phosphonopentanoic acid
- Win55212–2 (R-enantiomer)
- (+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthalenyl)methanone monomethanesulfonate
- Win55212–3
- S-enantiomer of Win55212
- SR141716
- N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazolecarboxamide
- CP55940
- [1α,2β(R),5α]-(−)-5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol
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- Received March 5, 1998.
- Accepted May 27, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
