A novel neuroprotective mechanism of riluzole

Direct inhibition of protein kinase C

Kyung Min Noh, Jee Yeon Hwang, Hyung Cheul Shin, Jae Young Koh

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

In addition to its antiexcitotoxic action, the anti-amyotrophic lateral sclerosis (ALS) neuroprotectant riluzole protects against nonexcitotoxic oxidative neuronal injury. In light of evidence that protein kinase C (PKC) mediates oxidative stress in cortical culture, we examined the possibility that riluzole's antioxidative neuroprotection involves PKC inhibition. Riluzole (30 μM) blocked phorbol 12-myristate 13-acetate (PMA)-induced increases in membrane PKC activity in cultured cortical cells. Suggesting a direct action, riluzole also inhibited the activity of purified PKC. Consistently, both PKC depletion and oxidative neuronal death induced by PMA were markedly attenuated by riluzole. The site of action of riluzole on PKC was not likely the diacylglycerol binding site but the catalytic domain, since riluzole did not alter radiolabeled phorbol-12,13-dibutyrate binding, but inhibited PKM, the catalytic domain of PKC. However, increasing ATP concentrations did not alter the inhibition of PKC by riluzole, making it unlikely that riluzole is a competitive inhibitor of ATP binding at PKM. Present results have demonstrated that riluzole directly inhibits PKC, which action may contribute to its antioxidative neuroprotective effects. In addition, it appears possible that PKC inhibition may be able to explain some of its well-known channel inhibitory and neuroprotective effects. Combined with findings that PKC activity is increased in ALS, the present results suggest that PKC may be a potential therapeutic target in ALS. (C) 2000 Academic Press.

Original languageEnglish (US)
Pages (from-to)375-383
Number of pages9
JournalNeurobiology of Disease
Volume7
Issue number4
DOIs
StatePublished - 2000
Externally publishedYes

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Riluzole
Protein Kinase C
Amyotrophic Lateral Sclerosis
Neuroprotective Agents
Catalytic Domain
Acetates
Adenosine Triphosphate
Phorbol 12,13-Dibutyrate
Diglycerides

ASJC Scopus subject areas

  • Neurology

Cite this

A novel neuroprotective mechanism of riluzole : Direct inhibition of protein kinase C. / Noh, Kyung Min; Hwang, Jee Yeon; Shin, Hyung Cheul; Koh, Jae Young.

In: Neurobiology of Disease, Vol. 7, No. 4, 2000, p. 375-383.

Research output: Contribution to journalArticle

Noh, Kyung Min ; Hwang, Jee Yeon ; Shin, Hyung Cheul ; Koh, Jae Young. / A novel neuroprotective mechanism of riluzole : Direct inhibition of protein kinase C. In: Neurobiology of Disease. 2000 ; Vol. 7, No. 4. pp. 375-383.
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