The PPAR-γ agonist pioglitazone modulates inflammation and induces neuroprotection in parkinsonian monkeysReportar como inadecuado




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Journal of Neuroinflammation

, 8:91

First Online: 05 August 2011Received: 06 April 2011Accepted: 05 August 2011

Abstract

BackgroundActivation 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.

MethodsRhesus 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.

ResultsWe 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.

ConclusionsOur 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.

List of AbbreviationsCRclinical rating

DAdopamine

FMSfine motor skill

GFAPglial fibrillary acidic protein

HO-1heme-oxygenase-1

MPTP1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

nitrotyrosine ODoptical density

PDParkinson-s disease

PPAR-γperoxisome proliferator activated receptor-gamma

SNsubstantia nigra

SPEsolid phase extraction

T2DMtype 2 diabetes mellitus

THtyrosine hydroxylase

VMAT-2vesicular monoamine transporter-2.

Electronic supplementary materialThe online version of this article doi:10.1186-1742-2094-8-91 contains supplementary material, which is available to authorized users.

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Fuente: https://link.springer.com/







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