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Peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonist is neuroprotective and stimulates PGC-1 alpha expression and CREB phosphorylation in human dopaminergic neurons
Univ Helsinki, Dept Biochem & Dev Biol, Medicum, Fac Med, POB 63, FIN-00014 Helsinki, Finland.;Biomedicum Helsinki 2U, Minerva Fdn Inst Med Res, Tukholmankatu 8, FIN-00290 Helsinki, Finland..
Univ Helsinki, Dept Biochem & Dev Biol, Medicum, Fac Med, POB 63, FIN-00014 Helsinki, Finland.;Biomedicum Helsinki 2U, Minerva Fdn Inst Med Res, Tukholmankatu 8, FIN-00290 Helsinki, Finland..
Univ Helsinki, Unit Biochem & Cell Biol, Dept Vet Biosci, POB 66, FIN-00014 Helsinki, Finland..ORCID iD: 0000-0002-6989-1564
Biomedicum Helsinki 2U, Minerva Fdn Inst Med Res, Tukholmankatu 8, FIN-00290 Helsinki, Finland..
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2016 (English)In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 102, p. 266-275Article in journal (Refereed) Published
Abstract [en]

Mitochondrial dysfunction has been linked to several neurodegenerative diseases such as Parkinson's disease (PD). Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) is a master gene for mitochondrial biogenesis and has been shown to be neuroprotective in models of PD. In this work we have studied the mechanisms by which peroxisome proliferator-activated receptor-gamma (PPAR gamma) selective agonist N-(2-benzoylphenyl)-O-[2-(methyl-2-pyridinylamino)ethyl]-L-tyrosine hydrate (GW1929) acts on human dopaminergic neurons in culture. Data showed that GW1929 increased the viability of human dopaminergic neurons and protected them against oxidative stress induced by H2O2 and the mitochondrial toxin Rotenone. The enhanced resilience of the neurons was attributed to increased levels of mitochondrial antioxidants and of PGC-1 alpha. GW1929 treatment further increased cell respiration, mitochondrial biogenesis and sirtuin-1 (SIRT1) expression in the human dopaminergic neurons. Phosphorylation of cAMP responsive element-binding protein (CREB) was also robustly increased in GW1929-treated cells. Together these results show that the PPAR gamma agonist GW1929 influences CREB signaling and PGC-1 alpha activities in the human dopaminergic neurons contributing to an increased cell viability. This supports the view that drugs acting on the PPAR gamma-PGC-1 alpha signaling in neurons may have beneficial effects in PD and possible also in other brain disorders. (c) 2015 Elsevier Ltd. All rights reserved.

Place, publisher, year, edition, pages
PERGAMON-ELSEVIER SCIENCE LTD , 2016. Vol. 102, p. 266-275
Keywords [en]
PPAR gamma, PGC-1 alpha, SIRT1, CREB, Dopaminergic neurons, Mitochondria
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-167952DOI: 10.1016/j.neuropharm.2015.11.020ISI: 000368950400025PubMedID: 26631533OAI: oai:DiVA.org:liu-167952DiVA, id: diva2:1457502
Available from: 2020-08-11 Created: 2020-08-11 Last updated: 2021-07-13

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