Early melatonin supplementation alleviates oxidative stress in a transgenic mouse model of Alzheimer's disease.
Multiple lines of evidence demonstrated that increased brain oxidative stress is a key feature of Alzheimer's disease (AD). Melatonin is a potent endogenous antioxidant and free radical scavenger. A transgenic mouse model for AD mimics the accumulation of senile plaques, neuronal loss, and memory impairment. Four-month-old transgenic mice were administrated melatonin at 10 mg/kg for 4 months. We investigated the long-term influence of melatonin on these mice before amyloid plaques were deposited. We found an increase in the levels of brain thiobarbituric acid-reactive substances (TBARS) and a decrease in glutathione (GSH) content, as well as accelerated upregulation of the apoptotic-related factors, such as Bax, caspase-3, and prostate apoptosis response-4 (Par-4) in transgenic mice, but not in wild-type (WT) littermates. Significantly, the increase in TBARS levels, reduction in superoxide dismutase activity, and GSH content were reinstated by melatonin. In addition, transgenic mice administered melatonin (10 mg/kg) showed a significant reduction in upregulated expression of Bax, caspase-3 and Par-4, indicating inhibited triggering of neuronal apoptosis. These results supported the hypothesis that oxidative stress was an early event in AD pathogenesis and that antioxidant therapy may be beneficial only if given at this stage of the disease process. In sharp contrast to conventional antioxidants, melatonin crosses the blood-brain barrier, is relatively devoid of toxicity, and constitutes a potential therapeutic candidate in AD treatment.
Feng
Zheng
Z
Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Xiannong Tan Street, Beijing 10050, Peoples's Republic of China. zhengfengcns@hotmail.com
Qin
Chuan
C
Chang
Yang
Y
Zhang
Jun-tian
JT
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D019587:Dietary Supplements; D004195:Disease Models, Animal; D005260:Female; D005978:Glutathione / Q000378:metabolism; D008297:Male; D008550:Melatonin / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D013482:Superoxide Dismutase / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D017392:Thiobarbituric Acid Reactive Substances; D051028:bcl-2-Associated X Protein; C101296:prostate apoptosis response-4 protein; D013482:Superoxide Dismutase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D005978:Glutathione; D008550:Melatonin