Dynamic changes in pro- and anti-inflammatory cytokines in microglia after PPAR-γ agonist neuroprotective treatment in the MPTPp mouse model of progressive Parkinson's disease
Section snippets
Drugs
MPTP-HCl (Sigma, Italy) was dissolved in saline; probenecid (Sigma, Italy) was dissolved in 5% NaHCO3. Rosiglitazone (Santa Cruz Biotechnology) was suspended in 0.5% methylcellulose.
Treatment
Three-month-old male C57BL/6J mice (Charles River, Italy) were divided into seven groups (n = 5–10 for each group). The control group received saline as a vehicle, groups M1, M3, M7, and M10 received 1, 3, 7, and 10 doses of MPTP (25 mg/kg i.p.) respectively, plus probenecid (100 mg/kg i.p.) (MPTPp). MPTPp was injected
Evaluation of MPTP-induced nigral degeneration
MPTPp chronic treatment reduced both the density and the number of TH-positive neurons as well as Nissl-stained cells in the SNc by about 40% (Fig. 1). Neurodegeneration was gradual along the chronic neurotoxin treatment, with a slight reduction in the number of TH-positive neurons after three MPTP injections (M3), and a larger significant neuronal loss after subsequent injections, in agreement with the previous characterization of this MPTPp protocol (Schintu et al., 2009b). The daily
Discussion
We report that the progressive degeneration of nigral neurons and their rescue by rosiglitazone in the chronic MPTPp treatment were associated with dynamic changes in cytokine production by microglia/macrophages in the SNc. Although fluorescent immunohistochemistry only provides a semi-quantitative measurement of protein levels, it allows to assess the extent of proteins colocalization, and to use this value for comparison among experimental groups. Moreover this technique, by evaluating
Conclusions
Progression of neurodegeneration in a chronic model of PD was associated with a gradual increase of neurotoxic pro-inflammatory microglia over the anti-inflammatory phenotype. Moreover, pharmacological treatment with a PPAR-γ agonist switched microglia polarization to anti-inflammatory, turning microglia activation into a beneficial event in the diseased brain. Therefore, although microgliosis is generally regarded as a toxic event in PD pathogenesis, results suggest that microglia might
Acknowledgments
We thank Prof. Giacomo Diaz, PhD, Dept. of Biomedical Sciences, Univ. of Cagliari, for assistance in statistical analysis. We thank Susan Bos of Medical Edit for language revision of the manuscript.
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