Abstract

During the last decade of neurobiological research, it has become evident that inflammatory pathways in the CNS, involving a network of non-neuronal and neuronal cells, are important contributors to the onset and progress of several major neurodegenerative diseases [1]. One major component of inflammatory neuronal damage is the transformation of microglia cells into activated immunoeffector cells and their migration towards the sites of injury, where they produce large amounts of toxic cytokines and oxygen radicals [2]. During this transformation, PARP-1 is highly activated and enables microglia cells to cope with oxidative challenges, in particular by upregulating the proteasomal degradation of damaged nuclear proteins [3]. Besides the initiation of intracellular defense pathways, PARP-1-dependent signalling is also involved in regulating specific functions of activated microglia: It regulates the expression of the integrin CD11a through interaction with the translocated NF-kB and therefore strongly controls migration into the regions of neuronal injury [4]. Furthermore, it enhances the production of the proinflammatory cytokine TNF-alpha and of the antiinflammatory endocannabinoid 2-AG, which in turn downregulates the release of nitric oxide. We are therefore considering PARP-1 to be a multiple player in the concert of neuroinflammation, in which therapeutic interventions directed against PARP-1 would affect both neuronal and non-neuronal components. Downregulation of PARP-1 specifically in microglia almost completely abrogates microglial migration and prevents neurons from secondary damage. This renders PARP-1 a target for therapeutic strategies in neurodegenerative diseases, in which pathological microglia activation and migration play a major role. References: 1.Floyd RA et al: Free Radic Biol Med, 1999; 26: 1346-1355 2.Mabuchi T et al: Stroke, 2000; 31(7): 1735-1743 3.McGeer PL et al: Brain Res Rev, 1995; 21: 195-218 4.Ullrich O et al: FASEB J, 2001; 15: 1460-1462 5.Ullrich O et al: Nature Cell Biol, 2001; 3: 1035-1042

Keywords: neuroinflammation, Microglia, Cytokines, Integrins