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Title: Inhibiting BDNF expression by antisense oligonucleotide infusion causes loss of nigral dopaminergic neurons.
Austin Authors: Porritt, Michelle J;Batchelor, Peter Egerton;Howells, David William
Affiliation: Department of Medicine, University of Melbourne, Level 7, Lance Townsend Building, Austin Health, Studley Road, Heidelberg, Vic 3084 Australia
Issue Date: 1-Mar-2005
Publication information: Experimental Neurology; 192(1): 226-34
Abstract: 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.
Gov't Doc #: 15698637
DOI: 10.1016/j.expneurol.2004.11.030
Type: Journal Article
Subjects: Animals
Binding, Competitive.physiology
Brain-Derived Neurotrophic Factor.antagonists & inhibitors.genetics
Cell Death.drug effects.genetics
Cell Survival.drug effects.genetics
Disease Models, Animal
Dopamine Uptake Inhibitors.metabolism
Nerve Degeneration.chemically induced.genetics.metabolism
Neurons.drug effects.metabolism.pathology
Neuroprotective Agents.metabolism
Oligonucleotides, Antisense.toxicity
Parkinsonian Disorders.chemically induced.genetics.metabolism
RNA, Messenger.drug effects.metabolism
Radioligand Assay
Rats, Sprague-Dawley
Receptors, Dopamine.drug effects.metabolism
Substantia Nigra.drug effects.metabolism.physiopathology
Tyrosine 3-Monooxygenase.drug effects.metabolism
Appears in Collections:Journal articles

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