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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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Photomicrographs showing changes in microglial activation in the substantia nigra. Activated microglial cells at central levels of the substantia nigra stained with (A, B, E-H) isolectin B4 or (C, D) immunostained for CD45 and higher magnification. Photomicrographs show microglia in WT mice treated with vehicle (controls; A, C), with MPTP alone (B, D), with MPTP + telmisartan (E), or with MPTP + telmisartan + GW9662 (G). Microglial activation in AT1a- mice (AT1a-/-) treated with MPTP alone or MPTP + GW9662 is shown in F and H, respectively. Microglial activation was significantly higher in mice treated with MPTP alone (B, D), and in mice treated with the neurotoxin, AT1 inhibition and GW9662 (G, H). Scale bar: 100 μm.
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Figure 5: Photomicrographs showing changes in microglial activation in the substantia nigra. Activated microglial cells at central levels of the substantia nigra stained with (A, B, E-H) isolectin B4 or (C, D) immunostained for CD45 and higher magnification. Photomicrographs show microglia in WT mice treated with vehicle (controls; A, C), with MPTP alone (B, D), with MPTP + telmisartan (E), or with MPTP + telmisartan + GW9662 (G). Microglial activation in AT1a- mice (AT1a-/-) treated with MPTP alone or MPTP + GW9662 is shown in F and H, respectively. Microglial activation was significantly higher in mice treated with MPTP alone (B, D), and in mice treated with the neurotoxin, AT1 inhibition and GW9662 (G, H). Scale bar: 100 μm.

Mentions: In several recent studies, we have observed that the enhancing effect of AII on DA cell loss is mediated by microglial activation and exacerbation of the inflammatory response (for details, see [11,13]). In order to confirm that, in the present experiments, neuroprotection by telmisartan or AT1a deletion in mice is also associated with the same mechanism (inhibition of MPTP-induced microglial response), we analyzed the expression of the microglial markers isolectin B4 and CD45 in the substantia nigra. Control mice treated with vehicle showed minimal and non-significant microglial activation. In WT mice injected with MPTP (group B1), microglial activation was much higher than in WT mice injected with vehicle (group A1), and higher than mice injected with MPTP + telmisartan (group C1). However, WT mice injected with MPTP + telmisartan showed lower microglial activation than WT mice injected with MPTP + telmisartan + GW9662. No significant difference was observed between mice treated with vehicle and mice treated with telmisartan alone, or GW9662 alone, or telmisartan + GW9662 (Figures 5 and 6A).


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)

Photomicrographs showing changes in microglial activation in the substantia nigra. Activated microglial cells at central levels of the substantia nigra stained with (A, B, E-H) isolectin B4 or (C, D) immunostained for CD45 and higher magnification. Photomicrographs show microglia in WT mice treated with vehicle (controls; A, C), with MPTP alone (B, D), with MPTP + telmisartan (E), or with MPTP + telmisartan + GW9662 (G). Microglial activation in AT1a- mice (AT1a-/-) treated with MPTP alone or MPTP + GW9662 is shown in F and H, respectively. Microglial activation was significantly higher in mice treated with MPTP alone (B, D), and in mice treated with the neurotoxin, AT1 inhibition and GW9662 (G, H). Scale bar: 100 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3298706&req=5

Figure 5: Photomicrographs showing changes in microglial activation in the substantia nigra. Activated microglial cells at central levels of the substantia nigra stained with (A, B, E-H) isolectin B4 or (C, D) immunostained for CD45 and higher magnification. Photomicrographs show microglia in WT mice treated with vehicle (controls; A, C), with MPTP alone (B, D), with MPTP + telmisartan (E), or with MPTP + telmisartan + GW9662 (G). Microglial activation in AT1a- mice (AT1a-/-) treated with MPTP alone or MPTP + GW9662 is shown in F and H, respectively. Microglial activation was significantly higher in mice treated with MPTP alone (B, D), and in mice treated with the neurotoxin, AT1 inhibition and GW9662 (G, H). Scale bar: 100 μm.
Mentions: In several recent studies, we have observed that the enhancing effect of AII on DA cell loss is mediated by microglial activation and exacerbation of the inflammatory response (for details, see [11,13]). In order to confirm that, in the present experiments, neuroprotection by telmisartan or AT1a deletion in mice is also associated with the same mechanism (inhibition of MPTP-induced microglial response), we analyzed the expression of the microglial markers isolectin B4 and CD45 in the substantia nigra. Control mice treated with vehicle showed minimal and non-significant microglial activation. In WT mice injected with MPTP (group B1), microglial activation was much higher than in WT mice injected with vehicle (group A1), and higher than mice injected with MPTP + telmisartan (group C1). However, WT mice injected with MPTP + telmisartan showed lower microglial activation than WT mice injected with MPTP + telmisartan + GW9662. No significant difference was observed between mice treated with vehicle and mice treated with telmisartan alone, or GW9662 alone, or telmisartan + GW9662 (Figures 5 and 6A).

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