title: Rosiglitazone, a PPAR-γ agonist, protects against striatal dopaminergic neurodegeneration induced by 6-OHDA lesions in the substantia nigra of rats.
abstract: Rosiglitazone is a commonly prescribed insulin-sensitizing drug with selective agonistic activity at the peroxisome proliferator-activated receptor-γ (PPARγ). Previously, rosiglitazone was shown to attenuate dopaminergic cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD), an effect attributed to its anti-inflammatory properties. To elucidate the neuroprotective mechanisms of rosiglitazone, we investigated the effects of rosiglitazone on the expressions of striatal tyrosine hydroxylase (TH), cyclooxygenase-2 (COX-2) and glial fibrillary acidic protein (GFAP) in a 6-OHDA-lesioned rat PD model. Rosiglitazone (3 mg/kg) was administered intraperitoneally at 24 h and 30 min prior to the creation of an intranigral 6-OHDA lesion. A reduction in TH protein expression began at 3 days and a prominent decrease was observed at 7 days post-lesion, and decreases of dopamine (DA) levels began at 1 day post-lesion. In contrast, GFAP expression was significantly increased at 3 days and preserved for up to 7 days post-lesion and the patterns of GFAP expression was inversely correlated to changes in TH expression. Furthermore, COX-2 expression in the rostral striatum showed a significant increase at 6h post-lesion while that of the caudal striatum was increased at 12 h. In the 6-OHDA-lesioned model, the activation of PPARγ by rosiglitazone significantly prevented TH protein expression reductions, and inhibited 6-OHDA-induced microglia activation in striatum. In addition, rosiglitazone attenuated in production of both COX-2 and TNF-α expression. In contrast, rosiglitazone pretreatment led to greater increases in striatal GFAP expression than 6-OHDA alone and changes in the expression of this protein preceded the changes that were seen with TH expression. These results suggest that the neuroprotection observed with rosiglitazone treatment may be partially due to the attenuation of COX-2 production and the strengthening of astrocyte function. Our results provide insight into the neuroprotective mechanisms of rosiglitazone against 6-OHDA-induced neuronal damages.
authors: Department of Pharmacology, College of Medicine, Hanyang University, 133-791 Seoul, Republic of Korea.
authors: Eun Young
authors: EY
authors: Lee
authors: Jeong Eun
authors: JE
authors: Lee
authors: Jae Hyeon
authors: JH
authors: Park
authors: In Chul
authors: IC
authors: Shin
authors: Hyun Chul
authors: HC
authors: Koh
mesh_terms: D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D009410:Nerve Degeneration; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D016627:Oxidopamine; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C100745:Aif1 protein, rat; D002135:Calcium-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D018696:Neuroprotective Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D004298:Dopamine