Previous studies have shown that glial cell line-derived neurotrophic factor (GDNF) family ligands (GFL) are potent survival factors for dopaminergic neurons and motoneurons with therapeutic potential for Parkinson’s disease. However, little is known about direct influences of the GFL on microglia function, which are known to express part of the GDNF receptor system. Using RT-PCR and immunohistochemistrym we investigated the expression of the GDNF family receptor alpha 1 (GFR alpha) and the coreceptor transmembrane receptor tyrosine kinase (RET) in rat microglia in vitro as well as the effect of GFL on the expression of proinflammatory molecules in LPS activated microglia. We could show that GFL are able to regulate microglia functions and suggest that part of the well known neuroprotective action may be related to the suppression of microglial activation. We further elucidated the functional significance and pathophysiological implications of these findings and demonstrate that microglia are target cells of members of the GFL (GDNF and the structurally related neurotrophic factors neurturin (NRTN), artemin (ARTN), and persephin (PSPN)). 1. Introduction Microglia are distributed throughout the CNS as a network of resting immunocompetent cells derived from the monocyte/macrophage lineage. Alterations in the CNS homeostasis alert microglia and they become rapidly activated in response to injury or the presence of pathogens. Although microglial activation is necessary for host defense and neuroprotection, increased or prolonged activation can have detrimental and neurotoxic effects. By releasing various factors such as cytokines (i.e., interleukins: IL-1 , IL-6) or proinflammatory molecules (e.g., prostaglandins, proteolytic enzymes, reactive oxygen intermediates (ROI), or nitric oxide (NO)), [1–3] microglia are able to damage CNS cells. Interestingly, it was demonstrated that microglial inducible nitric oxide synthase (iNOS) as well as IL-1 levels is increased in the brain of patients suffering from Parkinson’s disease (PD) [4], leading to the hypothesis that the increased levels of iNOS or IL-1 may contribute to the pathophysiology of neurodegenerative disorders, especially for PD [5]. In search of new therapeutic agents for neurodegenerative disorders like PD, special interest has been devoted to neurotrophins because of their potential to promote survival and neuritic growth as well as influence the differentiation of several neuronal populations. The neurotrophin glial cell line-derived neurotrophic factor (GDNF) has received lots of attention because
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