Abstract
Compensatory changes occurring during presymptomatic stages of Parkinson's disease (PD) would explain that the clinical symptoms of the disease appear late, when the degenerative process is quite advanced. Several data support the proposition that brain-derived neurotrophic factor (BDNF) could play a role in these plastic changes. In the present study, we evaluated the expression of the specific BDNF receptor, trkB, in a rat model of presymptomatic PD generated by intrastriatal injection of the neurotoxin 6-OHDA. Immunohistochemical studies revealed a decrease in trkB expression in SN pars compacta (SNc) seven days after 6-OHDA injection. At this time point, no change in the number of tyrosine hydroxylase (TH) immunoreactive (TH-IR) cells is detected, although a decrease is evident 14 days after neurotoxin injection. The decrease in TH-positive cells and trkB expression in SNc was significantly prevented by systemic administration of Ifenprodil, a specific antagonist of NR2B-containing NMDA receptors. Therefore, an NR2B-NMDA receptor-dependent decrease in trkB expression precedes the disappearance of TH-IR cells in SNc in response to 6-OHDA injection. These results support the idea that a functional coupling between NMDA receptors and BDNF/trkB signalling may be important for the maintenance of the dopaminergic phenotype in SNc during presymptomatic stages of PD.
Highlights
Parkinson’s disease (PD) a progressive degenerative disorder that is characterized by the disappearance of dopaminergic neurons of the nigrostriatal pathway
We have recently reported a coupling between increased glutamate release, NMDA receptor activation, and brainderived neurotrophic factor (BDNF) expression in the adult substantia nigra (SN), which represents an important molecular signal triggered in this brain nucleus in response to the early and partial DA loss that occurs in striatal nerve endings during presymptomatic PD [13]
By using this model, which consists of a unilateral intrastriatal injection of the neurotoxin 6-OHDA, we have shown a progressive reduction in rat striatal DA levels 1 to 7 days after neurotoxin injection [13]
Summary
Parkinson’s disease (PD) a progressive degenerative disorder that is characterized by the disappearance of dopaminergic neurons of the nigrostriatal pathway. A number of studies have demonstrated transient increases of BDNF mRNA and protein in SN, early after partial lesions of the nigrostriatalDA pathway in a rat presymptomatic model of PD [11,12,13]. These changes in the expression of BDNF could play an important role during the compensatory changes at early stages of PD. Inhibiting endogenous BDNF expression by antisense oligonucleotide infusion causes loss of nigral dopaminergic neurons in SN [19]
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