The PPARgamma agonist pioglitazone is effective in the MPTP mouse model of Parkinson's disease through inhibition of monoamine oxidase B - PubMed (original) (raw)

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

L P Quinn et al. Br J Pharmacol. 2008 May.

Abstract

Background and purpose: 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+).

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.

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Figures

Figure 1

Figure 1

(a) MPTP-induced increase in time to traverse the beam and inhibition with the MAO-B inhibitor _R_-(−)-deprenyl and the PPARγ agonist pioglitazone (b) MPTP-induced increase in freeze time and inhibition with the MAO-B inhibitor _R_-(−)-deprenyl and the PPARγ agonist pioglitazone. All data are mean±s.e.mean, n_=6–10 per group. *P<0.05, **P<0.01: significantly different from vehicle/vehicle-treated mice, #P<0.05, ##P<0.01: significantly different from vehicle p.o./MPTP-treated mice, ††_P< 0.01: significantly different from vehicle s.c./MPTP-treated mice by two-way ANOVA with repeated measures followed by planned comparisons. MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PPARγ, peroxisome proliferator-activated receptor-γ.

Figure 2

Figure 2

(a) MPTP-induced decrease in TH-positive cell counts and inhibition with the MAO-B inhibitor _R_-(−)-deprenyl and the PPARγ agonist pioglitazone, day 7 post-MPTP administration. All data are mean±s.e.mean, n_=6–10 per group. **P<0.01: significantly different from vehicle/vehicle-treated mice, ##P<0.01: significantly different from vehicle p.o./MPTP-treated mice, ††_P< 0.01: significantly different from vehicle s.c./MPTP-treated mice by ANOVA and Dunnett's test. (b) Photomicrographs of MPTP-induced TH-positive cell decrease in the substantia nigra and inhibition with the MAO-B inhibitor _R_-(−)-deprenyl and the PPARγ agonist pioglitazone, day 7 post-MPTP administration. MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PPARγ, peroxisome proliferator-activated receptor-γ.

Figure 3

Figure 3

MPTP-induced increase in MPP+ and inhibition with the MAO-B inhibitor _R_-(−)-deprenyl and the PPARγ agonist pioglitazone, 3 h post-MPTP administration. All data are mean±s.e.mean, n_=7–10 per group. ##P<0.01: significantly different from vehicle p.o./MPTP-treated mice, ††_P<0.01: significantly different from vehicle s.c./MPTP-treated mice by ANOVA and LSD test. MPP+, 1-methyl-4-phenylpyridinium; PPARγ, peroxisome proliferator-activated receptor-γ; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Figure 4

Figure 4

Inhibition of recombinant MAO-B activity by pioglitazone and _R_-(−)-deprenyl.

Figure 5

Figure 5

Inhibition of striatal MAO-B in MPTP-treated mice, pretreated with either _R_-(−)-deprenyl or pioglitazone. All data are mean±s.e.mean, _n_=4 per group. **P<0.01: significantly different from vehicle p.o./MPTP-treated mice, ##P<0.01: significantly different from vehicle s.c./MPTP-treated mice by ANOVA followed by planned comparisons on the predicted means. MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Figure 6

Figure 6

MPTP-induced decrease in TH-positive cell counts and inhibition with the PPARγ agonist pioglitazone on chronic pretreatment, day 7 post-MPTP administration. All data are mean±s.e.mean, _n_=8–12 per treatment group. **P<0.01: significantly different from vehicle/vehicle-treated mice, ##P<0.01: significantly different from vehicle/MPTP-treated mice, by ANOVA and Dunnett's test. MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PPARγ, peroxisome proliferator-activated receptor-γ.

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