The PPARgamma agonist pioglitazone is effective in the MPTP mouse model of Parkinson's disease through inhibition of monoamine oxidase B

The peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist pioglitazone has previously been shown to attenuate dopaminergic cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease, an effect attributed to its anti-inflammatory proper...

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Bibliographic Details
Published in:British journal of pharmacology 2008-05, Vol.154 (1), p.226
Main Authors: Quinn, L P, Crook, B, Hows, M E, Vidgeon-Hart, M, Chapman, H, Upton, N, Medhurst, A D, Virley, D J
Format: Article
Language:English
Subjects:
Animals
Cell Count
Chromatography, High Pressure Liquid
Dopamine - metabolism
Dopamine - physiology
Electrochemistry
Hypoglycemic Agents - therapeutic use
Immunohistochemistry
Male
Mice
Mice, Inbred C57BL
Monoamine Oxidase - metabolism
Monoamine Oxidase Inhibitors - pharmacology
MPTP Poisoning - drug therapy
Nerve Degeneration - pathology
Neuroglia - drug effects
Pioglitazone
Postural Balance - drug effects
PPAR gamma - agonists
Psychomotor Performance - drug effects
Selegiline - pharmacology
Serotonin - metabolism
Substantia Nigra - drug effects
Thiazolidinediones - therapeutic use
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Summary:The peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist pioglitazone has previously been shown to attenuate dopaminergic cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease, an effect attributed to its anti-inflammatory properties. In the present investigation, we provide evidence that pioglitazone is effective in the MPTP mouse model, not via an anti-inflammatory action, but through inhibition of MAO-B, the enzyme required to biotransform MPTP to its active neurotoxic metabolite 1-methyl-4-phenylpyridinium (MPP+). Mice were treated with pioglitazone (20 mg kg(-1) b.i.d. (twice a day), p.o., for 7 days), prior and post or post-MPTP (30 mg kg(-1) s.c.) treatment. Mice were then assessed for motor impairments on a beam-walking apparatus and for reductions in TH immunoreactivity in the substantia nigra and depletions in striatal dopamine. The effects of pioglitazone on striatal MPP+ levels and MAO-B activity were also assessed. Mice treated with MPTP showed deficits in motor performance, marked depletions in striatal dopamine levels and a concomitant reduction in TH immunoreactivity in the substantia nigra. Pretreatment with pioglitazone completely prevented these effects of MPTP. However, pretreatment with pioglitazone also significantly inhibited the MPTP-induced production of striatal MPP+ and the activity of MAO-B in the striatum. The neuroprotection observed with pioglitazone pretreatment in the MPTP mouse model was due to the blockade of the conversion of MPTP to its active toxic metabolite MPP+, via inhibition of MAO-B.
ISSN:0007-1188
DOI:10.1038/bjp.2008.78