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Cellular Mechanism of Action of Cognitive Enhancers: Effects of Nefiracetam on Neuronal Ca2+ Channels

Yoshii, Mitsunobu*; Watabe, Shigeo*‡; Murashima, Yoshiya L.*; Nukada, Toshihide; Shiotani, Tadashi

Alzheimer Disease & Associated Disorders: 2000 - Volume 14 - Issue 1 - p S95-S102
Strategies Targeting Alzheimer-type Dementia

Cellular mechanisms underlying the cognition-enhancing actions of piracetam-like nootropics were studied by recording Ca2+ channel currents from neuroblastoma x glioma hybrid (NG108-15) cells and Xenopus oocytes expressing Ca2+ channels. In NG108-15 cells, nefiracetam (1 μM) produced a twofold increase in L-type Ca2+ channel currents. A similar, but slightly less potent effect was observed with aniracetam, whereas piracetam and oxiracetam exerted no such effects. Cyclic AMP analogs mimicked the nefiracetam action. N-type Ca2+ channel currents inhibited by leucine (Leu)-enkephalin by means of inhibitory G proteins (Go/Gi) were recovered promptly by nefiracetam, whereas those inhibited by prostaglandin E1 via stimulatory G proteins were not affected by nefiracetam. Cells treated with pertussis toxin (500 ng/mL, > 20 hours) were insensitive to nefiracetam. In Xenopus oocytes functionally expressing N-type (α1B) Ca2+ channels and δ-opioid receptors, nefiracetam was also effective in facilitating the recovery from Leu-enkephalin–induced inhibition. These results suggest that nefiracetam, and possibly aniracetam, may activate N- and L-type Ca2+ channels in a differential way depending on how they recover from Go/Gi-mediated inhibition.

Departments of *Neurophysiology and †Neurochemistry, Tokyo Institute of Psychiatry, Tokyo; ‡Tokyo Research and Development Center, Daiichi Pharmaceutical Co. Ltd., Tokyo, Japan

Address correspondence and reprint requests to Mitsunobu Yoshii, M.D., Ph.D., Department of Neurophysiology, Tokyo Institute of Psychiatry, 2-1-8 Setagaya-ku, Tokyo 156-8585, Japan.

© 2000 Lippincott Williams & Wilkins, Inc.