The PPAR-γ agonist pioglitazone modulates inflammation and induces neuroprotection in parkinsonian monkeys

J Neuroinflammation. 2011 Aug 5:8:91. doi: 10.1186/1742-2094-8-91.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / physiology
  • Brain / anatomy & histology
  • Brain / pathology
  • Corpus Striatum / cytology
  • Corpus Striatum / metabolism
  • Corpus Striatum / pathology
  • Dopamine / metabolism
  • Female
  • Hypoglycemic Agents / therapeutic use
  • Inflammation / drug therapy*
  • Macaca mulatta*
  • Male
  • Neuroprotective Agents / therapeutic use*
  • PPAR gamma / agonists*
  • PPAR gamma / metabolism
  • Parkinsonian Disorders / drug therapy*
  • Parkinsonian Disorders / physiopathology*
  • Pioglitazone
  • Placebos
  • Random Allocation
  • Substantia Nigra / cytology
  • Substantia Nigra / metabolism
  • Substantia Nigra / pathology
  • Thiazolidinediones / therapeutic use*
  • Tyrosine 3-Monooxygenase / metabolism

Substances

  • Hypoglycemic Agents
  • Neuroprotective Agents
  • PPAR gamma
  • Placebos
  • Thiazolidinediones
  • Tyrosine 3-Monooxygenase
  • Dopamine
  • Pioglitazone