RT Journal Article
T1 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
A1 Garrido Gil, Pablo
A1 Joglar, Belén
A1 Rodríguez Pérez, Ana Isabel
A1 Guerra Seijas, María Josefa Natividad
A1 Labandeira García, José Luis
K1 Angiotensin
K1 AT1
K1 Neuroinflammation
K1 Neuroprotection
K1 Microglia
K1 Parkinson
K1 Peroxisome proliferatoractivated receptor gamma
K1 Telmisartan
AB Background: Several recent studies have shown that angiotensin type 1 receptor (AT1) antagonists such ascandesartan inhibit the microglial inflammatory response and dopaminergic cell loss in animal models ofParkinson’s disease. However, the mechanisms involved in the neuroprotective and anti-inflammatory effects of AT1blockers in the brain have not been clarified. A number of studies have reported that AT1 blockers activateperoxisome proliferator-activated receptor gamma (PPAR g). PPAR-g activation inhibits inflammation, and may beresponsible for neuroprotective effects, independently of AT1 blocking actions.Methods: We have investigated whether oral treatment with telmisartan (the most potent PPAR-g activator amongAT1 blockers) provides neuroprotection against dopaminergic cell death and neuroinflammation, and the possiblerole of PPAR-g activation in any such neuroprotection. We used a mouse model of parkinsonism induced by thedopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and co-administration of the PPAR-gantagonist GW9662 to study the role of PPAR-g activation. In addition, we used AT1a-null mice lesioned with MPTPto study whether deletion of AT1 in the absence of any pharmacological effect of AT1 blockers providesneuroprotection, and investigated whether PPAR-g activation may also be involved in any such effect of AT1deletion by co-administration of the PPAR-g antagonist GW9662.Results: We observed that telmisartan protects mouse dopaminergic neurons and inhibits the microglial responseinduced by administration of MPTP. The protective effects of telmisartan on dopaminergic cell death and microglialactivation were inhibited by co-administration of GW9662. Dopaminergic cell death and microglial activation weresignificantly lower in AT1a-null 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 celldeath and that the neuroprotective effect is mediated by PPAR-g activation. However, the results in AT1-deficientmice show that blockage of AT1, unrelated to the pharmacological properties of AT1 blockers, also protects againstdopaminergic cell death and neuroinflammation. Furthermore, the results show that PPAR-g activation is involvedin the anti-inflammatory and neuroprotective effects of AT1 deletion.
PB BioMED Central
YR 2012
FD 2012
LK http://hdl.handle.net/10347/21602
UL http://hdl.handle.net/10347/21602
LA eng
NO Garrido-Gil, P., Joglar, B., Rodriguez-Perez, A.I. et al. 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. "J Neuroinflammation" 9, 38 (2012)
NO Funding was provided by the Spanish Ministry of Science and Innovation (BFU2009-12310), Spanish Ministry of Health (RD06/0010/0013 and CIBERNED) and Galician Government (XUGA)
DS Minerva
RD 4 may 2026