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


METHODS
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.


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
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.
Quinn
L P
LP
Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Harlow, Essex, UK. leann.p.quinn@gsk.com
Crook
B
B
Hows
M E
ME
Vidgeon-Hart
M
M
Chapman
H
H
Upton
N
N
Medhurst
A D
AD
Virley
D J
DJ
D000818:Animals; D002452:Cell Count; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000378:metabolism / Q000502:physiology; D004563:Electrochemistry; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007150:Immunohistochemistry; D020267:MPTP Poisoning / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009410:Nerve Degeneration / Q000473:pathology; D009457:Neuroglia / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D004856:Postural Balance / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D012642:Selegiline / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects; D045162:Thiazolidinediones / Q000627:therapeutic use*
D007004:Hypoglycemic Agents; D008996:Monoamine Oxidase Inhibitors; D047495:PPAR gamma; D045162:Thiazolidinediones; D012642:Selegiline; D012701:Serotonin; D008995:Monoamine Oxidase; D004298:Dopamine; D000077205:Pioglitazone