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-ORDA) 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 less than or equal to 0.05) in response to dopaminergic receptor stimulation by apomorphine. 40% of substantia nigra pars compacta tyrosine hydroxylase immunoreactive neurons are lost ( P less than or equal to 0.00001) and dopamine uptake site density measured by H-3-mazindol autoradiography is reduced by 34% (P less than or equal to 0.005). Loss of haematoxylin and eosin stained nigral neurons is significant (P less than or equal to 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. (C) 2004 Elsevier Inc. All rights reserved.