Background and purpose: The peroxisome proliferator-activated receptor-g (PPARg) 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 þ ). Experimental approach: Mice were treated with pioglitazone (20 mg kg À1 b.i.d. (twice a day), p.o., for 7 days), prior and post or post-MPTP (30 mg kg À1 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 þ 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 þ 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 þ , via inhibition of MAO-B.

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1 Although an important regulatory role for serotonin (5-HT) in seizure activation and propagation is well established, relatively little is known of the function of specific 5-HT receptor subtypes on seizure modulation. 2 The aim of the present study was to investigate the role of 5-HT 1A, 1B and 1D receptors in modulating generalised seizures in the rat maximal electroshock seizure threshold (MEST) test. 3 The mixed 5-HT receptor agonists SKF 99101 (5-20 mg kg À1 i.p.) and RU 24969 (1-5 mg kg À1 i.p.), 0.5 h pretest, both produced marked dose-related increases in seizure threshold. These agents share high affinity for 5-HT 1A, 1B and 1D receptors. 4 Antiseizure effects induced by submaximal doses of these agonists were maintained following p-chlorophenylalanine (150 mg kg À1 i.p. Â 3 days)-induced 5-HT depletion. 5 The anticonvulsant action of both SKF 99101 (15 mg kg À1 i.p.) and RU 24969 (2.5 mg kg À1 i.p.) was dose-dependently abolished by the selective 5-HT 1B receptor antagonist SB-224289 (0.1-3 mg kg À1 p.o., 3 h pretest) but was unaffected by the selective 5-HT 1A receptor antagonist WAY 100635 (0.01-0.3 mg kg À1 s.c., 1 h pretest). This indicates that 5-HT 1B receptors are primarily involved in mediating the anticonvulsant properties of these agents. 6 In addition, the ability of the 5-HT 1B/1D receptor antagonist GR 127935 (0.3-3 mg kg À1 s.c., 60 min pretest) to dose-dependently inhibit SKF 99101-induced elevation of seizure threshold also suggests possible downstream involvement of 5-HT 1D receptors in the action of this agonist, although confirmation awaits the identification of a selective 5-HT 1D receptor antagonist. 7 Overall, these data demonstrate that stimulation of postsynaptic 5-HT 1B receptors inhibits electroshock-induced seizure spread in rats.

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