Advertisement

Cellular and Molecular Neurobiology

, Volume 38, Issue 4, pp 929–939 | Cite as

The PGC-1α Activator ZLN005 Ameliorates Ischemia-Induced Neuronal Injury In Vitro and In Vivo

  • Yazhou Xu
  • John Alimamy Kabba
  • Wenchen Ruan
  • Yunjie Wang
  • Shunyi Zhao
  • Xiaoyue Song
  • Luyong Zhang
  • Jia Li
  • Tao Pang
Original Research

Abstract

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.

Keywords

Ischemic stroke PGC-1α HO-1 Neuroprotection 

Notes

Acknowledgements

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.

Author Contributions

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

Ethical Approval

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.

References

  1. Bian M et al (2016) Celastrol protects mouse retinas from bright light-induced degeneration through inhibition of oxidative stress and inflammation. J Neuroinf 13:50.  https://doi.org/10.1186/s12974-016-0516-8 CrossRefGoogle Scholar
  2. 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
  3. Chang S et al (2017) The natural product 4,10-aromadendranediol induces neuritogenesis in neuronal cells in vitro through activation of the ERK pathway. Acta Pharmacol Sin 38:29–40.  https://doi.org/10.1038/aps.2016.115 CrossRefPubMedGoogle Scholar
  4. 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
  5. Chen SD, Yang DI, Lin TK, Shaw FZ, Liou CW, Chuang YC (2011) Roles of oxidative stress, apoptosis, PGC-1α and mitochondrial biogenesis in cerebral ischemia. Int J Mol Sci 12:7199–7215.  https://doi.org/10.3390/ijms12107199 CrossRefPubMedPubMedCentralGoogle Scholar
  6. Chen T et al (2014) Nafamostat mesilate attenuates neuronal damage in a rat model of transient focal cerebral ischemia through thrombin inhibition. Sci Rep 4:5531.  https://doi.org/10.1038/srep05531 CrossRefPubMedPubMedCentralGoogle Scholar
  7. di Penta A et al (2013) Oxidative stress and proinflammatory cytokines contribute to demyelination and axonal damage in a cerebellar culture model of neuroinflammation. PLoS ONE 8:e54722.  https://doi.org/10.1371/journal.pone.0054722 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Ding Y, Chen M, Wang M, Li Y, Wen A (2015) Posttreatment with 11-Keto-β-Boswellic acid ameliorates cerebral ischemia-reperfusion injury: nrf2/HO-1 pathway as a potential mechanism. Mol Neurobiol 52:1430–1439.  https://doi.org/10.1007/s12035-014-8929-9 CrossRefPubMedGoogle Scholar
  9. Gao Y et al (2015) Totarol prevents neuronal injury in vitro and ameliorates brain ischemic stroke: potential roles of Akt activation and HO-1 induction. Toxicol Appl Pharmacol 289:142–154.  https://doi.org/10.1016/j.taap.2015.10.001 CrossRefPubMedGoogle Scholar
  10. Garcia G et al (2017) Bioaccessible (poly)phenol metabolites from raspberry protect neural cells from oxidative stress and attenuate microglia activation. Food Chem 215:274–283.  https://doi.org/10.1016/j.foodchem.2016.07.128 CrossRefPubMedGoogle Scholar
  11. García-Quintans N et al (2016) Oxidative stress induces loss of pericyte coverage and vascular instability in PGC-1α-deficient mice. Angiogenesis 19:217–228.  https://doi.org/10.1007/s10456-016-9502-0 CrossRefPubMedGoogle Scholar
  12. 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
  13. Ho YH, Lin YT, Wu CW, Chao YM, Chang AY, Chan JY (2015) Peripheral inflammation increases seizure susceptibility via the induction of neuroinflammation and oxidative stress in the hippocampus. J Biomed Sci 22:46.  https://doi.org/10.1186/s12929-015-0157-8 CrossRefPubMedPubMedCentralGoogle Scholar
  14. Li L et al (2015) Chinese herbal medicine formula tao hong si wu decoction protects against cerebral ischemia-reperfusion injury via PI3 K/Akt and the Nrf2 signaling pathway. J Nat Med 69:76–85.  https://doi.org/10.1007/s11418-014-0865-5 CrossRefPubMedGoogle Scholar
  15. Li L et al (2016a) Sestrin2 silencing exacerbates cerebral ischemia/reperfusion injury by decreasing mitochondrial biogenesis through the AMPK/PGC-1α pathway in rats. Sci Rep 6:30272.  https://doi.org/10.1038/srep30272 CrossRefPubMedPubMedCentralGoogle Scholar
  16. Li W et al (2016b) ZLN005 protects cardiomyocytes against high glucose-induced cytotoxicity by promoting SIRT1 expression and autophagy. Exp Cell Res 345:25–36.  https://doi.org/10.1016/j.yexcr.2016.05.012 CrossRefPubMedGoogle Scholar
  17. Liu P et al (2015) MicroRNA-424 protects against focal cerebral ischemia and reperfusion injury in mice by suppressing oxidative stress. Stroke 46:513–519.  https://doi.org/10.1161/STROKEAHA.114.007482 CrossRefPubMedGoogle Scholar
  18. Liu X, Zhu X, Chen M, Ge Q, Shen Y, Pan S (2016) Resveratrol protects PC12 cells against OGD/R-induced apoptosis via the mitochondrial-mediated signaling pathway. Acta Biochim Biophys Sin (Shanghai) 48:342–353.  https://doi.org/10.1093/abbs/gmw011 CrossRefGoogle Scholar
  19. Liu SG, Wang YM, Zhang YJ, He XJ, Ma T, Song W, Zhang YM (2017) ZL006 protects spinal cord neurons against ischemia-induced oxidative stress through AMPK-PGC-1α-Sirt3 pathway. Neurochem Int 108:230–237.  https://doi.org/10.1016/j.neuint.2017.04.005 CrossRefPubMedGoogle Scholar
  20. Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20:84–91CrossRefPubMedGoogle Scholar
  21. Ma X, Xie Y, Chen Y, Han B, Li J, Qi S (2016) Post-ischemia mdivi-1 treatment protects against ischemia/reperfusion-induced brain injury in a rat model. Neurosci Lett 632:23–32.  https://doi.org/10.1016/j.neulet.2016.08.026 CrossRefPubMedGoogle Scholar
  22. 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
  23. Mossakowski AA et al (2015) Tracking CNS and systemic sources of oxidative stress during the course of chronic neuroinflammation. Acta Neuropathol 130:799–814.  https://doi.org/10.1007/s00401-015-1497-x CrossRefPubMedPubMedCentralGoogle Scholar
  24. Mudò G et al (2012) Transgenic expression and activation of PGC-1α protect dopaminergic neurons in the MPTP mouse model of Parkinson’s disease. Cell Mol Life Sci 69:1153–1165.  https://doi.org/10.1007/s00018-011-0850-z CrossRefPubMedGoogle Scholar
  25. O’Hare Doig RL, Bartlett CA, Maghzal GJ, Lam M, Archer M, Stocker R, Fitzgerald M (2014) Reactive species and oxidative stress in optic nerve vulnerable to secondary degeneration. Exp Neurol 261:136–146.  https://doi.org/10.1016/j.expneurol.2014.06.007 CrossRefPubMedGoogle Scholar
  26. Pang T et al (2016) A novel GSK-3β inhibitor YQ138 prevents neuronal injury induced by glutamate and brain ischemia through activation of the Nrf2 signaling pathway. Acta Pharmacol Sin 37:741–752.  https://doi.org/10.1038/aps.2016.3 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Park JH, Park YS, Lee JB, Park KH, Paik MK, Jeong M, Koh HC (2016) Meloxicam inhibits fipronil-induced apoptosis via modulation of the oxidative stress and inflammatory response in SH-SY5Y cells. J Appl Toxicol 36:10–23.  https://doi.org/10.1002/jat.3136 CrossRefPubMedGoogle Scholar
  28. Peng H et al (2015) Lack of PGC-1α exacerbates high glucose-induced apoptosis in human umbilical vein endothelial cells through activation of VADC1. Int J Clin Exp Pathol 8:4639–4650PubMedPubMedCentralGoogle Scholar
  29. Qi D et al (2014) HO-1 attenuates hippocampal neurons injury via the activation of BDNF-TrkB-PI3 K/Akt signaling pathway in stroke. Brain Res 1577:69–76.  https://doi.org/10.1016/j.brainres.2014.06.031 CrossRefPubMedGoogle Scholar
  30. Qiao H et al (2012) Protective effect of luteolin in experimental ischemic stroke: upregulated SOD1, CAT, Bcl-2 and claudin-5, down-regulated MDA and Bax expression. Neurochem Res 37:2014–2024.  https://doi.org/10.1007/s11064-012-0822-1 CrossRefPubMedGoogle Scholar
  31. Ritzel RM et al (2016) Early retinal inflammatory biomarkers in the middle cerebral artery occlusion model of ischemic stroke. Mol Vis 22:575–588PubMedPubMedCentralGoogle Scholar
  32. 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
  33. Shirley R, Ord EN, Work LM (2014) Oxidative stress and the use of antioxidants in stroke. Antioxidants (Basel) 3:472–501.  https://doi.org/10.3390/antiox3030472 CrossRefGoogle Scholar
  34. 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
  35. 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
  36. St-Pierre J et al (2006) Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 127:397–408CrossRefPubMedGoogle Scholar
  37. Szalardy L, Molnar M, Torok R, Zadori D, Kovacs GG, Vecsei L, Klivenyi P (2016) Lack of age-related clinical progression in PGC-1α-deficient mice – implications for mitochondrial encephalopathies. Behav Brain Res 313:272–281.  https://doi.org/10.1016/j.bbr.2016.07.021 CrossRefPubMedGoogle Scholar
  38. Wang LQ et al (2014) Timing and dose regimens of marrow mesenchymal stem cell transplantation affect the outcomes and neuroinflammatory response after ischemic stroke. CNS Neurosci Ther 20:317–326.  https://doi.org/10.1111/cns.12216 CrossRefPubMedGoogle Scholar
  39. Wang Y et al (2017a) A dual AMPK/Nrf2 activator reduces brain inflammation after stroke by enhancing microglia M2 polarization. Antioxid Redox Signal.  https://doi.org/10.1089/ars.2017.7003 Google Scholar
  40. Wang Y et al (2017b) Balasubramide derivative 3C modulates microglia activation via CaMKKβ-dependent AMPK/PGC-1α pathway in neuroinflammatory conditions. Brain Behav Immun.  https://doi.org/10.1016/j.bbi.2017.08.006 PubMedCentralGoogle Scholar
  41. Won YW, Lee M, Kim HA, Bull DA, Kim SW (2013) Hypoxia-inducible plasmid expressing both miSHP-1 and HO-1 for the treatment of ischemic disease. J Control Release 165:22–28.  https://doi.org/10.1016/j.jconrel.2012.10.014 CrossRefPubMedGoogle Scholar
  42. Wu Y, Shang Y, Sun SG, Liu RG, Yang WQ (2007) Protective effect of erythropoietin against 1-methyl-4-phenylpyridinium-induced neurodegenaration in PC12 cells. Neurosci Bull 23:156–164CrossRefPubMedGoogle Scholar
  43. 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
  44. 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
  45. Xu Y et al (2015) Telmisartan prevention of LPS-induced microglia activation involves M2 microglia polarization via CaMKKβ-dependent AMPK activation. Brain Behav Immun 50:298–313.  https://doi.org/10.1016/j.bbi.2015.07.015 CrossRefPubMedGoogle Scholar
  46. Xue F et al (2016) Nrf2/antioxidant defense pathway is involved in the neuroprotective effects of Sirt1 against focal cerebral ischemia in rats after hyperbaric oxygen preconditioning. Behav Brain Res 309:1–8.  https://doi.org/10.1016/j.bbr.2016.04.045 CrossRefPubMedGoogle Scholar
  47. Yang F et al (2014) NLRP3 deficiency ameliorates neurovascular damage in experimental ischemic stroke. J Cereb Blood Flow Metab 34:660–667.  https://doi.org/10.1038/jcbfm.2013.242 CrossRefPubMedPubMedCentralGoogle Scholar
  48. Yin W, Signore AP, Iwai M, Cao G, Gao Y, Chen J (2008) Rapidly increased neuronal mitochondrial biogenesis after hypoxic-ischemic brain injury. Stroke 39:3057–3063.  https://doi.org/10.1161/STROKEAHA.108.520114 CrossRefPubMedPubMedCentralGoogle Scholar
  49. 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
  50. Zhang LN et al (2013) Novel small-molecule PGC-1α transcriptional regulator with beneficial effects on diabetic db/db mice. Diabetes 62:1297–1307.  https://doi.org/10.2337/db12-0703 CrossRefPubMedPubMedCentralGoogle Scholar
  51. 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

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Jiangsu Key Laboratory of Drug Screening, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic DiseasesChina Pharmaceutical UniversityNanjingPeople’s Republic of China
  2. 2.School of Biological SciencesUniversity of LiverpoolLiverpoolUK
  3. 3.State Key Laboratory of Drug Research, National Center for Drug Screening, Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghaiPeople’s Republic of China

Personalised recommendations