[Abstract Title]. - Society for Neuroscience

Topic: C.02.d. Therapies
Support: Michael J, Fox Foundation for Parkinson‟s disease
NCRR Grant P51 RR000167
Kinetics Foundation
Title: Neuroanatomical effects of chronic oral administration of pioglitazone to MPTP-treated
monkeys
Authors: C. SWANSON 1,2 , J. MOIRANO 3 , V. JOERS 1 , K. BRUNNER 1 , H. SIMMONS 1 , J.
RASCHKE 1 , V. BONDARENKO 1 , M. VARGUS 4 , D. JOHNSON 4 , J. KEMNITZ 1,2 , J.
JOHNSON 2,4 , *M. E. EMBORG 1,2,3 ;
1 Wisconsin Natl. Primate Res. Ctr., Univ. Wisconsin, Madison, WI; 2 Neurosci. Training
Program, 3 Med. Physics, 4 Sch. of Pharm., Univ. of Wisconsin, Madison, WI
Abstract: Pioglitazone is a thiazoledinedione, currently used as an anti-diabetic drug due to its
ability to stimulate insulin-mediated glucose transport and metabolism. It targets the peroxisome
proliferators-activated receptor gamma and has anti-inflammatory properties. Neurosphere
cultures derived from ARE-hPAP reporter mouse exposed to pioglitazone show a dosedependent
increase in ARE activity, suggesting activation of the Nrf2 anti-oxidative pathway. In
MPTP mice models of PD, oral administration of pioglitazone prevents dopaminergic nigral cell
loss. Based on this information we examined the neuroanatomical effects of chronic oral
administration of pioglitazone to parkinsonian monkeys. Sixteen male rhesus monkeys (Macaca
mulatta), age 5-7 years old, received one single intracarotid injection of MPTP, Twenty- four
hours later therapy treatment was initiated after they were assessed using a clinical rating scale,
matched and assigned to one of three groups: placebo (n=5), 15 mg (n=6), 30 mg (n=5). Three
months after daily oral treatment the animals were necropsied. Our results revealed a modest but
significant protection of the nigrostriatal pathway measured as a significantly higher tyrosine
hydroxylase (TH) putaminal optical density (p= 0.0003) and significantly higher stereological
cell counts of TH (p= 0.02) and VMAT2 (p= 0.039, positive nigral neurons in the pioglitazonetreated
monkeys compared to control. We also found modulation of microglia activation
observed as significantly less CD68 immunostaining in animals treated with pioglitazone 30 mg
compared to placebo (p= 0.047). There was also an increase in GFAP positive cells in the
substantia nigra ipsilateral to MPTP administration compared to the contralateral side in all
monkeys, yet comparison between groups did not reach statistical significance. Morphological
and behavioral datasets showed significant correlations. For example, better clinical performance
was associated with more TH positive nigral cells (p = 0.003) and less CD68 immunostaining
(p= 0.002). Our results strongly suggest that oral administration of pioglitazone has protective
effects against the functional and anatomical consequences of MPTP administration and could be
a potential therapy in neurodegenerative disorders such as Parkinson‟s disease.
Disclosures: C. Swanson, None; M.E. Emborg, None; J. Moirano, None; J. Raschke,
None; V. Bondarenko, None; V. Joers, None; K. Brunner, None; H. Simmons, None; M.
Vargus, None; D. Johnson, None; J. Kemnitz, None; J. Johnson, None.