PPAR-gamma-mediated neuroprotection in a chronic mouse model of Parkinson's disease.
Rosiglitazone is a commonly prescribed insulin-sensitizing drug with a selective agonistic activity on the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). PPAR-gamma can modulate inflammatory responses in the brain, and agonists might be beneficial in neurodegenerative diseases. In the present study we used a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine plus probenecid (MPTPp) mouse model of progressive Parkinson's disease (PD) to assess the therapeutic efficacy of rosiglitazone on behavioural impairment, neurodegeneration and inflammation. Mice chronically treated with MPTPp displayed typical features of PD, including impairment of motor and olfactory functions associated with partial loss of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNc), decrease of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) content and dynorphin (Dyn) mRNA levels in the caudate-putamen (CPu), intense microglial and astroglial response in the SNc and CPu. Chronic rosiglitazone, administered in association with MPTPp, completely prevented motor and olfactory dysfunctions and loss of TH-positive cells in the SNc. In the CPu, loss of striatal DA was partially prevented, whereas decreases in DOPAC content and Dyn were fully counteracted. Moreover, rosiglitazone completely inhibited microglia reactivity in SNc and CPu, as measured by CD11b immunostaining, and partially inhibited astroglial response assessed by glial fibrillary acidic protein immunoreactivity. Measurement of striatal MPP+ levels 2, 4, 6 h and 3 days after chronic treatment indicated that MPTP metabolism was not altered by rosiglitazone. The results support the use of PPAR-gamma agonists as a putative anti-inflammatory therapy aimed at arresting PD progression, and suggest that assessment in PD clinical trials is warranted.
Schintu
Nicoletta
N
Department of Toxicology, National Institute of Neuroscience, University of Cagliari, via Ospedale 72, 09124 Cagliari, Italy.
Frau
Lucia
L
Ibba
Marcello
M
Caboni
Pierluigi
P
Garau
Arianna
A
Carboni
Ezio
E
Carta
Anna R
AR
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D002375:Catalepsy; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D002908:Chronic Disease; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004347:Drug Interactions; D004399:Dynorphins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005917:Globus Pallidus / Q000187:drug effects / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects; D020267:MPTP Poisoning / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D011597:Psychomotor Performance / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D000077154:Rosiglitazone; D012903:Smell / Q000187:drug effects; D053719:Tandem Mass Spectrometry / Q000379:methods; D045162:Thiazolidinediones / Q000627:therapeutic use*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D039481:CD11b Antigen; D005904:Glial Fibrillary Acidic Protein; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D015102:3,4-Dihydroxyphenylacetic Acid; D004399:Dynorphins; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine