We previously demonstrated that pups born to gravid females treated with the bacteriotoxin lipopolysaccharide (LPS) were born with fewer than normal dopamine (DA) neurons. We have extended these studies out through 16 months and showed that rats exposed to LPS prenatally exhibit progressive loss of DA neurons (46%) associated with increased DA activity, elevations in the proinflammatory cytokine tumor necrosis factor (TNFalpha), aggregates of alpha-synuclein, and Lewy-like bodies. We have recently received funding from NINDS to characterize this new animal model of Parkinson's disease (PD) through 22 months. However, the mechanism(s) responsible for this DA neuron loss during development are currently unknown. Recent preliminary data (Real-time RT-PCR) suggests that the ratio of pro-/anti-inflammatory cytokine mRNA is increased.
In specific aim 1 we will therefore assess both mRNA and cytokine protein (ELISA) content for TNF-a, interleukin (IL) -113, IL-6, transforming growth factor (TGFbeta), and IL-6 in the mesencephalon, striatum, and cerebellum (control region) to determine if prenatal LPS alters transcriptional and translational control of these factors during development or early postnatal life (P 1-21). Since Nurr-1, sonic hedgehog, Ptx-3, fibroblast growth factor-8 (FGF8) and glial cell line derived neurotrophic factor (GDNF) are transcriptional and neurotrophic factors, respectively, that regulate the development of the DA neuron phenotype, we will assess mRNA and protein levels of these factors in Specific Aim 2 to determine their involvement in the LPS-induced reduction in DA neurons. Our preliminary data further suggests that LPS induces increases in TNF-alpha in microglia and we will assess the specific roles of both microglia and astrocytes in the LPS effect in Aim 3. The results of these studies will not only compliment our long-term studies, but will test the hypothesis that prenatal LPS permanently alters genes that regulate the development of the DA neuron and affect its phenotype during adult life. The results of these studies will also provide a unique opportunity to determine if prenatal neurotoxin exposure can permanently alter genes that increase the risk of neurodegenerative disease in later life.
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