Dietary restriction and 2-deoxyglucose administration improve behavioral outcome and reduce degeneration of dopaminergic neurons in models of Parkinson's disease.
Parkinson's disease (PD) is an age-related disorder characterized by progressive degeneration of dopaminergic neurons in the substantia nigra (SN) and corresponding motor deficits. Oxidative stress and mitochondrial dysfunction are implicated in the neurodegenerative process in PD. Although dietary restriction (DR) extends lifespan and reduces levels of cellular oxidative stress in several different organ systems, the impact of DR on age-related neurodegenerative disorders is unknown. We report that DR in adult mice results in resistance of dopaminergic neurons in the SN to the toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP-induced loss of dopaminergic neurons and deficits in motor function were ameliorated in DR rats. To mimic the beneficial effect of DR on dopaminergic neurons, we administered 2-deoxy-D-glucose (2-DG; a nonmetabolizable analogue of glucose) to mice fed ad libitum. Mice receiving 2-DG exhibited reduced damage to dopaminergic neurons in the SN and improved behavioral outcome following MPTP treatment. The 2-DG treatment suppressed oxidative stress, preserved mitochondrial function, and attenuated cell death in cultured dopaminergic cells exposed to the complex I inhibitor rotenone or Fe2+. 2-DG and DR induced expression of the stress proteins heat-shock protein 70 and glucose-regulated protein 78 in dopaminergic cells, suggesting involvement of these cytoprotective proteins in the neuroprotective actions of 2-DG and DR. The striking beneficial effects of DR and 2-DG in models of PD, when considered in light of recent epidemiological data, suggest that DR may prove beneficial in reducing the incidence of PD in humans.
Sanders-Brown Research Center on Aging and Department of Anatomy and Neurobiology, University of Kentucky, Lexington, USA. mmattson@aging.coa.uky.edu
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D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D002352:Carrier Proteins / Q000378:metabolism; D003342:Corpus Striatum / Q000166:cytology / Q000503:physiopathology; D003847:Deoxyglucose / Q000494:pharmacology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology; D015259:Dopamine Agents / Q000633:toxicity; D000091342:Endoplasmic Reticulum Chaperone BiP; D002149:Energy Intake; D005296:Ferrous Compounds / Q000494:pharmacology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins; D018869:Heat-Shock Response / Q000502:physiology; D020267:MPTP Poisoning; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000502:physiology; D018832:Molecular Chaperones / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000503:physiopathology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000178:diet therapy / Q000503:physiopathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D013378:Substantia Nigra / Q000166:cytology / Q000503:physiopathology; D014475:Uncoupling Agents / Q000494:pharmacology
D000963:Antimetabolites; D002352:Carrier Proteins; D015259:Dopamine Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; D005296:Ferrous Compounds; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; D012402:Rotenone; C020748:ferrous sulfate; D003847:Deoxyglucose; D004298:Dopamine