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 language | English |
|---|---|
| Pages (from-to) | 191-203 |
| Number of pages | 13 |
| Journal | Neuroscience |
| Volume | 240 |
| DOIs | |
| Publication status | Published - 14 Jun 2013 |
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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 journal › Article
}
TY - JOUR
T1 - 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
AU - Martin, H L
AU - Mounsey, R B
AU - Sathe, K
AU - Mustafa, S
AU - Nelson, M C
AU - Evans, R M
AU - Teismann, P
N1 - Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.
PY - 2013/6/14
Y1 - 2013/6/14
N2 - 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.
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.
KW - 3,4-dihydroxyphenylacetic Acid
KW - animals
KW - cell count
KW - cells, cultured
KW - disease models, animal
KW - dopamine
KW - dose-response relationship, drug
KW - female
KW - glial fibrillary acidic protein
KW - humans
KW - macrophage-1 antigen
KW - male
KW - mice
KW - mice, inbred C57BL
KW - mice, transgenic
KW - neuroprotective agents
KW - PPAR delta
KW - Parkinsonian disorders
KW - rats
KW - sulfones
KW - thiazoles
KW - thiophenes
KW - tyrosine 3-monooxygenase
U2 - 10.1016/j.neuroscience.2013.02.058
DO - 10.1016/j.neuroscience.2013.02.058
M3 - Article
VL - 240
SP - 191
EP - 203
JO - Neuroscience
JF - Neuroscience
SN - 0306-4522
ER -