Rotenone destroys dopaminergic neurons and induces parkinsonian symptoms in rats

Alam, Mesbah; Schmidt, Werner

doi:10.1016/s0166-4328(02)00180-8

Cited by 421 publications

(252 citation statements)

References 11 publications

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“…Dopaminergic neurons are thought to have high basal levels of oxidative stress due to the highly reactive nature of dopamine (9)(10)(11). Exposure to environmental agents that induce further oxidative stress leads to selective dopaminergic neuron degeneration in animal models (6,(12)(13)(14)(15)(16), reflective of increased risk by such agents for Parkinson's disease in humans (5,12,(17)(18)(19)(20)(21)(22).…”

mentioning

confidence: 99%

Mutational analysis of DJ-1 in Drosophila implicates functional inactivation by oxidative damage and aging

Meulener

Xu²,

Thomson³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

224

191

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Inherited mutations in PARK7 , the gene encoding DJ-1, are associated with loss of protein function and early-onset parkinsonism. Like human DJ-1 (hDJ-1), Drosophila DJ-1b protects against oxidative insult and is modified with oxidation. We demonstrate that hDJ-1 rescues flies mutant for DJ-1b, and that a conserved cysteine residue in the fly protein (C104, analogous to C106 in hDJ-1) is critical for biological antioxidant function in vivo . Targeted mutagenesis suggests that modification of DJ-1b at this residue inactivates the protective activity of the protein against oxidative stress. Further studies show that DJ-1 modification increases dramatically with age in flies, mice, and humans, with aged flies showing strikingly increased susceptibility to oxidative stress and markedly enhanced DJ-1b modification upon oxidative challenge. Overoxidation of DJ-1 with age and exposure to oxidative toxins may lead to inactivation of DJ-1 function, suggesting a role in susceptibility to sporadic Parkinson’s disease.

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mentioning

confidence: 99%

Mutational analysis of DJ-1 in Drosophila implicates functional inactivation by oxidative damage and aging

Meulener

Xu²,

Thomson³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

224

191

View full text Add to dashboard Cite

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“…Chronic administration of rotenone reproduced key features of PD in rodents, and microglial activation might be the predominant mechanism for rotenone-induced dopaminergic neuronal degeneration (Alam and Schmidt, 2002;Bonetta, 2002;Gao et al, 2002Gao et al, , 2003aPerier et al, 2003;Sherer et al, 2003;Hirsch et al, 2005). Therefore, inhibition of microglial activation and subsequent neuroinflammation may offer prospective clinical therapeutic benefit for PD and other neuroinflammation-related neurodegenerative disorders.…”

Section: Discussionmentioning

confidence: 96%

“…Rotenone, a classic and high-affinity inhibitor of mitochondrial complex I, can induce selective dopamine neurons degeneration in substantia nigra (Helmuth, 2000;Jenner, 2001;Alam and Schmidt, 2002), and K ATP channel is considered as a potential downstream target of mitochondrial complex I inhibition (Liss et al, 2005). It is notable that microglial activation and subsequent inflammatory process induced by rotenone have been suggested to be the predominant mechanisms for degeneration of dopaminergic neurons in vivo and in vitro (Gao et al, 2002(Gao et al, , 2003aPerier et al, 2003;Sherer et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Iptakalim Alleviates Rotenone-Induced Degeneration of Dopaminergic Neurons through Inhibiting Microglia-Mediated Neuroinflammation

Zhou

Sun

et al. 2007

Neuropsychopharmacol

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Inhibition of microglia-mediated neuroinflammation has been regarded as a prospective strategy for treating neurodegenerative disorders, such as Parkinson's disease (PD). In the present study, we demonstrated that systematic administration with iptakalim (IPT), an adenosine triphosphate (ATP)-sensitive potassium channel (K ATP ) opener, could alleviate rotenone-induced degeneration of dopaminergic neurons in rat substantia nigra along with the downregulation of microglial activation and mRNA levels of tumor necrosis factor-a (TNF-a) and cyclooxygenase-2 (COX-2). In rat primary cultured microglia, pretreatment with IPT suppressed rotenone-induced microglial activation evidenced by inhibition of microglial amoeboid morphological alteration, declined expression of ED1 (a marker for activated microglia), and decreased production of TNF-a and prostaglandin E2 (PGE 2 ). These inhibitory effects of IPT could be reversed by selective mitochondrial K ATP (mitoK ATP ) channel blocker 5-hydroxydecanoate (5-HD). Furthermore, pretreatment with IPT prevented rotenone-induced mitochondrial membrane potential loss and p38/c-jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) activation in microglia, which might in turn regulate microglial activation and subsequent production of TNF-a and PGE 2 . These data strongly suggest that the K ATP opener IPT may be a novel and promising neuroprotective drug via inhibiting microgliamediated neuroinflammation.

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“…type 5) might boost the level of transgene expression (34). Third, we have thus far employed an acute model of PD, and the next step could be to examine chronic animal models that are currently available for mouse and rat (17,23,35).…”

Section: Discussionmentioning

confidence: 99%

In Vivo Complementation of Complex I by the Yeast Ndi1 Enzyme

Seo

Nakamaru‐Ogiso

Flotte

et al. 2006

Journal of Biological Chemistry

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Recent studies suggest that dysfunction of the NADH-quinone oxidoreductase (complex I) is associated with a number of human diseases, including neurodegenerative disorders such as Parkinson disease. We have shown previously that the single subunit rotenone-insensitive NADH-quinone oxidoreductase (Ndi1) of Saccharomyces cerevisiae mitochondria can restore NADH oxidation in complex I-deficient mammalian cells. The Ndi1 enzyme is insensitive to complex I inhibitors such as rotenone and 1-methyl-4-phenylpyridinium ion, known as a metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). To test the possible use of the NDI1 gene as a therapeutic agent in vivo, we chose a mouse model of Parkinson disease. The NDI1-recombinant adeno-associated virus particles (rAAV-NDI1) were injected unilaterally into the substantia nigra of mice. The animals were then subjected to treatment with MPTP. The degree of neurodegeneration in the nigrostriatal system was assessed immunohistochemically through the analysis of tyrosine hydroxylase and glial fibrillary acidic protein. It was evident that the substantia nigra neurons on the side used for injection of rAAV-NDI1 retained a high level of tyrosine hydroxylase-positive cells, and the ipsilateral striatum exhibited significantly less denervation than the contralateral striatum. Furthermore, striatal concentrations of dopamine and its metabolites in the hemisphere that received rAAV-NDI1 were substantially higher than those of the untreated hemisphere, reaching more than 50% of the normal levels. These results indicate that the expressed Ndi1 protein elicits resistance to MPTP-induced neuronal injury. The present study is the first successful demonstration of complementation of complex I by the Ndi1 enzyme in animals.The mammalian proton-translocating NADH-quinone oxidoreductase (complex I) 4 is located in the inner mitochondrial membranes, is composed of 46 different subunits, and bears one FMN and eight ironsulfur clusters as cofactors (1-3). It has been known for many years that the structural and functional defects of this enzyme complex are involved in a number of human mitochondrial diseases (4 -6). Therefore, it is expected that a strategy to reestablish the function of complex I would lead to the treatment of human diseases caused by the defects of this enzyme complex. The respiratory chain of certain organisms in bacteria and fungi, but not in mammals, lacks the complex I-type enzyme. Instead, the functionality of complex I, namely oxidation of NADH and reduction of quinone, is performed by structurally simpler alternatives (collectively called NDH-2). Therefore, a simple question was asked: can the NDH-2-type enzyme be implemented in mammalian mitochondria, and can it supplement malfunctioning complex I? As a therapeutic method that works irrespective of the cause of complex I deficiencies, we have proposed using the Ndi1 protein, which is one of the NDH-2-type enzymes, found in the mitochondria of Saccharomyces cerevisiae (7-12). The Ndi1 enzyme is composed of a ...

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Rotenone destroys dopaminergic neurons and induces parkinsonian symptoms in rats

Cited by 421 publications

References 11 publications

Mutational analysis of DJ-1 in Drosophila implicates functional inactivation by oxidative damage and aging

Mutational analysis of DJ-1 in Drosophila implicates functional inactivation by oxidative damage and aging

Iptakalim Alleviates Rotenone-Induced Degeneration of Dopaminergic Neurons through Inhibiting Microglia-Mediated Neuroinflammation

In Vivo Complementation of Complex I by the Yeast Ndi1 Enzyme

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