Mitochondrial complex I inhibitor rotenone-induced toxicity and its potential mechanisms in Parkinson’s disease models

Xiong, Nian; Liu, Xi; Xiong, Jing; Jia, Min; Chen, Chunnuan; Huang, Jinsha; Ghoorah, Devina; Kong, Xiangquan; Lin, Zhicheng; Wang, Tao

doi:10.3109/10408444.2012.680431

Cited by 170 publications

(99 citation statements)

References 166 publications

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“…Some studies reveal that certain pesticides (like rotenone) may induce PC-specific symptoms 26,27 . Structurally and functionally, some types of pesticides act like inhibitors of mitochondrial complex I.…”

Section: Discussionmentioning

confidence: 99%

Nullity of GSTT1/GSTM1 related to pesticides is associated with Parkinson's disease

Pinhel

Sado

Longo

et al. 2013

Arq. Neuro-Psiquiatr.

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Parkinson's disease (PD) is a progressive neurodegenerative disorder, clinically characterized by bradykinesia, rigidity, resting tremor, and postural instability. Early symptoms of PD are primarily due to the selective degeneration of dopaminergic neurons of the substantia nigra, innervating the neostriatum. The primary cause of PD is unknown, however, mitochondrial failure, oxidative stress and genetic factors, responsible for neurodegeneration in the substantia nigra are investigated hypotheses for the etiology of idiopathic PD 1 . The progression of cell loss is thought to occur over a somewhat protracted period of time in a defined spatiotemporal manner, and the onset of PD symptoms is typically ABSTRACTGenetic and environmental factors affect the pathogenesis of Parkinson's disease (PD). Genetic variants of the enzyme glutathione S-transferases (GST) may be related to the disease. This study aimed to evaluate the influence of genetic variants of GST (GSTT1/GSTM1) and their association with the exposure to environmental toxins in PD patients. We studied 254 patients with PD and 169 controls. The GSTM1/GSTT1 variants were analyzed by polymerase chain reaction. We applied the Fisher's exact test and the χ 2 test for statistical analysis (p<0.05). The present and absence for GSTT1 and GSTM1 were similar in patients and controls. The null for GSTT1 and GSTM1 (0/0) and exposure to pesticides prevailed in patients (18%) compared to controls (13%, p=0.014). This study suggests the association between PD and previous exposure to pesticides, whose effect may be enhanced in combination with null for GSTT1/GSTM1.Key words: Parkinson disease, glutathione transferase, polymorphism genetic, xenobiotics. RESUMOFatores genéticos e ambientais influenciam a patogênese da doença de Parkinson (DP). Variantes genéticas das enzimas glutationa S-transferases (GST) parecem estar envolvidas com a doença. Os objetivos deste estudo foram avaliar a influência de variantes genéticas de GST (GSTT1/GSTM1) e sua associação com exposição a toxinas ambientais em pacientes com DP. Foram estudados 254 pacientes com DP e 169 controles. As variantes para GSTM1/GSTT1 foram analisadas por reação em cadeia da polimerase. Para análise estatística foram aplicados os testes de Fisher e do χ 2 (p<0,05). Tanto a presença quanto a nulidade para GSTT1 e GSTM1 foram semelhantes em pacientes e controles. A nulidade para GSTT1 e GSTM1 (0/0) e contato com agrotóxicos prevaleceu nos pacientes (18%) em relação aos controles (13%, p=0,014). Este estudo sugere associação entre DP e contato prévio com agrotóxicos, cujo efeito parece potencializado em combinação com nulidade para GSTT1/GSTM1. Palavras-Chave: doença de Parkinson, glutationa transferase, polimorfismo genético, xenobióticos.

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Section: Discussionmentioning

confidence: 99%

Nullity of GSTT1/GSTM1 related to pesticides is associated with Parkinson's disease

Pinhel

Sado

Longo

et al. 2013

Arq. Neuro-Psiquiatr.

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“…Oxidative stress damage can specifically be evaluated by protein carbonylation, which is a widespread and irreversible oxidative modification in protein structure where no repair system has been described to date 14 . Rotenone is a natural pesticide, an inhibitor of mitochondrial complex I, which currently is being employed to model neurodegenerative diseases, since exposure to it triggers cellular and molecular alterations common to a variety of neurodegenerative diseases 15,16 . Nevertheless, rotenone is useful in understanding neurodegeneration associated with protein aggregation and for testing neuroprotective strategies 17 .…”

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confidence: 99%

Aged Lewis rats exposed to low and moderate doses of rotenone are a good model for studying the process of protein aggregation and its effects upon central nervous system cell physiology

Almeida

Silva

D'Unhao

et al. 2016

Arq. Neuro-Psiquiatr.

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ARTICLEAged Lewis rats exposed to low and moderate doses of rotenone are a good model for studying the process of protein aggregation and its effects upon central nervous system cell physiology Ratos Lewis idosos expostos a baixa e moderada doses de rotenona são um bom modelo para estudar o processo de agregação proteica e seus efeitos sobre a fisiologia celular do sistema nervoso central Increase in lifespan is the reality for a number of countries around the world and is frequently associated with a rise in chronic diseases such as hypertension, diabetes, cancer, chronic obstructive pulmonary disease, visual impairment and neurodegeneration ABSTRACTCell physiology is impaired before protein aggregation and this may be more relevant than inclusions themselves for neurodegeneration. The present study aimed to characterize an animal model to enable the analysis of the cell biology before and after protein aggregation. Ten-month-old Lewis rats were exposed either to 1 or 2 mg/kg/day of rotenone, delivered subcutaneously through mini-pumps, for one month. Hyperphosphorylated TAU, alpha-synuclein, amyloid-beta peptide and protein carbonylation (indicative of oxidative stress) were evaluated in the hippocampus, substantia nigra and locus coeruleus through immunohistochemistry or western blot. It was found that 2 mg/kg/day rotenone increased amyloid-beta peptide, hyperphosphorylation of TAU and alpha-synuclein. Rotenone at 1mg/kg/day did not alter protein levels. Protein carbonylation remained unchanged. This study demonstrated that aged Lewis rats exposed to a low dose of rotenone is a useful model to study cellular processes before protein aggregation, while the higher dose makes a good model to study the effects of protein inclusions.Keywords: protein aggregates; rats; neurodegeneration. RESUMOA fisiologia celular está prejudicada antes da agregação proteica podendo ser mais importante para a neurodegeneração do que as próprias inclusões. Assim, o objetivo deste estudo é caracterizar um modelo animal para analisar os mecanismos e efeitos da agregação proteica. Ratos Lewis com 10 meses de idade foram expostos a rotenona (1 ou 2 mg/kg/dia), administrada subcutaneamente, utilizando minibombas osmóticas. Os níveis de peptídeo beta-amiloide, TAU hiperfosforilada, alfa-sinucleína e proteínas carboniladas (indicativo de estresse oxidativo) foram avaliados por imunohistoquímica e western blot no hipocampo, substância negra e locus coeruleus. Foi demonstrado que 2 mg/kg/dia de rotenona promoveu aumento do peptídeo beta-amiloide, hiperfosforilação da TAU e alfa-sinucleína. Já 1 mg/kg/dia de rotenona não alterou os níveis dessas proteína nessas regiões. As proteínas carboniladas não se alteraram. Foi demonstrado que ratos Lewis idosos expostos a baixas doses de rotenona são modelo de estudo dos processos celulares antes da agregação proteica, enquanto 2 mg/kg/dia de rotenona permite estudos sobre os efeitos da agregação proteica.Palavras-chave: agregados proteicos; ratos; neurodegeneração.

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“…A mitochondrial complex I inhibitor, rotenone, led to the selective death of DA neurons and Parkinsonism in rodents (13,14). This PD model is superior for use in the present study on the effects of gastrodin on PD.…”

Section: Introductionmentioning

confidence: 89%

Gastrodin ameliorates Parkinson’s disease by downregulating connexin 43

Wang

Liu

et al. 2013

Molecular Medicine Reports

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Abstract. Gastrodin, the predominant constituent of a Chinese herbal medicine, has been utilized in the prevention of Parkinson's disease (PD); however, its mechanism of action remains unknown. Astrocytes are involved in PD and are proposed to be coupled with gap junction connexin 43 (Cx43). To evaluate the effects of gastrodin on PD, the effect of gastrodin on Cx43 in astrocytes and in a PD model were observed. Different doses of gastrodin were added to the astrocyte culture medium or injected into the rotenone model of PD. The relative expression of Cx43 was determined by qPCR and western blot analysis, while gap junctional intercellular communication (GJIC) was quantified using fluorescence recovery after photobleaching (FRAP). The phosphorylated Cx43 was significantly inhibited by gastrodin and the quantity of GJIC was significantly downregulated compared with that of the control cells (P<0.05). In addition, in the rat model of PD induced by rotenone, phosphorylated Cx43 was selectively enhanced in the striatal and hippocampal regions. The enhanced activity was inhibited significantly by gastrodin treatment (P<0.01). Gastrodin results in the prevention of PD by reducing the expression of Cx43 and inhibiting the phosphorylation of Cx43; therefore, it may offer a potential therapeutic alternative for patients with PD.

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Mitochondrial complex I inhibitor rotenone-induced toxicity and its potential mechanisms in Parkinson’s disease models

Cited by 170 publications

References 166 publications

Nullity of GSTT1/GSTM1 related to pesticides is associated with Parkinson's disease

Nullity of GSTT1/GSTM1 related to pesticides is associated with Parkinson's disease

Aged Lewis rats exposed to low and moderate doses of rotenone are a good model for studying the process of protein aggregation and its effects upon central nervous system cell physiology

Gastrodin ameliorates Parkinson’s disease by downregulating connexin 43

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