Early Markers of Microglia Activation in Inflammatory Diseases

The last two decades has witnessed many achievements in our understanding of the molecular-mechanisms underlying various neuroinflammatory-disorders. Microglia activation is thought to be a driving force of neurodegeneration that follows neuroinflammation in many neurological disorders, but confirmatory evidence is still elusive. In particular, the possible relationship between cause and consequence for microglia activation and pathological landmarks, such as neuronal demyelination and cell death in adult vs neonatal age is still disputed. In this thesis we tried to highlight the potential of early biomarkers for microglia-activation, using two rat models of diseases where microglia activation and neurodegeneration interact. In the paper included in chapter I, we performed a time-course investigation of neuroinflammation and demyelination biomarkers in the spinal cord, cerebrospinal fluid and blood in EAE induced in Dark-Agouti female rats compared with controls and adjuvant, focusing on the time-course between immunization and clinical-onset. We demonstrate that CSF1 was the first up-regulated protein at 1 DPI, in blood, cerebrospinal fluid and spinal cord. A treatment with GW2580, a selective CSF1R inhibitor, slowed the disease progression, significantly reduced the severity and prevented the relapse phase. Moreover, both pro-and ant-inflammatory cytokines were regulated starting from 8 DPI. In the manuscript included in chapter II, we investigated the effect of GW2580 on blood brain barrier disruption with the temporal evolution of EAE. We demonstrated that GW2580 treatment had a therapeutic effect in EAE rats, through reduction of BBB leakage by inhibiting activities of MMP-9 and consequent reduction of microglia activation, IgG-extravasation, and T-cell infiltration. In the manuscript included in chapter III, we investigated plasma and CSF-contents of inflammatory biomarkers after neonatal-HI on acute and chronic phases and their correlation with neurological disorders in rat model of HI. Our data revealed that several inflammatory modulators were most affected at the acute-phase and stabilized at the chronic-phase