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Title

Inhibition of alpha-ketoglutarate dehydrogenase by isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

Authors
McNaught, K. S.
Altomare, Cosimo
Cellamare, S.
Carotti, Angelo
Thull, Ulrike
Testa, Bernard
Jenner, P.
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Published in Neuroreport. 1995, vol. 6, no. 8, p. 1105-1108
Abstract Defects in complex I and alpha-ketoglutarate dehydrogenase (alpha-KGDH) occur in the substantia nigra in Parkinson's disease (PD). Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+) are implicated in the cause of PD as endogenous toxins and are inhibitors of complex I. However, their effects on alpha-KGDH and other mitochondrial non-respiratory chain enzymes are unknown. We have examined the effects of six isoquinoline derivatives (isoquinoline, N-methylisoquinolinium, N-n-propylisoquinolinium, 1,2,3,4-tetrahydroisoquinoline, N-methyl-1,2,3,4-tetrahydroisoquinoline and salsolinol) and MPP+ on the activities of alpha-KGDH, citrate synthase (CS) and glutamate dehydrogenase (GDH) in mitochondrial fragments from rat forebrain. None of the compounds examined had any effect on CS or GDH activity. In contrast, all isoquinoline derivatives investigated and MPP+ inhibited alpha-KGDH activity in a concentration-dependent manner with IC50s ranging from 2.0 to 18.9 mM. MPP+ was previously shown to inhibit alpha-KGDH, but this is the first report of inhibition of alpha-KGDH by isoquinoline derivatives. These findings may represent an additional mechanism contributing to mitochondrial dysfunction and cell death in Parkinson's disease.
Keywords AnimalsDose-Response Relationship, DrugIsoquinolines/*pharmacologyKetoglutarate Dehydrogenase Complex/*antagonists & inhibitors/drug effectsMaleMitochondria/metabolismNAD(P)H Dehydrogenase (Quinone)/metabolismParkinson Disease/enzymologyRatsRats, Wistar
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PMID: 7662887
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MCNAUGHT, K. S. et al. Inhibition of alpha-ketoglutarate dehydrogenase by isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In: Neuroreport, 1995, vol. 6, n° 8, p. 1105-1108. https://archive-ouverte.unige.ch/unige:9948

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Deposited on : 2010-08-06

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