title: Chronic systemic D-galactose exposure induces memory loss, neurodegeneration, and oxidative damage in mice: protective effects of R-alpha-lipoic acid.
abstract: Chronic systemic exposure of mice, rats, and Drosophila to D-galactose causes the acceleration of senescence and has been used as an aging model. The underlying mechanism is yet unclear. To investigate the mechanisms of neurodegeneration in this model, we studied cognitive function, hippocampal neuronal apoptosis and neurogenesis, and peripheral oxidative stress biomarkers, and also the protective effects of the antioxidant R-alpha-lipoic acid. Chronic systemic exposure of D-galactose (100 mg/kg, s.c., 7 weeks) to mice induced a spatial memory deficit, an increase in cell karyopyknosis, apoptosis and caspase-3 protein levels in hippocampal neurons, a decrease in the number of new neurons in the subgranular zone in the dentate gyrus, a reduction of migration of neural progenitor cells, and an increase in death of newly formed neurons in granular cell layer. The D-galactose exposure also induced an increase in peripheral oxidative stress, including an increase in malondialdehyde, a decrease in total anti-oxidative capabilities (T-AOC), total superoxide dismutase (T-SOD), and glutathione peroxidase (GSH-Px) activities. A concomitant treatment with lipoic acid ameliorated cognitive dysfunction and neurodegeneration in the hippocampus, and also reduced peripheral oxidative damage by decreasing malondialdehyde and increasing T-AOC and T-SOD, without an effect on GSH-Px. These findings suggest that chronic D-galactose exposure induces neurodegeneration by enhancing caspase-mediated apoptosis and inhibiting neurogenesis and neuron migration, as well as increasing oxidative damage. In addition, D-galactose-induced toxicity in mice is a useful model for studying the mechanisms of neurodegeneration and neuroprotective drugs and agents.
authors.affiliation: Institute of Gerontology and Geriatrics, Chinese PLA General Hospital, Beijing, People's Republic of China.
authors.forename: Xu
authors.initials: X
authors.lastname: Cui
authors.forename: Pingping
authors.initials: P
authors.lastname: Zuo
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Xuekun
authors.initials: X
authors.lastname: Li
authors.forename: Yazhuo
authors.initials: Y
authors.lastname: Hu
authors.forename: Jiangang
authors.initials: J
authors.lastname: Long
authors.forename: Lester
authors.initials: L
authors.lastname: Packer
authors.forename: Jiankang
authors.initials: J
authors.lastname: Liu
mesh_terms: D000375:Aging / Q000187:drug effects* / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D016166:Free Radical Scavengers / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D005690:Galactose / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism; D008063:Thioctic Acid / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000975:Antioxidants; D016166:Free Radical Scavengers; D005609:Free Radicals; D018696:Neuroprotective Agents; D008063:Thioctic Acid; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D005690:Galactose