title: The PPAR-γ agonist pioglitazone modulates inflammation and induces neuroprotection in parkinsonian monkeys.
abstract: BACKGROUND
  Activation of the peroxisome proliferator-activated receptor gamma (PPAR-γ) has been proposed as a possible neuroprotective strategy to slow down the progression of early Parkinson's disease (PD). Here we report preclinical data on the use of the PPAR-γ agonist pioglitazone (Actos®; Takeda Pharmaceuticals Ltd.) in a paradigm resembling early PD in nonhuman primates.
  
  
  METHODS
  Rhesus monkeys that were trained to perform a battery of behavioral tests received a single intracarotid arterial injection of 20 ml of saline containing 3 mg of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Twenty-four hours later the monkeys were assessed using a clinical rating scale, matched accordingly to disability, randomly assigned to one of three groups [placebo (n = 5), 2.5 (n = 6) or 5 (n = 5) mg/kg of pioglitazone] and their treatments started. Three months after daily oral dosing, the animals were necropsied.
  
  
  RESULTS
  We observed significant improvements in clinical rating score (P = 0.02) in the animals treated with 5 mg/kg compared to placebo. Behavioral recovery was associated with preservation of nigrostriatal dopaminergic markers, observed as higher tyrosine hydroxylase (TH) putaminal optical density (P = 0.011), higher stereological cell counts of TH-ir (P = 0.02) and vesicular monoamine transporter-2 (VMAT-2)-ir nigral neurons (P = 0.006). Stereological cell counts of Nissl stained nigral neurons confirmed neuroprotection (P = 0.017). Pioglitazone-treated monkeys also showed a dose-dependent modulation of CD68-ir inflammatory cells, that was significantly decreased for 5 mg/kg treated animals compared to placebo (P = 0.018). A separate experiment to assess CSF penetration of pioglitazone revealed that 5 mg/kg p.o. induced consistently higher levels than 2.5 mg/kg and 7.5 mg/kg. p.o.
  
  
  CONCLUSIONS
  Our results indicate that oral administration of pioglitazone is neuroprotective when administered early after inducing a parkinsonian syndrome in rhesus monkeys and supports the concept that PPAR-γ is a viable target against neurodegeneration.
authors.affiliation: Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI, USA.
authors.forename: Christine R
authors.initials: CR
authors.lastname: Swanson
authors.forename: Valerie
authors.initials: V
authors.lastname: Joers
authors.forename: Viktoriya
authors.initials: V
authors.lastname: Bondarenko
authors.forename: Kevin
authors.initials: K
authors.lastname: Brunner
authors.forename: Heather A
authors.initials: HA
authors.lastname: Simmons
authors.forename: Toni E
authors.initials: TE
authors.lastname: Ziegler
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Kemnitz
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Johnson
authors.forename: Marina E
authors.initials: ME
authors.lastname: Emborg
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000033:anatomy & histology / Q000473:pathology; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D004298:Dopamine / Q000378:metabolism; D005260:Female; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy*; D008253:Macaca mulatta; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000503:physiopathology*; D000077205:Pioglitazone; D010919:Placebos; D011897:Random Allocation; D013378:Substantia Nigra / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D045162:Thiazolidinediones / Q000627:therapeutic use*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; D018696:Neuroprotective Agents; D047495:PPAR gamma; D010919:Placebos; D045162:Thiazolidinediones; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D000077205:Pioglitazone