Integrating glutathione metabolism and mitochondrial dysfunction with implications for Parkinson’s disease: A dynamic model

Vali, Shireen; Mythri, Rajeswara Babu; Jagatha, Balusamy; Padiadpu, Jyothi; Ramanujan, Krishnan; Andersen, Julie K.; Gorin, Fredric A; Bharath, M. M. Srinivas

doi:10.1016/j.neuroscience.2007.08.028

Cited by 75 publications

(74 citation statements)

References 50 publications

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“…High levels of nitric oxide inhibit respiratory chain complexes by peroxynitrite (ONOO-) that formed by superoxide anion (O 2-) and nitric oxide (NO) [65]. Reduced glutathione (GSH) is one of the most important antioxidants in the brain that plays an important role in the prevention of oxidative stress and protecting cells from oxidative damage [66]. Reduction of the GSH level in the brain is correlated to the increase in oxidative stress induced by rotenone.…”

Section: Discussionmentioning

confidence: 99%

Non-Steroidal Anti-Inflammatory Drugs and Vitamin C in the Rotenone Induced Nigrostriatal Damage in Mice

Ibrahim¹

2017

EJCBS

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Abstract:The nigrostriatal pathway is a dopaminergic pathway that connects the substantia nigra with the dorsal striatum.Loss of dopamine neurons in the substantia nigra is one of the main pathological features of Parkinson's disease, leading to a marked reduction in dopamine function in this pathway. This study aimed at evaluating the protective role of two antiinflammatory drugs, indomethacin and nimesulide separately or in combination with vitamin C against biochemical disturbances, brain damage and motor impairment in rotenone-induced mice model of Parkinson's disease. Animals were divided into 7 groups. 1 st received the vehicle (DEMSO); 2 nd received rotenone (1.5 mg/kg); 3 rd received rotenone then were left for two weeks recovery; 4 th rotenone + indomethacin (10 mg/kg); 5 th received rotenone + indomethacin in combination with vitamin C (25 mg/kg). 6 th received rotenone + nimesulide (10 mg/kg); group 7 received rotenone + nimesulide in combination with vitamin C. All treatments were given subcutaneously three times per week for one month. Rotenone treatment caused significant Increases in brain malondialdehyde (MDA), nitric oxide (NO), but induced significant decreases in brain reduced glutathione (GSH) level, acetylcholinesterase (AChE) activity, dopamine (DA), norepinephrine (NE) and serotonin (5-HT) levels. These changes lasted for two weeks after the termination of rotenone treatment. Histologically, Rotenone caused degeneration of neurons in striatum, cellular infiltration, atrophy, pyknosis, necrosis, as well as focal gliosis in cerebral cortex and pyknosis of pyramidal cells in the hippocampus. Furthermore, rotenone treatment caused a significant impairment in the motor function of the mice (stair test). Co-administration of indomethacin or nimesulide separately or in combination with vitamin C to rotenone treated mice resulted in alleviation of biochemical and motor activity but not the histological disturbances caused by rotenone treatment alone.

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Section: Discussionmentioning

confidence: 99%

Non-Steroidal Anti-Inflammatory Drugs and Vitamin C in the Rotenone Induced Nigrostriatal Damage in Mice

Ibrahim¹

2017

EJCBS

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“…MPP þ provoked mitochondrial dysfunction by blocking complex I activity of the mitochondrial electron transport chain and which is accompanied by an accumulation of ROS in the cells [30]. We performed transduction of PEP-1-PON1 proteins in SH-SY5Y cells exposed to 4 mM of MPP þ and quantified the level of ROS production by DCF-DA staining.…”

Section: Pep-1-pon1 Proteins Suppress Oxidative Stress-mediated Cellumentioning

confidence: 99%

Transduced PEP-1-PON1 proteins regulate microglial activation and dopaminergic neuronal death in a Parkinson's disease model

et al. 2015

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“…After 24 h, the cells were exposed to buthionine sulfoximine (BSO) (inhibitor of glutathione (GSH) synthesis) immediately or after differentiation for 84 h. After 24 h of BSO exposure, the cells were treated with cardiotoxin (CTX) for 40 h. After the treatments, viable cells were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay [22]. Briefly, 20 ll of 5 mg/ml MTT was added to cells and incubated at 37°C for 2 h. The medium was discarded, the dark blue formazan crystalline product was dissolved in dimethyl sulfoxide, and the absorbance was analyzed in a plate reader (Tecan) at 570 nm.…”

Section: Cell Treatment and Viability Assaymentioning

confidence: 99%

Oxidative Damage in Muscular Dystrophy Correlates with the Severity of the Pathology: Role of Glutathione Metabolism

et al. 2012

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Muscular dystrophies (MDs) such as Duchenne muscular dystrophy (DMD), sarcoglycanopathy (Sgpy) and dysferlinopathy (Dysfy) are recessive genetic neuromuscular diseases that display muscle degeneration. Although these MDs have comparable endpoints of muscle pathology, the onset, severity and the course of these diseases are diverse. Different mechanisms downstream of genetic mutations might underlie the disparity in these pathologies. We surmised that oxidative damage and altered antioxidant function might contribute to these differences. The oxidant and antioxidant markers in the muscle biopsies from patients with DMD (n = 15), Sgpy (n = 15) and Dysfy (n = 15) were compared to controls (n = 10). Protein oxidation and lipid peroxidation was evident in all MDs and correlated with the severity of pathology, with DMD, the most severe dystrophic condition showing maximum damage, followed by Sgpy and Dysfy. Oxidative damage in DMD and Sgpy was attributed to the depletion of glutathione (GSH) and lowered antioxidant activities while loss of GSH peroxidase and GSH-S-transferase activities was observed in Dysfy. Lower GSH level in DMD was due to lowered activity of gamma-glutamyl cysteine ligase, the rate limiting enzyme in GSH synthesis. Similar analysis in cardiotoxin (CTX) mouse model of MD showed that the dystrophic muscle pathology correlated with GSH depletion and lipid peroxidation. Depletion of GSH prior to CTX exposure in C2C12 myoblasts exacerbated oxidative damage and myotoxicity. We deduce that the pro and anti-oxidant mechanisms could be correlated to the severity of MD and might influence the dystrophic pathology to a different extent in various MDs. On a therapeutic note, this could help in evolving novel therapies that offer myoprotection in MD.

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Integrating glutathione metabolism and mitochondrial dysfunction with implications for Parkinson’s disease: A dynamic model

Cited by 75 publications

References 50 publications

Non-Steroidal Anti-Inflammatory Drugs and Vitamin C in the Rotenone Induced Nigrostriatal Damage in Mice

Non-Steroidal Anti-Inflammatory Drugs and Vitamin C in the Rotenone Induced Nigrostriatal Damage in Mice

Transduced PEP-1-PON1 proteins regulate microglial activation and dopaminergic neuronal death in a Parkinson's disease model

Oxidative Damage in Muscular Dystrophy Correlates with the Severity of the Pathology: Role of Glutathione Metabolism

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