The PGC-1α Activator ZLN005 Ameliorates Ischemia-Induced Neuronal Injury In Vitro and In Vivo
- 293 Downloads
Oxidative stress is a great challenge to neurons following cerebral ischemia. PGC-1α has been shown to act as a potent modulator of oxidative metabolism. In this study, the effects of ZLN005, a small molecule that activate PGC-1α, against oxygen–glucose deprivation (OGD)- or ischemia-induced neuronal injury in vitro and in vivo were investigated. Transient middle cerebral artery occlusion (tMCAO) was performed in rats and ZLN005 was administered intravenously at 2 h, 4 h, or 6 h after ischemia onset. Infarct volume and neurological deficit score were detected to evaluate the neuroprotective effects of ZLN005. Well-differentiated PC12 cells, which were subjected to OGD for 2 h followed by reoxygenation for 22 h, were used as an in vitro ischemic model. Changes in expression of PGC-1α, its related genes, and antioxidant genes were determined by real-time quantitative PCR. The results showed that ZLN005 reduced cerebral infarct volume and improved the neurological deficit in rat with tMCAO, and significantly protected OGD-induced neuronal injury in PC12 cells. Furthermore, ZLN005 enhanced expression of PGC-1α in PC12 cells and in the ipsilateral hemisphere of rats with tMCAO. Additionally, ZLN005 increased antioxidant genes, including SOD1 and HO-1, and significantly prevented the ischemia-induced decrease in SOD activity. Taking together, the PGC-1α activator ZLN005 exhibits neuroprotective effects under ischemic conditions and molecular mechanisms possibly involve activation of PGC-1α signaling pathway and cellular antioxidant systems.
KeywordsIschemic stroke PGC-1α HO-1 Neuroprotection
This study was supported by the National Natural Science Foundation of China (21402241), the Natural Science Foundation of Jiangsu Province (BK20160032), the Six Talent Peaks Project of Jiangsu Province (T.P.), and the Program for Jiangsu Province “Shuang Chuang” Team.
All authors listed contributed immensely to this study. YX and JAK performed the experiments and wrote the paper. WR, YW, SZ, and XS performed the animal experiments and analyzed the data. TP, JL, and LZ, as experts in molecular pharmacology, provided technical supports and designed the research.
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflict of interest
All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.
- Chang R et al (2016) Protective effects of aloin on oxygen and glucose deprivation-induced injury in PC12 cells. Brain Res Bull 121:75–83. https://doi.org/10.1016/j.brainresbull.2016.01.001 CrossRefPubMedGoogle Scholar
- Chen SD et al (2010) Activation of calcium/calmodulin-dependent protein kinase IV and peroxisome proliferator-activated receptor γ coactivator-1α signaling pathway protects against neuronal injury and promotes mitochondrial biogenesis in the hippocampal CA1 subfield after transient global ischemia. J Neurosci Res 88:3144–3154. https://doi.org/10.1002/jnr.22469 CrossRefPubMedGoogle Scholar
- Gu WW et al (2016) 2-(3′,5′-Dimethoxybenzylidene) cyclopentanone, a novel synthetic small-molecule compound, provides neuroprotective effects against ischemic stroke. Neuroscience 316:26–40. https://doi.org/10.1016/j.neuroscience.2015.11.052 CrossRefPubMedGoogle Scholar
- Mäkelä J, Tselykh TV, Kukkonen JP, Eriksson O, Korhonen LT, Lindholm D (2016) Peroxisome proliferator-activated receptor-γ (PPARγ) agonist is neuroprotective and stimulates PGC-1α expression and CREB phosphorylation in human dopaminergic neurons. Neuropharmacology 102:266–275. https://doi.org/10.1016/j.neuropharm.2015.11.020 CrossRefPubMedGoogle Scholar
- Sharma DR, Sunkaria A, Wani WY, Sharma RK, Kandimalla RJ, Bal A, Gill KD (2013) Aluminium induced oxidative stress results in decreased mitochondrial biogenesis via modulation of PGC-1α expression. Toxicol Appl Pharmacol 273:365–380. https://doi.org/10.1016/j.taap.2013.09.012 CrossRefPubMedGoogle Scholar
- Shulyakova N, Sidorova-Darmos E, Fong J, Zhang G, Mills LR, Eubanks JH (2014) Over-expression of the Sirt3 sirtuin Protects neuronally differentiated PC12 Cells from degeneration induced by oxidative stress and trophic withdrawal. Brain Res 1587:40–53. https://doi.org/10.1016/j.brainres.2014.08.066 CrossRefPubMedGoogle Scholar
- Singh SP, Schragenheim J, Cao J, Falck JR, Abraham NG, Bellner L (2016) PGC-1 alpha regulates HO-1 expression, mitochondrial dynamics and biogenesis: role of epoxyeicosatrienoic acid. Prostaglandins Other Lipid Mediat 125:8–18. https://doi.org/10.1016/j.prostaglandins.2016.07.004 CrossRefPubMedPubMedCentralGoogle Scholar
- Wu KL, Wu CW, Chao YM, Hung CY, Chan JY (2016) Impaired Nrf2 regulation of mitochondrial biogenesis in rostral ventrolateral medulla on hypertension induced by systemic inflammation. Free Radic Biol Med 97:58–74. https://doi.org/10.1016/j.freeradbiomed.2016.05.012 CrossRefPubMedGoogle Scholar
- Xiao W, Goswami PC (2015) Down-regulation of peroxisome proliferator activated receptor gamma coactivator 1α induces oxidative stress and toxicity of 1-(4-Chlorophenyl)-benzo-2,5-quinone in HaCaT human keratinocytes. Toxicol In Vitro 29:1332–1338. https://doi.org/10.1016/j.tiv.2015.05.009 CrossRefPubMedPubMedCentralGoogle Scholar
- Yu S, Cheng Q, Li L, Liu M, Yang Y, Ding F (2014) 2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-beta-d-pyranoside confers neuroprotection in cell and animal models of ischemic stroke through calpain1/PKA/CREB-mediated induction of neuronal glucose transporter 3. Toxicol Appl Pharmacol 277:259–269. https://doi.org/10.1016/j.taap.2014.03.025 CrossRefPubMedGoogle Scholar
- Zhang J et al (2014) Bicyclol upregulates transcription factor Nrf2, HO-1 expression and protects rat brains against focal ischemia. Brain Res Bull 100:38–43. https://doi.org/10.1016/j.brainresbull.2013.11.001 CrossRefPubMedGoogle Scholar