Oxidative Stress and BDNF Signaling in Dopaminergic Neurons


Charleen T. Chu, MD, Ph.D.
University of Pittsburgh

Once released from acidic vesicles, dopamine (DA) can undergo spontaneous or enzymatically catalyzed reactions to produce reactive oxygen species. 6-Hydroxydopamine (6-OHDA) is a DA analog used in a well-established rodent model to selectively injure the nigrostriatal system that degenerates in Parkinson’s disease (PD). 6-OHDA demonstrates enhanced, but similar, oxidative reactivity as DA. Thus, it will be useful for modeling oxidative mechanism by which DA metabolism contributes to selective neuronal vulnerability in PD. Differentiation, function and survival of Dopaminergic neurons are influenced by neurotrophic factors such as brain derived neurotrophic factor (BDNF).Significantly, BDNF is expressed into adulthood in the nigrostriatal system.BDNF signals through phosphotyrosine pathways that activate extracellular signal-regulated protein kinase (ERK, also know as mitogen activated protein kinase MAPK). The effects of oxidative stress upon transmission of these neuroprotective signals to Dopaminergic neurons are being investigated. This is an extension of the prior year ABDA grant, in which it was found that 6-OHDA treatment decreases BDNF-elicited phosphotyrosine signaling in the Dopaminergic B65 cell line.  B65 cells are also sensitive to toxicity from superoxide and nitric oxide.  Peroxynitrite generated from superoxide-nitric oxide interactions may comprise communication of BDNF signals.  To continue testing this hypothesis, the following aims will be pursued: (1) To investigate whether 6-OHDA toxicity is mediated by superoxide-nitric oxide interactions in cell culture; and (2) To investigate whether BDNF signaling proteins are nitrated during 6-OHDA treatment in cell culture.

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