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Vol. 54, Issue 3, 459-462, September 1998
Department of Pharmacology, University of Minnesota Medical School,
Minneapolis, Minnesota 55455
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 of
N-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.
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