Idebenone attenuates neuronal
degeneration induced by intrastriatal injection of excitotoxins.
Miyamoto M, Coyle JT.
Department of Psychiatry,
Johns Hopkins University School of Medicine,
Baltimore, Maryland 21205.
Exp Neurol 1990 Apr;108(1):38-45
ABSTRACT
Previous studies with the
N18-RE-105 neuronal-like cell line and primary cortical cultures demonstrate
that glutamate can produce a calcium-dependent, delayed form of neuronal
degeneration that results from its competitive inhibition of cystine
transport, which leads to cellular glutathione depletion and death by
oxidative stress. Idebenone, a centrally active antioxidant used to treat
multiinfarct dementia, protects cells from this form of glutamate-induced
cytotoxicity in vitro. In the present study, we have examined the effects of
systemic treatment with idebenone on the neurotoxic consequences of
intrastriatal injection of kainic acid, quisqualic acid, or quinolinic acid,
an NMDA receptor agonist, on neuronal degeneration. Striatal damage was
assessed by quantitative neurochemistry with measurement of choline
acetyltransferase activity and glutamate decarboxylase activity, by
histochemical analysis for acetylcholinesterase and NADPH diaphorase staining
and by behavioral assessment of circling produced by systemic apomorphine
treatment 10 days after the unilateral lesion. The results indicate that
treatment with idebenone provides significant protection against the neuronal
degeneration induced by intrastriatal injection of kainic acid and quisqualic
acid, but not the NMDA receptor agonist, quinolinic acid. The results suggest
that oxidative stress may contribute to the proximate cause of neuronal
degeneration induced by quisqualate and by kainate receptor agonists and that
the mechanisms of neuronal degeneration caused by quisqualate/kainate receptor
agonists differ from those associated with NMDA receptor agonists.
