title: 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.
abstract: Neuroinflammatory changes play a pivotal role in the progression of Parkinson's disease (PD) pathogenesis. Recent findings have suggested that activated microglia may polarize similarly to peripheral macrophages in the central nervous system (CNS), assuming a pro-inflammatory M1 phenotype or the alternative anti-inflammatory M2 phenotype via cytokine production. A skewed M1 activation over M2 has been related to disease progression in Alzheimer disease, and modulation of microglia polarization may be a therapeutic target for neuroprotection. By using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-probenecid (MPTPp) mouse model of progressive PD, we investigated dynamic changes in the production of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, and anti-inflammatory cytokines, such as transforming growth factor (TGF)-β and IL-10, within Iba-1-positive cells in the substantia nigra compacta (SNc). In addition, to further characterize changes in the M2 phenotype, we measured CD206 in microglia. Moreover, in order to target microglia polarization, we evaluated the effect of the peroxisome-proliferator-activated receptor (PPAR)-γ agonist rosiglitazone, which has been shown to exert neuroprotective effects on nigral dopaminergic neurons in PD models, and acts as a modulator of cytokine production and phenotype in peripheral macrophages. Chronic treatment with MPTPp induced a progressive degeneration of SNc neurons. The neurotoxin treatment was associated with a gradual increase in both TNF-α and IL-1β colocalization with Iba-1-positive cells, suggesting an increase in pro-inflammatory microglia. In contrast, TGF-β colocalization was reduced by the neurotoxin treatment, while IL-10 was mostly unchanged. Administration of rosiglitazone during the full duration of MPTPp treatment reverted both TNF-α and IL-1β colocalization with Iba-1 to control levels. Moreover, rosiglitazone induced an increase in TGF-β and IL-10 colocalization compared with the MPTPp treatment. CD206 was gradually reduced by the chronic MPTPp treatment, while rosiglitazone restored control levels, suggesting that M2 anti-inflammatory microglia were stimulated and inflammatory microglia were inhibited by the neuroprotective treatment. The results show that the dopaminergic degeneration was associated with a gradual microglia polarization to the inflammatory over the anti-inflammatory phenotype in a chronic mouse model of PD. Neuroprotective treatment with rosiglitazone modulated microglia polarization, boosting the M2 over the pro-inflammatory phenotype. PPAR-γ agonists may offer a novel approach to neuroprotection, acting as disease-modifying drugs through an immunomodulatory action in the CNS.
authors.affiliation: National Research Council, Institute of Neuroscience, via Ospedale 72, 09124 Cagliari, Italy. Electronic address: augustapisanu@tiscali.it.
authors.forename: Augusta
authors.initials: A
authors.lastname: Pisanu
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, via Ospedale 72, 09124 Cagliari, Italy. Electronic address: d-lecca@yahoo.it.
authors.forename: Daniela
authors.initials: D
authors.lastname: Lecca
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, via Ospedale 72, 09124 Cagliari, Italy. Electronic address: giovannamulas2@gmail.com.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Mulas
authors.affiliation: Department of Neuropsychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna St., 31-343 Krakow, Poland. Electronic address: wardas@if-pan.krakow.pl.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Wardas
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, via Ospedale 72, 09124 Cagliari, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Simbula
authors.affiliation: Department of Life and Environmental Sciences, Via Fiorelli 1, 09126 Cagliari, Italy. Electronic address: sspiga@unica.it.
authors.forename: Saturnino
authors.initials: S
authors.lastname: Spiga
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, via Ospedale 72, 09124 Cagliari, Italy. Electronic address: acarta@unica.it.
authors.forename: Anna R
authors.initials: AR
authors.lastname: Carta
mesh_terms: D000818:Animals; D002452:Cell Count; D016764:Cell Polarity / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D017628:Microglia / Q000145:classification / Q000187:drug effects* / Q000378:metabolism; D009410:Nerve Degeneration / Q000209:etiology / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D016207:Cytokines; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D014446:Tyrosine 3-Monooxygenase
keywords: Cytokines; MPTP; Microglia; Neuroprotection; PPAR-γ; Parkinson's disease