Therapeutic attenuation of mitochondrial dysfunction and oxidative stress in neurotoxin models of Parkinson's disease

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder for which there is no current therapy preventing cumulative neuronal loss. There is substantial evidence that mitochondrial dysfunction, oxidative stress, and associated caspase activity underlie the neurodegeneration observed. One potential drug therapy is the potent free radical scavenger and antioxidant cystamine, which has demonstrated significant clinical potential in models of neurodegenerative disorders and human neurological disease. This study examined the oral efficacy of cystamine in the MPTP and 6-hydroxydopamine neurotoxin models of PD. The neuroprotective effects of cystamine treatment significantly ameliorated nigral neuronal loss, preserved striatal dopaminergic projections, and improved striatal dopamine and metabolite levels, as compared to MPTP alone. Cystamine normalized striatal 8-hydroxy-2'-deoxyguanosine levels and ATP concentrations, consistent with reduced oxidative stress and improved mitochondrial function. Cystamine also protected against MPTP-induced mitochondrial loss, as identified by mitochondrial heat shock protein 70 and superoxide dismutase 2, with concomitant reductions in cytochrome c and caspase-3 activities. The neuroprotective value of cystamine was confirmed in the 6-hydroxydopamine model. Together these findings show cystamine's therapeutic benefit to reduce neuronal loss through attenuation of oxidative stress and mitochondrial dysfunction, providing the rationale for human clinical trials in PD patients.

Assessment of metabolic changes in the striatum of a MPTP-intoxicated canine model: in vivo 1H-MRS study of an animal model for Parkinson's disease

“…To our knowledge, few in vivo 1 H-MRS studies have assessed the metabolic alterations in the canine MPTP model while most of the animal model studies for Parkinsonism induced by neurotoxin substrates were focused in small vertebrate animals like mice or rat [28][29][30][31][39][40][41].…”

Neuroprotective efficacy of naringin on 3-nitropropionic acid-induced mitochondrial dysfunction through the modulation of Nrf2 signaling pathway in PC12 cells

“…Attenuation of oxidative stress and mitochondrial dysfunction protects against neurodegenerative disease [48]. Induction of endogenous antioxidant genes by the transcription factor Nrf2 is considered as the major regulator of redox homeostasis.…”

Ameliorative and neuroprotective effect in MPTP model of Parkinson's disease by Zhen-Wu-Tang (ZWT), a traditional Chinese medicine

“…All groups except control group were administered intraperitonially (i.p.) with MPTP-HCl at the dosage of 20 mg/kg per day for 5 consecutive days (Xu et al, 2006;Stack et al, 2008). Then, mice were treated with gastric irrigation of ZWT, Madopar and sodium chloride solution as followings: control group (sodium chloride solution), low dosage group (ZWT, 8 g/kg day), high dosage group (ZWT, 16 g/kg day), model group (sodium chloride solution) and Madopar group (120 mg/kg day) were drenched the corresponding reagents for 2 weeks.…”