Implicaciones funcionales del cambio fenotípico inducido por la activación de las vias mediadas por GMP cíclico en células gliales

Microglial and astroglial cells are responsible for the innate inmune response in the CNS and their activation is one of the most notable characteristics of neuroinflamtion. Reactive gliosis involves Typical alterations in the glial phenotype that involve an important reorganization of the cytoskeleton and cellular morphology, migration, phagocytosis, inflamatory gene expression and release of cytotoxic compounds. Depending on the type, duration and intensity of the inflmatory stimulus reactive gliosis can have beneficial (isolation of the healthy tissue by the glial scar, release of neurotrophic factors, ellimination of cellular debris by the microglial phagocytic activity) or neurotoxic effects (oxidative stress, inhibition of axonal regeneration). Our recent work shows thatv stimulation of cGMP-protein kinase G pathway by nitric oxide or nariuretic peptides induces a drástic reorganization of the cytoskeleton in both astroglial and microglial cells in culture, promoting a reactive-type morphology. Furthermore, it enhances astroglial migration in a scratch-wound assay in vitro accelerating wound closure, and stimulates the phagocytic activity of microglia. However, on its own cGMP is not able to induce expression of the typical inflammatory gene NOS-2, but potentiates its induction by immflamatory compounds. On the other hand, the NO-cGMP pathway is also involved in the change to stellate morfology in astrocytes induced by neurones in vitro which could be interpreted as a differentiating effect. The general objective of this project is to investigate further the functional implications of the phenotypic changes induced by activation of cGMP-mediated pathways in astroglial and microglial cells. The precise objectives are: 1. to elucidate if the cGMP-mediated pathways are involved in the induction of astroglial reactivity or defferentiation; 2. To elucidate if microglial activation by natriuretic peptides has neurotoxic or neuroprotective effects;3. (...)