A peroxisome proliferator-activated receptor-δ agonist provides neuroprotection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease

H L Martin, R B Mounsey, K Sathe, S Mustafa, M C Nelson, R M Evans, P Teismann

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Abstract

Peroxisome proliferator-activated receptor (PPAR)-γ and PPARα have shown neuroprotective effects in models of Parkinson's disease (PD). The role of the third, more ubiquitous isoform PPARδ has not been fully explored. This study investigated the role of PPARδ in PD using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to model the dopaminergic neurodegeneration of PD. In vitro administration of the PPARδ antagonist GSK0660 (1 μM) increased the detrimental effect of 1-methyl-4-phenylpyridinium iodide (MPP⁺) on cell viability, which was reversed by co-treatment with agonist GW0742 (1 μM). GW0742 alone did not affect MPP⁺ toxicity. PPARδ was expressed in the nucleus of dopaminergic neurons and in astrocytes. Striatal PPARδ levels were increased (over two-fold) immediately after MPTP treatment (30 mg/kg for 5 consecutive days) compared to saline-treated mice. PPARδ heterozygous mice were not protected against MPTP toxicity. Intra-striatal infusion of GW0742 (84 μg/day) reduced the MPTP-induced loss of dopaminergic neurons (5036±195) when compared to vehicle-infused mice (3953±460). These results indicate that agonism of PPARδ provides protection against MPTP toxicity, in agreement with the effects of other PPAR agonists.

Original languageEnglish
Pages (from-to)191-203
Number of pages13
JournalNeuroscience
Volume240
DOIs
Publication statusPublished - 14 Jun 2013

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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Peroxisome Proliferator-Activated Receptors
Parkinson Disease
Corpus Striatum
Dopaminergic Neurons
Iodides
Neuroprotection
1-Methyl-4-phenylpyridinium
Neuroprotective Agents
Astrocytes
Cell Survival
Protein Isoforms

Keywords

  • 3,4-dihydroxyphenylacetic Acid
  • animals
  • cell count
  • cells, cultured
  • disease models, animal
  • dopamine
  • dose-response relationship, drug
  • female
  • glial fibrillary acidic protein
  • humans
  • macrophage-1 antigen
  • male
  • mice
  • mice, inbred C57BL
  • mice, transgenic
  • neuroprotective agents
  • PPAR delta
  • Parkinsonian disorders
  • rats
  • sulfones
  • thiazoles
  • thiophenes
  • tyrosine 3-monooxygenase

Cite this

A peroxisome proliferator-activated receptor-δ agonist provides neuroprotection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. / Martin, H L; Mounsey, R B; Sathe, K; Mustafa, S; Nelson, M C; Evans, R M; Teismann, P.

In: Neuroscience, Vol. 240, 14.06.2013, p. 191-203.

Research output: Contribution to journalArticle

Martin, H L ; Mounsey, R B ; Sathe, K ; Mustafa, S ; Nelson, M C ; Evans, R M ; Teismann, P. / A peroxisome proliferator-activated receptor-δ agonist provides neuroprotection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. In: Neuroscience. 2013 ; Vol. 240. pp. 191-203.
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AU - Martin, H L

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AU - Sathe, K

AU - Mustafa, S

AU - Nelson, M C

AU - Evans, R M

AU - Teismann, P

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AB - Peroxisome proliferator-activated receptor (PPAR)-γ and PPARα have shown neuroprotective effects in models of Parkinson's disease (PD). The role of the third, more ubiquitous isoform PPARδ has not been fully explored. This study investigated the role of PPARδ in PD using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to model the dopaminergic neurodegeneration of PD. In vitro administration of the PPARδ antagonist GSK0660 (1 μM) increased the detrimental effect of 1-methyl-4-phenylpyridinium iodide (MPP⁺) on cell viability, which was reversed by co-treatment with agonist GW0742 (1 μM). GW0742 alone did not affect MPP⁺ toxicity. PPARδ was expressed in the nucleus of dopaminergic neurons and in astrocytes. Striatal PPARδ levels were increased (over two-fold) immediately after MPTP treatment (30 mg/kg for 5 consecutive days) compared to saline-treated mice. PPARδ heterozygous mice were not protected against MPTP toxicity. Intra-striatal infusion of GW0742 (84 μg/day) reduced the MPTP-induced loss of dopaminergic neurons (5036±195) when compared to vehicle-infused mice (3953±460). These results indicate that agonism of PPARδ provides protection against MPTP toxicity, in agreement with the effects of other PPAR agonists.

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KW - humans

KW - macrophage-1 antigen

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KW - mice

KW - mice, inbred C57BL

KW - mice, transgenic

KW - neuroprotective agents

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KW - Parkinsonian disorders

KW - rats

KW - sulfones

KW - thiazoles

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JO - Neuroscience

JF - Neuroscience

SN - 0306-4522

ER -