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Rosiglitazone, a PPAR-γ agonist, protects against striatal dopaminergic neurodegeneration induced by 6-OHDA lesions in the substantia nigra of rats.
Toxicol Lett. 2012 Sep 18; 213(3):332-44.TL

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+Show Affiliations

Department of Pharmacology, College of Medicine, Hanyang University, 133-791 Seoul, Republic of Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22842585

Citation

Lee, Eun Young, et al. "Rosiglitazone, a PPAR-γ Agonist, Protects Against Striatal Dopaminergic Neurodegeneration Induced By 6-OHDA Lesions in the Substantia Nigra of Rats." Toxicology Letters, vol. 213, no. 3, 2012, pp. 332-44.
Lee EY, Lee JE, Park JH, et al. Rosiglitazone, a PPAR-γ agonist, protects against striatal dopaminergic neurodegeneration induced by 6-OHDA lesions in the substantia nigra of rats. Toxicol Lett. 2012;213(3):332-44.
Lee, E. Y., Lee, J. E., Park, J. H., Shin, I. C., & Koh, H. C. (2012). Rosiglitazone, a PPAR-γ agonist, protects against striatal dopaminergic neurodegeneration induced by 6-OHDA lesions in the substantia nigra of rats. Toxicology Letters, 213(3), 332-44. https://doi.org/10.1016/j.toxlet.2012.07.016
Lee EY, et al. Rosiglitazone, a PPAR-γ Agonist, Protects Against Striatal Dopaminergic Neurodegeneration Induced By 6-OHDA Lesions in the Substantia Nigra of Rats. Toxicol Lett. 2012 Sep 18;213(3):332-44. PubMed PMID: 22842585.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Rosiglitazone, a PPAR-γ agonist, protects against striatal dopaminergic neurodegeneration induced by 6-OHDA lesions in the substantia nigra of rats. AU - Lee,Eun Young, AU - Lee,Jeong Eun, AU - Park,Jae Hyeon, AU - Shin,In Chul, AU - Koh,Hyun Chul, Y1 - 2012/07/27/ PY - 2011/09/23/received PY - 2012/06/13/revised PY - 2012/07/19/accepted PY - 2012/7/31/entrez PY - 2012/7/31/pubmed PY - 2012/11/9/medline SP - 332 EP - 44 JF - Toxicology letters JO - Toxicol Lett VL - 213 IS - 3 N2 - 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. SN - 1879-3169 UR - https://www.unboundmedicine.com/medline/citation/22842585/Rosiglitazone_a_PPAR_γ_agonist_protects_against_striatal_dopaminergic_neurodegeneration_induced_by_6_OHDA_lesions_in_the_substantia_nigra_of_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-4274(12)01228-3 DB - PRIME DP - Unbound Medicine ER -