The anti-dementia drug FK960 stimulates glial glutamate release via a PKA pathway.
The present study was conducted to understand the mechanism underlying the facilitatory action of FK960, an anti-dementia drug, on hippocampal neurotransmission. FK960 facilitated hippocampal neurotransmission in normal mice, and also in mice lacking the glial glutamate transporter, GLT-1 (glut-1(-/-)), but to a lesser extent. FK960 enhanced glutamate release from cultured hippocampal astrocytes from normal rats and mice, while the drug had no effect on the release from cultured rat hippocampal neurons. The glutamate release was still obtained with cultured hippocampal astrocytes from glut-1(-/-) mice, suggesting that the release is not due to GLT-1-mediated counter transport of glutamate. The FK960 action was inhibited by H-89, a selective inhibitor of cAMP-dependent protein kinase (PKA), bafilomycin A1, an inhibitor of vesicular transport, or BAPTA-AM, a chelator of intracellular Ca(2+). FK960 caused an increase in intracellular Ca(2+) concentrations by stored Ca(2+) release in cultured rat hippocampal astrocytes, and H-89 abolished the increase. Forskolin, a PKA activator, mimicked the effect of FK960 on intracellular Ca(2+) mobilizations. Taken together, it appears that FK960 stimulates glutamate release from astrocytes, likely as a result of raising intracellular Ca(2+) concentrations via a PKA pathway. The FK960 action would increase synaptic glutamate concentrations, in part responsible for the facilitation of hippocampal neurotransmission. The results of the present study may provide a new idea that agents targeting astrocytes could serve as anti-dementia drugs.
Tada
Hitoshi
H
Department of Physiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan.
Uchino
Motoi
M
Nagai
Kaoru
K
Nomura
Tamotsu
T
Kondoh
Takeshi
T
Saito
Naoaki
N
Yamamura
Takehira
T
Yajima
Yukio
Y
Nishizaki
Tomoyuki
T
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018697:Nootropic Agents / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D009435:Synaptic Transmission / Q000187:drug effects*
D001549:Benzamides; D004791:Enzyme Inhibitors; D027342:Excitatory Amino Acid Transporter 2; C102991:N-(4-acetyl-1-piperazinyl) -4-fluorobenzamide monohydrate; D018697:Nootropic Agents; D010879:Piperazines; D018698:Glutamic Acid; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium