l-DOPA neurotoxicity is mediated by glutamate release in cultured rat striatal neurons

Maeda, Takehiko; Cheng, Neng-neng; Kume, Toshiaki; Kaneko, Satoshi; Kouchiyama, Hanae; Akaike, Akinori; Ueda, Masafumi; Satoh, Masamichi; Goshima, Yoshio; Misu, Yoshimi

doi:10.1016/s0006-8993(97)00908-6

Cited by 44 publications

(11 citation statements)

References 10 publications

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“…Previous in vitro studies have shown that levodopa has a neurotoxic effect on cultured striatal neurones involving both auto‐oxidative processes and glutamate‐mediated mechanisms (Cheng et al . 1996; Maeda et al . 1997).…”

Section: Discussionmentioning

confidence: 99%

Nigrostriatal denervation does not affect glutamate transporter mRNA expression but subsequent levodopa treatment selectively increases GLT1 mRNA and protein expression in the rat striatum

Liévens

Salin

Nieoullon

et al. 2001

Journal of Neurochemistry

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There is growing evidence that the loss of the nigrostriatal dopaminergic neurones induces an overactivity of the corticostriatal glutamatergic pathway which seems to be central to the physiopathology of parkinsonism. Moreover, glutamatergic mechanisms involving NMDA receptors have been shown to interfere with the therapeutical action of levodopa. Given the key role played by uptake processes in glutamate neurotransmission, this study examined the effects of nigrostriatal deafferentation and of levodopa treatment on the striatal expression of the glutamate transporters GLT1, GLAST and EAAC1 in the rat. No signi®cant changes in striatal mRNA levels of these transporters were detected after either levodopa treatment (100 mg/kg; i.p., twice a day for 21 days) or unilateral lesion of the nigrostriatal pathway by intranigral 6-hydroxydopamine injection. In contrast, animals with the lesion subsequently treated with levodopa showed a selective increase (36%) in GLT1 mRNA levels in the denervated striatum versus controls. These animals also showed increased GLT1 protein expression, as assessed by immunostaining and western blotting. These data provide the ®rst evidence that levodopa therapy may interfere with striatal glutamate transmission through change in expression of the primarily glial glutamate transporter GLT1. We further suggest that levodopa-induced GLT1 overexpression may represent a compensatory mechanism preventing neurotoxic accumulation of endogenous glutamate.

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Section: Discussionmentioning

confidence: 99%

Nigrostriatal denervation does not affect glutamate transporter mRNA expression but subsequent levodopa treatment selectively increases GLT1 mRNA and protein expression in the rat striatum

Liévens

Salin

Nieoullon

et al. 2001

Journal of Neurochemistry

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“…Micromolar DOPA releases glutamate in a partially TTX‐sensitive and Ca 2+ ‐dependent manner from slices (Goshima et al . 1993) and cultured fetal neurons (Maeda et al . 1997).…”

Section: Discussionmentioning

confidence: 99%

“…1993; Cheng et al . 1996; Maeda et al . 1997), suggested the involvement of endogenously released DOPA in an upstream process of mechanisms for glutamate release.…”

Section: Discussionmentioning

confidence: 99%

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Endogenously released DOPA is a causal factor for glutamate release and resultant delayed neuronal cell death by transient ischemia in rat striata

Furukawa

Arai

Goshima

et al. 2001

Journal of Neurochemistry

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Glutamate is implicated in neuronal cell death. Exogenously applied DOPA by itself releases neuronal glutamate and causes neuronal cell death in in vitro striatal systems. Herein, we attempt to clarify whether endogenous DOPA is released by 10 min transient ischemia due to four-vessel occlusion during rat striatal microdialysis and, further, whether DOPA, when released, functions to cause glutamate release and resultant delayed neuronal cell death. Ischemia increased extracellular DOPA, dopamine, and glutamate, and elicited neuronal cell death 96 h after ischemic insult. Inhibition of striatal L-aromatic amino acid decarboxylase 10 min before ischemia increased markedly basal DOPA, tripled glutamate release with a tendency of decrease in dopamine release by ischemia, and exaggerated neuronal cell death. Intrastriatal perfusion of 10±30 nM DOPA cyclohexyl ester, a competitive DOPA antagonist, 10 min before ischemia, concentrationdependently decreased glutamate release without modi®cation of dopamine release by ischemia. At 100 nM, the antagonist elicited a slight ceiling effect on decreases in glutamate release by ischemia and protected neurons from cell death. Glutamate was released concentrationdependently by intrastriatal perfusion of 0.3±1 mM DOPA and stereoselectively by 0.6 mM DOPA. The antagonist elicited no hypothermia during and after ischemia. Endogenously released DOPA is an upstream causal factor for glutamate release and resultant delayed neuronal cell death by brain ischemia in rat striata. DOPA antagonist has a neuroprotective action.

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“…These findings may be attributable to neurotoxicity due to the production of reactive oxygen species [13]. Neurotoxicity of catecholamines produced by l ‐DOPA therapy [14] and enhanced cell death due to release of glutamate in the striatum [15] are reported to play important roles in these findings. That is, even when conservative therapy using l ‐DOPA is successful, degeneration of dopaminergic neurons advances and thus new treatments that can delay the neurodegeneration and improve dopaminergic function are required.…”

Section: Discussionmentioning

confidence: 99%

Cabergoline scavenges peroxynitrite enhanced by l‐DOPA therapy in patients with Parkinson's disease

Isobe

Abe

Kikuchi

et al. 2006

Euro J of Neurology

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Long-term or high-dose L-DOPA therapy in patients with Parkinson's disease (PD) may accelerate degeneration of dopaminergic neurons, possibly by increasing oxidative stress. To investigate the effects of cabergoline on peroxynitrite-mediated oxidative damage caused by L-DOPA, the concentration of 3-nitrotyrosine in cerebrospinal fluid (CSF) of 18 PD patients was compared with that in 20 normal controls. The concentration of 3-nitrotyrosine in patients following L-DOPA therapy was significantly higher than in untreated PD patients and controls. On the other hand, the concentration in PD patients after cabergoline therapy was significantly lower than in PD patients after L-DOPA therapy alone. These data suggest that cabergoline scavenges peroxynitrite induced by L-DOPA in patients with PD.

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l-DOPA neurotoxicity is mediated by glutamate release in cultured rat striatal neurons

Cited by 44 publications

References 10 publications

Nigrostriatal denervation does not affect glutamate transporter mRNA expression but subsequent levodopa treatment selectively increases GLT1 mRNA and protein expression in the rat striatum

Nigrostriatal denervation does not affect glutamate transporter mRNA expression but subsequent levodopa treatment selectively increases GLT1 mRNA and protein expression in the rat striatum

Endogenously released DOPA is a causal factor for glutamate release and resultant delayed neuronal cell death by transient ischemia in rat striata

Cabergoline scavenges peroxynitrite enhanced by l‐DOPA therapy in patients with Parkinson's disease

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