Curcumin treatment alleviates the effects of glutathione depletion in vitro and in vivo: therapeutic implications for Parkinson's disease explained via in silico studies.
Oxidative stress has been implicated in the degeneration of dopaminergic neurons in the substantia nigra (SN) of Parkinson's disease (PD) patients. An important biochemical feature of presymptomatic PD is a significant depletion of the thiol antioxidant glutathione (GSH) in these neurons resulting in oxidative stress, mitochondrial dysfunction, and ultimately cell death. We have earlier demonstrated that curcumin, a natural polyphenol obtained from turmeric, protects against peroxynitrite-mediated mitochondrial dysfunction both in vitro and in vivo. Here we report that treatment of dopaminergic neuronal cells and mice with curcumin restores depletion of GSH levels, protects against protein oxidation, and preserves mitochondrial complex I activity which normally is impaired due to GSH loss. Using systems biology and dynamic modeling we have explained the mechanism of curcumin action in a model of mitochondrial dysfunction linked to GSH metabolism that corroborates the major findings of our experimental work. These data suggest that curcumin has potential therapeutic value for neurodegenerative diseases involving GSH depletion-mediated oxidative stress.
Jagatha
Balusamy
B
Department of Neurochemistry, National Institute of Mental Health and Neurosciences, 2900 Hosur Road, Bangalore, Karnataka, India.
Mythri
Rajeswara Babu
RB
Vali
Shireen
S
Bharath
M M Srinivas
MM
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002478:Cells, Cultured; D003198:Computer Simulation; D003474:Curcumin / Q000627:therapeutic use*; D004298:Dopamine / Q000502:physiology; D005978:Glutathione / Q000172:deficiency*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000502:physiology; D008962:Models, Theoretical; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D049490:Systems Biology
D000970:Antineoplastic Agents; D018696:Neuroprotective Agents; D019328:Buthionine Sulfoximine; D005978:Glutathione; D003474:Curcumin; D004298:Dopamine