Research Paper
Subject Category: Neuropharmacology
British Journal of Pharmacology (2008) 154, 226–233; doi:10.1038/bjp.2008.78; published online 10 March 2008
The PPAR
agonist pioglitazone is effective in the MPTP mouse model of Parkinson's disease through inhibition of monoamine oxidase B
L P Quinn1, B Crook1, M E Hows1, M Vidgeon-Hart1, H Chapman1, N Upton1, A D Medhurst1 and D J Virley1
1Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Harlow, Essex, UK
Correspondence: Dr LP Quinn, Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, NFSP-N, Third Avenue, Harlow, Essex CM19 5AW, UK. E-mail: leann.p.quinn@gsk.com
Received 6 December 2007; Revised 14 January 2008; Accepted 4 February 2008; Published online 10 March 2008.
Abstract
Background and purpose:
The peroxisome proliferator-activated receptor-
(PPAR) 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+).
Experimental approach:
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.
Key results:
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.
Conclusions and implications:
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.
Keywords:
Parkinson's disease, MPTP, mouse, peroxisome proliferator-activated receptor- (PPAR), pioglitazone, MAO-B
Abbreviations:
DAT, dopamine transporter; DOPAC, dihydroxyphenylacetic acid; HPLC-ECD, HPLC electrochemical detection; HVA, homovanillic acid; 5-HIAA, hydroxyindoleacetic acid; iNOS, inducible NOS; LC-MS/MS, liquid chromatography coupled to a mass spectrometer; MPP+, 1-methyl-4-phenylpyridinium; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NF-
B, nuclear factor-B; PPAR, peroxisome proliferator-activated receptor-
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