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Involvement of PPAR-γ in the neuroprotective and anti-inflammatory effects of angiotensin type 1 receptor inhibition: effects of the receptor antagonist telmisartan and receptor deletion in a mouse MPTP model of Parkinson's disease.

Garrido-Gil P, Joglar B, Rodriguez-Perez AI, Guerra MJ, Labandeira-Garcia JL - J Neuroinflammation (2012)

Bottom Line: Interestingly, the protective effects of AT1 deletion were also inhibited by co-administration of GW9662.The results suggest that telmisartan provides effective neuroprotection against dopaminergic cell death and that the neuroprotective effect is mediated by PPAR-γ activation.Furthermore, the results show that PPAR-γ activation is involved in the anti-inflammatory and neuroprotective effects of AT1 deletion.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, Faculty of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain.

ABSTRACT

Background: Several recent studies have shown that angiotensin type 1 receptor (AT1) antagonists such as candesartan inhibit the microglial inflammatory response and dopaminergic cell loss in animal models of Parkinson's disease. However, the mechanisms involved in the neuroprotective and anti-inflammatory effects of AT1 blockers in the brain have not been clarified. A number of studies have reported that AT1 blockers activate peroxisome proliferator-activated receptor gamma (PPAR γ). PPAR-γ activation inhibits inflammation, and may be responsible for neuroprotective effects, independently of AT1 blocking actions.

Methods: We have investigated whether oral treatment with telmisartan (the most potent PPAR-γ activator among AT1 blockers) provides neuroprotection against dopaminergic cell death and neuroinflammation, and the possible role of PPAR-γ activation in any such neuroprotection. We used a mouse model of parkinsonism induced by the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and co-administration of the PPAR-γ antagonist GW9662 to study the role of PPAR-γ activation. In addition, we used AT1a- mice lesioned with MPTP to study whether deletion of AT1 in the absence of any pharmacological effect of AT1 blockers provides neuroprotection, and investigated whether PPAR-γ activation may also be involved in any such effect of AT1 deletion by co-administration of the PPAR-γ antagonist GW9662.

Results: We observed that telmisartan protects mouse dopaminergic neurons and inhibits the microglial response induced by administration of MPTP. The protective effects of telmisartan on dopaminergic cell death and microglial activation were inhibited by co-administration of GW9662. Dopaminergic cell death and microglial activation were significantly lower in AT1a- mice treated with MPTP than in mice not subjected to AT1a deletion. Interestingly, the protective effects of AT1 deletion were also inhibited by co-administration of GW9662.

Conclusion: The results suggest that telmisartan provides effective neuroprotection against dopaminergic cell death and that the neuroprotective effect is mediated by PPAR-γ activation. However, the results in AT1-deficient mice show that blockage of AT1, unrelated to the pharmacological properties of AT1 blockers, also protects against dopaminergic cell death and neuroinflammation. Furthermore, the results show that PPAR-γ activation is involved in the anti-inflammatory and neuroprotective effects of AT1 deletion.

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DA (TH-ir) neurons and terminals in AT1a- mice. TH-ir neurons in the (A) SNc and (B) TH-ir terminals in the striatum one week after treatment with vehicle, GW9662 alone, MPTP alone, or MPTP + GW9662 in AT1a- mice (AT1a-/-). The DA neurons were quantified as the total number of TH-ir neurons in the SNc, and density of striatal DA terminals was estimated as optical density and expressed as a percentage of the value obtained in the group treated with vehicle. Data are presented as mean ± SEM. *P < 0.05 compared with mice treated with vehicle, #P < 0.05 compared with AT1a- mice treated with MPTP alone, ФP < 0.05 compared with mice treated with MPTP + GW9662 (one-way ANOVA and Student-Newman-Keuls post-hoc test).
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Figure 4: DA (TH-ir) neurons and terminals in AT1a- mice. TH-ir neurons in the (A) SNc and (B) TH-ir terminals in the striatum one week after treatment with vehicle, GW9662 alone, MPTP alone, or MPTP + GW9662 in AT1a- mice (AT1a-/-). The DA neurons were quantified as the total number of TH-ir neurons in the SNc, and density of striatal DA terminals was estimated as optical density and expressed as a percentage of the value obtained in the group treated with vehicle. Data are presented as mean ± SEM. *P < 0.05 compared with mice treated with vehicle, #P < 0.05 compared with AT1a- mice treated with MPTP alone, ФP < 0.05 compared with mice treated with MPTP + GW9662 (one-way ANOVA and Student-Newman-Keuls post-hoc test).

Mentions: In control AT1a- mice (those not injected with MPTP; group A2) DA neurons in the SNc were intensely immunoreactive to TH and a dense evenly distributed TH-ir was observed throughout the striatum (Figure 3A, B). In AT1a- mice injected with MPTP (group B/C2) there was a bilateral reduction in the number of TH-ir neurons in the substantia nigra and their striatal terminals relative to vehicle-injected mice (Figures 3C, D and 4), although this reduction was lower than that observed in group B1 mice injected with MPTP and not subjected to AT1a deletion (that is, mice in which brain endogenous AII can act synergistically with MPTP on the DA system via AT1). However, the protective effects of AT1 deletion were inhibited by co-administration of the PPAR-γ antagonist GW9662 (group-D2 mice; Figures 3E, F and 4). No significant changes were observed in AT1a- mice treated with GW9662 alone in comparison with mice treated with vehicle.


Involvement of PPAR-γ in the neuroprotective and anti-inflammatory effects of angiotensin type 1 receptor inhibition: effects of the receptor antagonist telmisartan and receptor deletion in a mouse MPTP model of Parkinson's disease.

Garrido-Gil P, Joglar B, Rodriguez-Perez AI, Guerra MJ, Labandeira-Garcia JL - J Neuroinflammation (2012)

DA (TH-ir) neurons and terminals in AT1a- mice. TH-ir neurons in the (A) SNc and (B) TH-ir terminals in the striatum one week after treatment with vehicle, GW9662 alone, MPTP alone, or MPTP + GW9662 in AT1a- mice (AT1a-/-). The DA neurons were quantified as the total number of TH-ir neurons in the SNc, and density of striatal DA terminals was estimated as optical density and expressed as a percentage of the value obtained in the group treated with vehicle. Data are presented as mean ± SEM. *P < 0.05 compared with mice treated with vehicle, #P < 0.05 compared with AT1a- mice treated with MPTP alone, ФP < 0.05 compared with mice treated with MPTP + GW9662 (one-way ANOVA and Student-Newman-Keuls post-hoc test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
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Figure 4: DA (TH-ir) neurons and terminals in AT1a- mice. TH-ir neurons in the (A) SNc and (B) TH-ir terminals in the striatum one week after treatment with vehicle, GW9662 alone, MPTP alone, or MPTP + GW9662 in AT1a- mice (AT1a-/-). The DA neurons were quantified as the total number of TH-ir neurons in the SNc, and density of striatal DA terminals was estimated as optical density and expressed as a percentage of the value obtained in the group treated with vehicle. Data are presented as mean ± SEM. *P < 0.05 compared with mice treated with vehicle, #P < 0.05 compared with AT1a- mice treated with MPTP alone, ФP < 0.05 compared with mice treated with MPTP + GW9662 (one-way ANOVA and Student-Newman-Keuls post-hoc test).
Mentions: In control AT1a- mice (those not injected with MPTP; group A2) DA neurons in the SNc were intensely immunoreactive to TH and a dense evenly distributed TH-ir was observed throughout the striatum (Figure 3A, B). In AT1a- mice injected with MPTP (group B/C2) there was a bilateral reduction in the number of TH-ir neurons in the substantia nigra and their striatal terminals relative to vehicle-injected mice (Figures 3C, D and 4), although this reduction was lower than that observed in group B1 mice injected with MPTP and not subjected to AT1a deletion (that is, mice in which brain endogenous AII can act synergistically with MPTP on the DA system via AT1). However, the protective effects of AT1 deletion were inhibited by co-administration of the PPAR-γ antagonist GW9662 (group-D2 mice; Figures 3E, F and 4). No significant changes were observed in AT1a- mice treated with GW9662 alone in comparison with mice treated with vehicle.

Bottom Line: Interestingly, the protective effects of AT1 deletion were also inhibited by co-administration of GW9662.The results suggest that telmisartan provides effective neuroprotection against dopaminergic cell death and that the neuroprotective effect is mediated by PPAR-γ activation.Furthermore, the results show that PPAR-γ activation is involved in the anti-inflammatory and neuroprotective effects of AT1 deletion.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, Faculty of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain.

ABSTRACT

Background: Several recent studies have shown that angiotensin type 1 receptor (AT1) antagonists such as candesartan inhibit the microglial inflammatory response and dopaminergic cell loss in animal models of Parkinson's disease. However, the mechanisms involved in the neuroprotective and anti-inflammatory effects of AT1 blockers in the brain have not been clarified. A number of studies have reported that AT1 blockers activate peroxisome proliferator-activated receptor gamma (PPAR γ). PPAR-γ activation inhibits inflammation, and may be responsible for neuroprotective effects, independently of AT1 blocking actions.

Methods: We have investigated whether oral treatment with telmisartan (the most potent PPAR-γ activator among AT1 blockers) provides neuroprotection against dopaminergic cell death and neuroinflammation, and the possible role of PPAR-γ activation in any such neuroprotection. We used a mouse model of parkinsonism induced by the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and co-administration of the PPAR-γ antagonist GW9662 to study the role of PPAR-γ activation. In addition, we used AT1a- mice lesioned with MPTP to study whether deletion of AT1 in the absence of any pharmacological effect of AT1 blockers provides neuroprotection, and investigated whether PPAR-γ activation may also be involved in any such effect of AT1 deletion by co-administration of the PPAR-γ antagonist GW9662.

Results: We observed that telmisartan protects mouse dopaminergic neurons and inhibits the microglial response induced by administration of MPTP. The protective effects of telmisartan on dopaminergic cell death and microglial activation were inhibited by co-administration of GW9662. Dopaminergic cell death and microglial activation were significantly lower in AT1a- mice treated with MPTP than in mice not subjected to AT1a deletion. Interestingly, the protective effects of AT1 deletion were also inhibited by co-administration of GW9662.

Conclusion: The results suggest that telmisartan provides effective neuroprotection against dopaminergic cell death and that the neuroprotective effect is mediated by PPAR-γ activation. However, the results in AT1-deficient mice show that blockage of AT1, unrelated to the pharmacological properties of AT1 blockers, also protects against dopaminergic cell death and neuroinflammation. Furthermore, the results show that PPAR-γ activation is involved in the anti-inflammatory and neuroprotective effects of AT1 deletion.

Show MeSH
Related in: MedlinePlus