Inhibiting BDNF expression by antisense oligonucleotide infusion causes loss of nigral dopaminergic neurons.
Brain derived neurotrophic factor (BDNF) expression is significantly reduced in the Parkinson's disease substantia nigra. This neurotrophin has potent affects on dopaminergic neuron survival protecting them from the neurotoxins MPTP and 6-hydroxydopamine (6-OHDA) commonly used to create animal models of Parkinson's disease and also promoting dopaminergic axonal sprouting. In this study, we demonstrate that an antisense oligonucleotide infusion (200 nM for 28 days) to prevent BDNF production in the substantia nigra of rats mimics many features of the classical animal models of Parkinson's disease. 62% of antisense treated rats rotate (P < or = 0.05) in response to dopaminergic receptor stimulation by apomorphine. 40% of substantia nigra pars compacta tyrosine hydroxylase immunoreactive neurons are lost (P < or = 0.00001) and dopamine uptake site density measured by (3)H-mazindol autoradiography is reduced by 34% (P < or = 0.005). Loss of haematoxylin and eosin stained nigral neurons is significant (P < or = 0.0001) but less extensive (34%). These observations indicate that loss of BDNF expression leads both to down regulation of the dopaminergic phenotype and to dopaminergic neuronal death. Therefore, reduced BDNF mRNA expression in Parkinson's disease substantia nigra may contribute directly to the death of nigral dopaminergic neurons and the development of Parkinson's disease.
Porritt
M J
MJ
Department of Medicine, University of Melbourne, Level 7, Lance Townsend Building, Austin Health, Studley Road, Heidelberg, Vic 3084 Australia.
Batchelor
P E
PE
Howells
D W
DW
D000818:Animals; D001667:Binding, Competitive / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D008297:Male; D008454:Mazindol / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000633:toxicity*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D014446:Tyrosine 3-Monooxygenase / Q000187:drug effects / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D018765:Dopamine Uptake Inhibitors; D018696:Neuroprotective Agents; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D011954:Receptors, Dopamine; D008454:Mazindol; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine