Physiological neuroprotection by melatonin in a 6-hydroxydopamine model of Parkinson's disease.
There is considerable evidence that pharmacological doses of the pineal hormone, melatonin, are neuroprotective in diverse models of neurodegeneration including Parkinson's disease. However, there is limited information about the effects of physiological doses of this hormone in similar models. In this study, rats were chronically treated with melatonin via drinking water following partial 6-hydroxydopamine lesioning in the striatum. The two doses of melatonin (0.4 microg/ml and 4.0 microg/ml) were within the reported physiological concentrations present in the serum and cerebrospinal fluid respectively. At 2 weeks after surgery, the higher dose of melatonin significantly attenuated rotational behavior in hemi-parkinsonian rats compared to similarly lesioned animals receiving either vehicle (P < 0.001) or the lower dose of melatonin (P < 0.01). Animals were perfused or sacrificed 10 weeks after commencing melatonin treatment for immunohistochemical or mRNA studies. Animals treated with 4.0 microg/ml melatonin exhibited normal tyrosine hydroxylase (TH) immunoreactivity in the lesioned striatum, whereas little or no TH immunofluorescence was visible in similarly lesioned animals receiving vehicle. In contrast, semiquantitative RT-PCR analysis revealed no group differences in TH mRNA, suggesting spontaneous recovery of this transcript as observed previously in partially lesioned animals. There were no significant differences in striatal GDNF mRNA levels between sham and lesioned animals. However, there was a significant (P < 0.01) increase in GDNF mRNA expression in the intact contralateral striata of lesioned animals treated with vehicle. Interestingly, melatonin treatment attenuated this novel compensatory contralateral increase in striatal GDNF expression, presumably due to its neuroprotective effect. These findings support a physiological role for melatonin in protecting against parkinsonian neurodegeneration in the nigrostriatal system.
Sharma
Rohita
R
Department of Psychiatry and Behavioural Neurosciences, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5.
McMillan
Catherine R
CR
Tenn
Catherine C
CC
Niles
Lennard P
LP
D000818:Animals; D001058:Apomorphine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000235:genetics; D003720:Densitometry; D018491:Dopamine Agonists / Q000494:pharmacology; D007839:Functional Laterality / Q000502:physiology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000235:genetics; D007150:Immunohistochemistry; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D017072:Neostriatum / Q000187:drug effects / Q000201:enzymology; D018696:Neuroprotective Agents; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000517:prevention & control*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D044122:Receptor, Melatonin, MT1 / Q000187:drug effects; D044094:Receptors, Melatonin / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013239:Stereotyped Behavior / Q000187:drug effects; D013565:Sympatholytics; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D018491:Dopamine Agonists; D051100:Glial Cell Line-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D044122:Receptor, Melatonin, MT1; D044094:Receptors, Melatonin; D013565:Sympatholytics; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D008550:Melatonin; D001058:Apomorphine