title: Chronic low-dose melatonin treatment maintains nigrostriatal integrity in an intrastriatal rotenone model of Parkinson's disease.
abstract: Parkinson's disease is a major neurodegenerative disorder which primarily involves the loss of dopaminergic neurons in the substantia nigra and related projections in the striatum. The pesticide/neurotoxin, rotenone, has been shown to cause systemic inhibition of mitochondrial complex I activity in nigral dopaminergic neurons, with consequent degeneration of the nigrostriatal pathway, as observed in Parkinson's disease. A novel intrastriatal rotenone model of Parkinson's disease was used to examine the neuroprotective effects of chronic low-dose treatment with the antioxidant indoleamine, melatonin, which can upregulate neurotrophic factors and other protective proteins in the brain. Sham or lesioned rats were treated with either vehicle (0.04% ethanol in drinking water) or melatonin at a dose of 4 µg/mL in drinking water. The right striatum was lesioned by stereotactic injection of rotenone at three sites (4 μg/site) along its rostrocaudal axis. Apomorphine administration to lesioned animals resulted in a significant (p<0.001) increase in ipsilateral rotations, which was suppressed by melatonin. Nine weeks post-surgery, animals were sacrificed by transcardial perfusion. Subsequent immunohistochemical examination revealed a decrease in tyrosine hydroxylase immunoreactivity within the striatum and substantia nigra of rotenone-lesioned animals. Melatonin treatment attenuated the decrease in tyrosine hydroxylase in the striatum and abolished it in the substantia nigra. Stereological cell counts indicated a significant (p<0.05) decrease in dopamine neurons in the substantia nigra of rotenone-lesioned animals, which was confirmed by Nissl staining. Importantly, chronic melatonin treatment blocked the loss of dopamine neurons in rotenone-lesioned animals. These findings strongly support the therapeutic potential of long-term and low-dose melatonin treatment in Parkinson's disease.
authors.affiliation: Department of Psychiatry and Behavioural Neurosciences, Faculty of Health Sciences, McMaster University, HSC-4N77, 1200 Main Street West, Hamilton, ON, Canada L8N 3Z5. Electronic address: carriech@mcmaster.ca.
authors.forename: Candace H
authors.initials: CH
authors.lastname: Carriere
authors.affiliation: Department of Psychiatry and Behavioural Neurosciences, Faculty of Health Sciences, McMaster University, HSC-4N77, 1200 Main Street West, Hamilton, ON, Canada L8N 3Z5. Electronic address: rachel.nh.kang@gmail.com.
authors.forename: Na Hyea
authors.initials: NH
authors.lastname: Kang
authors.affiliation: Department of Psychiatry and Behavioural Neurosciences, Faculty of Health Sciences, McMaster University, HSC-4N77, 1200 Main Street West, Hamilton, ON, Canada L8N 3Z5. Electronic address: niles@mcmaster.ca.
authors.forename: Lennard P
authors.initials: LP
authors.lastname: Niles
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects*; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D020734:Parkinsonian Disorders / Q000473:pathology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone / Q000633:toxicity; D013378:Substantia Nigra / Q000187:drug effects*; D014475:Uncoupling Agents / Q000633:toxicity
chemical_list: D000975:Antioxidants; D014475:Uncoupling Agents; D012402:Rotenone; D008550:Melatonin
keywords: Intrastriatal; Low-dose melatonin; Neuroprotection; Parkinson׳s disease; Rotenone; Tyrosine hydroxylase