Chronic restraint stress triggers dopaminergic and noradrenergic neurodegeneration: Possible role of chronic stress in the onset of Parkinson's disease.
Parkinson's disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and, to a lesser extent, in the noradrenergic neurons of the locus coeruleus (LC). Most cases of PD are idiopathic and sporadic and are believed to be the result of both environmental and genetic factors. Here, to the best of our knowledge, we report the first evidence that chronic restraint stress (8h/day, 5days/week) substantially reduces nigral DA and LC noradrenergic neuronal cell numbers in rats. Loss of DA neurons in the SNpc was evident after 2weeks of stress and progressed in a time-dependent manner, reaching up to 61% at 16weeks. This reduction was accompanied by robust microglial activation and oxidative stress and was marked by nitrotyrosine in the SNpc and LC of the midbrain. These results indicate that chronic stress triggers DA and noradrenergic neurodegeneration by increasing oxidative stress, and that activated microglia in the substantia nigra and LC may play an important role in modulating the neurotoxic effects of oxidative stress. Taken together, these data suggest that exposure to chronic stress triggers DA and noradrenergic neurodegeneration, which is a cause of PD.
Department of Physiology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan. Electronic address: Sugama@nms.ac.jp.
Shuei
S
Sugama
Division of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-0057, Japan.
Kazunari
K
Sekiyama
Division of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-0057, Japan.
Tohru
T
Kodama
Division of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-0057, Japan.
Yoshiki
Y
Takamatsu
Animal Immune and Cell Biology Research Unit, Division of Animal Sciences, National Institute of Agrobiological Sciences, 1-2 Ohwashi, Tsukuba, Ibaraki 305-8634, Japan.
Takato
T
Takenouchi
Division of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-0057, Japan.
Makoto
M
Hashimoto
Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Conti
C
Bruno
Department of Physiology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
Yoshihiko
Y
Kakinuma
D059331:Adrenergic Neurons / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology*; D005684:Gait; D008125:Locus Coeruleus / Q000378:metabolism / Q000473:pathology*; D008297:Male; D017628:Microglia / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000473:pathology*; D065842:Pars Compacta / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012149:Restraint, Physical; D012701:Serotonin / Q000378:metabolism; D013315:Stress, Psychological / Q000473:pathology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D012333:RNA, Messenger; D012701:Serotonin; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D009638:Norepinephrine
Dopamine; Microglia; Neurodegeneration; Oxidative stress; Parkinson’s disease; Stress; Substantia nigra