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- Title
Ion Channel Modulation as the Basis for Neuroprotective Action of MS-153.
- Authors
UENISHI, HIROAKI; HUANG, CHAO-SHENG; SONG, JIN-HO; MARSZALEC, WILLIAM; NARAHASHI, TOSHIO
- Abstract
ABSTRACT: MS-153, ( R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline, is a new neuroprotective durg. Recent data in the literature suggest that it inhibits glutamate accumulation occurring during ischemia and the translocation of protein kinase C gamma (PKCγ). The present study was undertaken to prove the hypothesis that MS-153 blocks neuroreceptors and ion channels involved in glutamate accumulation. Neurons isolated from rat dorsal root ganglia and frontal cortex were used for recording channel currents by the whole-cell patch clamp technique. The effects of bath-applied MS-153 were examined on tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels and high voltage-gated calcium channels of dorsal root ganglion neurons, and channels activated by glutamate, N-methyl-d-aspartate (NMDA), kainate, α-amino-3-hydroxy-5-methyl-4-isoxarole propionic acid (AMPA), γ-aminobutyric acid (GABA) and acetyloholine (ACH) in cortical neurons. MS-153 at a concentration of 300 μM had no effect on either tetrodotoxin-sensitive or tetrodotoxin-resistant sodium channels. High voltage-gated calcium channels were either suprressed or not affected by 1-300 μM MS-153. The variable blocking effect of MS-153 was due to the variable activity of intracellular components in individual neurons, especially that of PKC, whose translocation is known to be inhibited by MS-153. When 100 nM phorbol 12-Myristate-13-acetate (PMA) was applied to neurons, MS-153 suppressed the calcium channel current more frequently. Calphostin C (0.5 μM), a specific PKC inhibitor, applied intracellularly via recording patch pipette, completely abolished MS-153 suppression of the calcium channel current. Currents induced by glutamate, NMDA, kainate, AMPA, GABA or ACH were not affected by MS-153 at 300 μM. It was concluded that MS-153 inhibited high voltage-gated calcium channels through interactions with PKC, thereby preventing massive release of glutamate from nerve terminals in ischemic conditions.
- Publication
Annals of the New York Academy of Sciences, 1999, Vol 890, Issue 1, p385
- ISSN
0077-8923
- Publication type
Article
- DOI
10.1111/j.1749-6632.1999.tb08018.x