MPTP-reactive “in situ” inflammation as a key event in the molecular cascade linking nigrostriatal injury to repair

Current evidence points to neuroinflammation as a pivotalpathogenetic factor in Parkinson’s disease (PD), with mechanismspoorly understood. To assess the relevance of the neuroinflam-matory response, behavioral, neurochemical, neuropathological,cerebrospinal fluid (CSF) and peripheral blood analyses wereperformed in male adult C57Bl/6 mice exposed to systemicadministration of MPTP (4 × 20mgkg −1 free base; 2 hours apart inone day) and data correlated with [at both early (3–24h) and late(1–6 weeks) time points upon MPTP administration] wide geneexpression analysis of mRNA species involved in inflammation,immunity, stemness, self-renewal, neural differentiation, usingTaqMan ® Low-Density-based Array (TLDA) in ventral midbrain (VM) and striata (Str). Here we describe that MPTP-inducedDA neurodegeneration and self-repair is likely to be associated toa localized biphasic astroglial response, a spatiotemporal recoveryof tyrosine hydroxylase (TH) and dopamine transporter (DAT) fiberdensity paralleling the spatiotemporal return of synaptosmial DAuptake together with a remarkable recovery of damaged DA cellbodies. Among a total of 93 mRNA species analysed, we identifiedmajor up-regulation of inflammatory chemokines (i.e. CCL3/MIP-1a) and key transcripts involved in DA neurodevelopment (i.e.wingless-type MMTV integration site, Wnt1). Activated astrocyteswere identified as critical elements of the Wnt signalling pathwaysustaining nigrostriatal self-repair, implicating the MPTP-reactive“in situ” inflammation as key event in the molecular cascade linkingtissue injury to repair. A deeper understanding (and manipulation)of the neurodevelopmental cues undergoing recapitulation uponCNS tissue injury is likely to have important implications for thetreatment neurodenegerative diseases including PD