Abstract
The neuroprotective effects of Delta(9)-tetrahydrocannabinol (THC) were examined using an in vitro model in which the AF5 CNS cell line was exposed to toxic levels of N-methyl-d-aspartate (NMDA), an agonist of the NMDA glutamate receptor. NMDA toxicity was reduced by THC, but not by the more specific cannabinoid receptor agonist, WIN55,212-2. Addition of dibutyryl cAMP (dbcAMP) to the culture medium did not alter the neuroprotective effect of THC and did not unmask a neuroprotective effect of WIN55,212-2. The cannabinoid antagonist SR141716A did not inhibit the neuroprotection induced by THC or alter the response to WIN55,212-2, even in the presence of dbcAMP, indicating that the neuroprotective effect of THC was cannabinoid receptor-independent. On the other hand, both THC and WIN55,212-2 produced cellular toxicology at higher dosages, an effect which was blocked in part by SR141716A. Capsaicin, an antioxidant and vanilloid receptor agonist, also produced a protective effect against NMDA toxicology. The protective effect of capsaicin was blocked by co-application of ruthenium red, but was not blocked by the specific vanilloid receptor antagonist capsazepine, and the transient receptor potential vanilloid type 1 (TRPV1) and ANKTM1 transcripts were not detected in AF5 cells. Thus, the neuroprotective effects of THC and capsaicin did not appear to be mediated by TRP ion channel family receptors. The antioxidant alpha-tocopherol prevented neurotoxicity in a dose-dependent manner. Therefore, THC may function as an antioxidant to increase cell survival in NMDA-induced neurotoxicity in the AF5 cell model, while higher dosages produce toxicity mediated by CB1 receptor stimulation.
MeSH terms
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Animals
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Benzimidazoles / metabolism
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Benzoxazines
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Blotting, Northern / methods
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Blotting, Western
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Calcium Channel Blockers / pharmacology
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Calcium Channels / genetics
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Calcium Channels / metabolism
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Capsaicin / analogs & derivatives*
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Capsaicin / pharmacology
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Cell Count
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Cell Death / drug effects
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Cell Lineage
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DNA, Single-Stranded / metabolism
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Dizocilpine Maleate / pharmacology
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Dose-Response Relationship, Drug
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Dronabinol / pharmacology*
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Drug Interactions
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Excitatory Amino Acid Agonists / toxicity*
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Immunohistochemistry / methods
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In Situ Nick-End Labeling / methods
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Morpholines / pharmacology
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N-Methylaspartate / toxicity*
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Naphthalenes / pharmacology
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Neurons / cytology
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Neurons / drug effects*
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Neuroprotective Agents / pharmacology*
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Piperidines / pharmacology
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Pyrazoles / pharmacology
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RNA, Messenger / biosynthesis
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Rats
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Receptor, Cannabinoid, CB1 / antagonists & inhibitors
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Receptor, Cannabinoid, CB1 / genetics
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Receptor, Cannabinoid, CB1 / metabolism
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Receptors, N-Methyl-D-Aspartate / genetics
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Receptors, N-Methyl-D-Aspartate / metabolism
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Reverse Transcriptase Polymerase Chain Reaction / methods
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Rimonabant
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Ruthenium / pharmacology
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TRPC Cation Channels
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Tetrazolium Salts
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Thiazoles
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alpha-Tocopherol / pharmacology
Substances
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Benzimidazoles
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Benzoxazines
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Calcium Channel Blockers
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Calcium Channels
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DNA, Single-Stranded
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Excitatory Amino Acid Agonists
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Morpholines
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Naphthalenes
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Neuroprotective Agents
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Piperidines
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Pyrazoles
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RNA, Messenger
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Receptor, Cannabinoid, CB1
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Receptors, N-Methyl-D-Aspartate
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TRPC Cation Channels
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Tetrazolium Salts
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Thiazoles
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(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
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N-Methylaspartate
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Dizocilpine Maleate
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Dronabinol
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Ruthenium
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thiazolyl blue
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alpha-Tocopherol
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capsazepine
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bisbenzimide ethoxide trihydrochloride
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Rimonabant
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Capsaicin