BAPTA-AM and ethanol protect cerebellar granule neurons from the destructive effect of the weaver gene.
The mechanisms by which the weaver gene (Reeves et al., 1989; Patil et al., 1995) inhibits neurite extension and/or induces death of the granule neurons in homozygous weaver mouse cerebellum are not presently understood. Here we show that BAPTA-AM and ethanol, which either reduce cytosolic levels of free calcium or prevent calcium entry, promote neurite outgrowth of the weaver neurons similar to the L-type calcium channel blocker verapamil (Liesi and Wright, 1996). Importantly, BAPTA-AM, ethanol, and verapamil not only restore neurite outgrowth of the weaver neurons but adjust their depolarized resting membrane potentials to the levels of normal neurons. These results indicate that calcium-dependent mechanisms mediate the action of the weaver gene and that the weaver neurons can be normalized by blocking this calcium effect. We further report that BAPTA-AM and verapamil also have a neuroprotective effect on normal neurons exposed to high concentrations of ethanol. We suggest that verapamil should be evaluated as a drug for treatment of alcohol-induced brain damage and neurodegenerative disorders.
Liesi
P
P
Laboratory of Molecular and Cellular Neurobiology, National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland 20852, USA. liesi@helix.nih.gov
Wright
J M
JM
Krauthamer
V
V
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000037:antagonists & inhibitors* / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects*; D020746:Calcium Channels, L-Type; D016923:Cell Death; D002465:Cell Movement / Q000235:genetics; D002525:Cerebellar Cortex / Q000187:drug effects* / Q000473:pathology; D002526:Cerebellar Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002614:Chelating Agents / Q000494:pharmacology*; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology*; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D051379:Mice; D008818:Mice, Neurologic Mutants / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000172:deficiency / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D002614:Chelating Agents; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D000431:Ethanol; D004533:Egtazic Acid; D014700:Verapamil; D002118:Calcium