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The PPAR-γ agonist pioglitazone modulates inflammation and induces neuroprotection in parkinsonian monkeys
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نویسنده
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swanson c.r. ,joers v. ,bondarenko v. ,brunner k. ,simmons h.a. ,ziegler t.e. ,kemnitz j.w. ,johnson j.a. ,emborg m.e.
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منبع
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journal of neuroinflammation - 2011 - دوره : 8 - شماره : 0
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چکیده
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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. © 2011 swanson et al; licensee biomed central ltd.
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آدرس
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wisconsin national primate research center,university of wisconsin,madison,wi,united states,neuroscience training program,university of wisconsin,madison,wi, United States, wisconsin national primate research center,university of wisconsin,madison,wi,united states,neuroscience training program,university of wisconsin,madison,wi, United States, wisconsin national primate research center,university of wisconsin,madison,wi, United States, wisconsin national primate research center,university of wisconsin,madison,wi, United States, wisconsin national primate research center,university of wisconsin,madison,wi, United States, wisconsin national primate research center,university of wisconsin,madison,wi, United States, wisconsin national primate research center,university of wisconsin,madison,wi,united states,neuroscience training program,university of wisconsin,madison,wi,united states,department of physiology,university of wisconsin,madison,wi, United States, wisconsin national primate research center,university of wisconsin,madison,wi,united states,neuroscience training program,university of wisconsin,madison,wi,united states,school of pharmacy,university of wisconsin,madison,wi, United States, wisconsin national primate research center,university of wisconsin,madison,wi,united states,neuroscience training program,university of wisconsin,madison,wi,united states,department of medical physics,university of wisconsin,madison wi, United States
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Authors
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