Chronic restraint stress triggers dopaminergic and noradrenergic neurodegeneration: Possible role of chronic stress in the onset of Parkinson’s disease

• The present study investigated the effects of chronic stress on dopaminergic neurodegeneration.
• The chronic stress significantly triggered the dopaminergic neuron loss in the substantia nigra.
• The chronic stress also reduced noradrenergic neuron in the locus coeruleus.
• The activated microglia induced by stress exposures is detected in the substantia nigra and locus coeruleus.
• Nitrotyrosine as a marker of oxidative stress is also significantly increased in the substantia nigra and locus coeruleus.

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 (8 h/day, 5 days/week) substantially reduces nigral DA and LC noradrenergic neuronal cell numbers in rats. Loss of DA neurons in the SNpc was evident after 2 weeks of stress and progressed in a time-dependent manner, reaching up to 61% at 16 weeks. 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.