Hippocampal neurotoxicity of Delta9-tetrahydrocannabinol.
Marijuana consumption elicits diverse physiological and psychological effects in humans, including memory loss. Here we report that Delta9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, is toxic for hippocampal neurons. Treatment of cultured neurons or hippocampal slices with THC caused shrinkage of neuronal cell bodies and nuclei as well as genomic DNA strand breaks, hallmarks of neuronal apoptosis. Neuron death induced by THC was inhibited by nonsteroidal anti-inflammatory drugs, including indomethacin and aspirin, as well as vitamin E and other antioxidants. Furthermore, treatment of neurons with THC stimulated a significant increase in the release of arachidonic acid. We hypothesize that THC neurotoxicity is attributable to activation of the prostanoid synthesis pathway and generation of free radicals by cyclooxygenase. These data suggest that some of the memory deficits caused by cannabinoids may be caused by THC neurotoxicity.
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Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA.
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Impey
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D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D013759:Dronabinol / Q000633:toxicity*; D004789:Enzyme Activation; D006624:Hippocampus / Q000187:drug effects*; D066298:In Vitro Techniques; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure; D009498:Neurotoxins / Q000633:toxicity*; D010741:Phospholipases A / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014810:Vitamin E / Q000494:pharmacology
D000067956:Adenylyl Cyclase Inhibitors; D009498:Neurotoxins; D014810:Vitamin E; D016718:Arachidonic Acid; D013759:Dronabinol; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D002118:Calcium