title: 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.
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-null 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-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, Faculty of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Garrido-Gil
authors.forename: Belen
authors.initials: B
authors.lastname: Joglar
authors.forename: Ana I
authors.initials: AI
authors.lastname: Rodriguez-Perez
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Guerra
authors.forename: Jose L
authors.initials: JL
authors.lastname: Labandeira-Garcia
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000704:Analysis of Variance; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use*; D001565:Benzoates / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects; D004660:Encephalitis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D037102:Lectins; D017493:Leukocyte Common Antigens / Q000378:metabolism; D020267:MPTP Poisoning / Q000139:chemically induced / Q000150:complications; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency*; D000077333:Telmisartan; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D047228:Angiotensin II Type 1 Receptor Blockers; D000813:Anilides; D001562:Benzimidazoles; D001565:Benzoates; D037102:Lectins; D047495:PPAR gamma; D044140:Receptor, Angiotensin, Type 1; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D017493:Leukocyte Common Antigens; D000077333:Telmisartan