Ion channel modulation as the basis for neuroprotective action of MS-153.
MS-153, (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline, is a new neuroprotective drug. Recent data in the literature suggest that it inhibits glutamate accumulation occurring during ischemia and the translocation of protein kinase C gamma (PKC gamma). 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, alpha-amino-3-hydroxy-5-methyl-4-isoxarole propionic acid (AMPA), gamma-aminobutyric acid (GABA) and acetylcholine (ACh) in cortical neurons. MS-153 at a concentration of 300 microM had no effect on either tetrodotoxin-sensitive or tetrodotoxin-resistant sodium channels. High voltage-gated calcium channels were either suppressed or not affected by 1-300 microM 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 microM), 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 microM. 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.
Uenishi
H
H
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Huang
C S
CS
Song
J H
JH
Marszalec
W
W
Narahashi
T
T
D000818:Animals; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D002273:Carcinogens / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009539:Nicotinic Acids / Q000494:pharmacology*; D011493:Protein Kinase C / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000187:drug effects / Q000502:physiology; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000502:physiology; D019782:Riluzole / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects* / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
C101692:5-methyl-1-nicotinoyl-2-pyrazoline; D015220:Calcium Channels; D002273:Carcinogens; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D018696:Neuroprotective Agents; D009539:Nicotinic Acids; D017470:Receptors, Glutamate; D011978:Receptors, Nicotinic; D015222:Sodium Channels; D018698:Glutamic Acid; D019782:Riluzole; D011493:Protein Kinase C; C058819:calphostin C; D013755:Tetradecanoylphorbol Acetate