Cellular responses to inflammation in the central nervous system: nitric oxide synthase isoform expression in cell culture and animal models (LB501)

Abstract

Inflammation plays a significant role in dopaminergic neuron damage associated with the development and progression of Parkinson’s disease (PD). Microglia within the central nervous system play are known to be activated during the inflammatory process and activated microglia can induce pleiotropic downstream sequellae. Activated microglia can serve a neuronal protective role, including their synthesis of glial cell line‐derived neurotrophic factor (GDNF). However, chronic or uncontrolled activation of microglia can lead to the production of pro‐inflammatory cytokines and other neurotoxic factors. A rat model of inflammation involving exposure to lipopolysaccharide (LPS) demonstrates many of the patho‐physiologic markers of PD. Furthermore our data has shown that there is a close temporal relationship between GDNF appearance and freely diffusible nitric oxide (NO) production. In the cardiovascular system an inflammatory response leads to a multiphasic production of NO and expression of different isoforms of nitric oxide synthase (NOS) which in turn activate protective pathways. We hypothesized that in the CNS, NO production can also regulate the activation of protective pathways. Our studies employed LPS exposure in both cell cultures and animal models. Cells and tissues were probed for the presence of GDNF and inducible, neuronal and endothelial nitric oxide synthase (iNOS, nNOS, eNOS), by fluorescence deconvolution microscopy in a time dependent manner after exposure to LPS. Both microglial cells and astrocytes in culture synthesized GDNF and nitric oxide synthase isoforms following LPS treatment. A similar time dependent production of these markers was observed in our animal model. Furthermore, we observed these differential changes were not generalized within the brain sections but occurred in specific areas.