Skip to main content

Advertisement

SpringerLink
Log in

The Protective Role of Peroxisome Proliferator-Activated Receptor-Gamma in Seizure and Neuronal Excitotoxicity

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

The peroxisome proliferator-activated receptor (PPAR) family, type II nucleus receptors have been successfully tested for their neuroprotective potential in certain central nervous system diseases. The aim of the present study was to determine if modulation by PPAR-γ could attenuate pilocarpine-induced seizures and decrease neuronal excitability. Adult male C57BL/6 mice were divided into two groups: one group received pretreatment with pioglitazone and the other received dimethyl sulfoxide (DMSO) for a period of 2 weeks. Status epilepticus was then induced in both groups by lithium-pilocarpine, after which seizure susceptibility, severity, and mortality were evaluated. Hippocampal histopathology was carried out on all mice at 24 h post-status epilepticus as well as blood–brain barrier (BBB) damage analysis. With the aid of patch clamp technology, the hippocampal neuronal excitability from mice with PPAR-γ 50% expression (PpargC/C) and PPAR-γ 25% expression (PpargC/−), as well as the effect of pioglitazone on the sodium currents in hippocampal neurons, were evaluated. It was found that pioglitazone, a PPAR-γ agonist, could attenuate pilocarpine-induced seizure severity in mice. Pathological examination showed that pioglitazone significantly attenuated pilocarpine-induced status epilepticus-related hippocampal neuronal loss and BBB damage. Further characterization of neuronal excitability revealed higher excitability in the brain slices from mice with PpargC/− expression, compared with the PpargC/C group. It was also found that pioglitazone could decrease sodium currents in hippocampal neurons. In conclusion, PPAR-γ deficiency aggravated neuronal excitability and excitotoxicity. PPAR-γ attenuated pilocarpine-induced seizure severity, neuronal loss, BBB damage, and sodium currents in hippocampal neurons. Modulation of PPAR-γ could be a potential novel treatment for epileptic seizures.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Sillanpaa M, Schmidt D (2006) Natural history of treated childhood-onset epilepsy: prospective, long-term population-based study. Brain 129:617–624

    Article  PubMed  Google Scholar 

  2. Kersten S, Desvergne B, Wahli W (2000) Roles of PPARs in health and disease. Nature 405:421–424

    Article  CAS  PubMed  Google Scholar 

  3. Tontonoz P, Spiegelman BM (2008) Fat and beyond: the diverse biology of PPARgamma. Annu Rev Biochem 77:289–312

    Article  CAS  Google Scholar 

  4. Schlachetzki JC, Winkler J (2015) The innate immune system in Parkinson's disease: a novel target promoting endogenous neuroregeneration. Neural Regen Res 10:704–706

    Article  PubMed  PubMed Central  Google Scholar 

  5. Kapadia R, Yi JH, Vemuganti R (2008) Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists. Front Biosci 13:813–826

    Article  Google Scholar 

  6. Sundararajan S, Jiang Q, Heneka M, Landreth G (2006) PPARgamma as a therapeutic target in central nervous system diseases. Neurochem Int 49:136–144

    Article  CAS  PubMed  Google Scholar 

  7. Chuang YC, Lin TK, Huang HY, Chang WN, Liou CW, Chen SD, Chang AY, Chan SH (2012) Peroxisome proliferator-activated receptors γ/mitochondrial uncoupling protein 2 signaling protects against seizure-induced neuronal cell death in the hippocampus following experimental status epilepticus. J Neuroinflammation 9:184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wong SB, Cheng SJ, Hung WC, Lee WT, Min MY (2015) Rosiglitazone suppresses in vitro seizures in hippocampal slice by inhibiting presynaptic glutamate release in a model of temporal lobe epilepsy. PLoS One 10:e0144806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Simeone TA, Matthews SA, Samson KK, Simeone KA (2017) Regulation of brain PPARgamma2 contributes to ketogenic diet anti-seizure efficacy. Exp Neurol 287:54–64

    Article  CAS  PubMed  Google Scholar 

  10. Tsai YS, Kim HJ, Takahashi N, Kim HS, Hagaman JR, Kim JK, Maeda N (2004) Hypertension and abnormal fat distribution but not insulin resistance in mice with P465L PPARgamma. J Clin Invest 114:240–249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tsai YS, Tsai PJ, Jiang MJ, Chou TY, Pendse A, Kim HS, Maeda N (2009) Decreased PPAR gamma expression compromises perigonadal-specific fat deposition and insulin sensitivity. Mol Endocrinol 23:1787–1798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chen CY, Chen TM, Shyu AB (1994) Interplay of two functionally and structurally distinct domains of the c-fos AU-rich element specifies its mRNA-destabilizing function. Mol Cell Biol 14:416–426

    Article  PubMed  PubMed Central  Google Scholar 

  13. Tsai YS, Pendse A, Moy SS, Mohri I, Perez A, Crawley JN, Suzuki K, Maeda N (2006) A de novo deafwaddler mutation of Pmca2 arising in ES cells and hitchhiking with a targeted modification of the Pparg gene. Mamm Genome 17:716–722

    Article  CAS  PubMed  Google Scholar 

  14. Barak Y, Nelson MC, Ong ES, Jones YZ, Ruiz-Lozano P, Chien KR, Koder A, Evans RM (1999) PPAR-gamma is required for placental, cardiac, and adipose tissue development. Mol Cell 4:585–595

    Article  CAS  PubMed  Google Scholar 

  15. Huang CW, Cheng JT, Tsai JJ, Wu SN, Huang CC (2009) Diabetic hyperglycemia aggravates seizures and status epilepticus-induced hippocampal damage. Neurotox Res 15:71–81

    Article  CAS  PubMed  Google Scholar 

  16. Huang CW, Wu SN, Cheng JT, Tsai JJ, Huang CC (2010) Diazoxide reduces status epilepticus neuron damage in diabetes. Neurotox Res 17:305–316

    Article  CAS  PubMed  Google Scholar 

  17. Pathak HR, Weissinger F, Terunuma M, Carlson GC, Hsu FC, Moss SJ, Coulter DA (2007) Disrupted dentate granule cell chloride regulation enhances synaptic excitability during development of temporal lobe epilepsy. J Neurosci 27:14012–14022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ferraro TN, Golden GT, Smith GG, St Jean P, Schork NJ, Mulholland N, Ballas C, Schill J et al (1999) Mapping loci for pentylenetetrazol-induced seizure susceptibility in mice. J Neurosci 19:6733–6739

    Article  CAS  PubMed  Google Scholar 

  19. Chang YC, Huang AM, Kuo YM, Wang ST, Chang YY, Huang CC (2003) Febrile seizures impair memory and cAMP response-element binding protein activation. Ann Neurol 54:706–718

    Article  CAS  PubMed  Google Scholar 

  20. Pitkanen A, Schwartzkroin PA, Moshe SL (2006) Models of seizures and epilepsy. Elsevier Academic Press, Burlington

    Google Scholar 

  21. Huang CW, Lin KM, Hung TY, Chuang YC, Wu SN (2018) Multiple actions of rotenone, an inhibitor of mitochondrial respiratory chain, on ionic currents and miniature end-plate potential in mouse hippocampal (mHippoE-14) neurons. Cell Physiol Biochem 47:330–343

    Article  CAS  PubMed  Google Scholar 

  22. Lin CH, Hsu SP, Cheng TC, Huang CW, Chiang YC, Hsiao IH, Lee MH, Shen ML et al (2017) Effects of anti-epileptic drugs on spreading depolarization-induced epileptiform activity in mouse hippocampal slices. Sci Rep 7:11884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Oby E, Janigro D (2006) The blood–brain barrier and epilepsy. Epilepsia 47:1761–1774

    Article  CAS  PubMed  Google Scholar 

  24. Friedman A, Heinemann U (2012) Role of blood–brain barrier dysfunction in epileptogenesis. In: Noebels JL et al. (eds) Jasper’s basic mechanisms of the epilepsies. National Center for Biotechnology Information (US)

  25. Seiffert E, Dreier JP, Ivens S, Bechmann I, Tomkins O, Heinemann U, Friedman A (2004) Lasting blood–brain barrier disruption induces epileptic focus in the rat somatosensory cortex. J Neurosci 24:7829–7836

    Article  CAS  PubMed  Google Scholar 

  26. Fabene PF, Navarro Mora G, Martinello M, Rossi B, Merigo F, Ottoboni L, Bach S, Angiari S et al (2008) A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nat Med 14:1377–1383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Vezzani A, Granata T (2005) Brain inflammation in epilepsy: experimental and clinical evidence. Epilepsia 46:1724–1743

    Article  CAS  PubMed  Google Scholar 

  28. Heneka MT, Sastre M, Dumitrescu-Ozimek L, Hanke A, Dewachter I, Kuiperi C, O'Banion K, Klockgether T et al (2005) Acute treatment with the PPARγ agonist pioglitazone and ibuprofen reduces glial inflammation and Aβ1–42 levels in APPV717I transgenic mice. Brain 128:1442–1453

    Article  PubMed  Google Scholar 

  29. Griggs RB, Donahue RR, Morgenweck J, Grace PM, Sutton A, Watkins LR, Taylor BK (2015) Pioglitazone rapidly reduces neuropathic pain through astrocyte and nongenomic PPARgamma mechanisms. Pain 156:469–482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hasegawa H, Takano H, Komuro I (2010) Therapeutic implications of PPARgamma in cardiovascular diseases. PPAR Res. https://doi.org/10.1155/2010/876049

  31. Kiss E, Popovic ZV, Bedke J, Adams J, Bonrouhi M, Babelova A, Schmidt C, Edenhofer F et al (2010) Peroxisome proliferator-activated receptor (PPAR)gamma can inhibit chronic renal allograft damage. Am J Pathol 176:2150–2162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Landreth G, Jiang Q, Mandrekar S, Heneka M (2008) PPARgamma agonists as therapeutics for the treatment of Alzheimer’s disease. Neurotherapeutics 5:481–489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Landreth GE, Heneka MT (2001) Anti-inflammatory actions of peroxisome proliferator-activated receptor gamma agonists in Alzheimer’s disease. Neurobiol Aging 22:937–944

    Article  CAS  PubMed  Google Scholar 

  34. Mohazab RA, Javadi-Paydar M, Delfan B, Dehpour AR (2012) Possible involvement of PPAR-gamma receptor and nitric oxide pathway in the anticonvulsant effect of acute pioglitazone on pentylenetetrazole-induced seizures in mice. Epilepsy Res 101:28–35

    Article  CAS  Google Scholar 

  35. Okada K, Yamashita U, Tsuji S (2006) Ameliorative effect of pioglitazone on seizure responses in genetically epilepsy-susceptible EL mice. Brain Res 1102:175–178

    Article  CAS  PubMed  Google Scholar 

  36. Vezzani A, French J, Bartfai T, Baram TZ (2011) The role of inflammation in epilepsy. Nat Rev Neurol 7:31–40

    Article  CAS  PubMed  Google Scholar 

  37. Marchi N, Fan Q, Ghosh C, Fazio V, Bertolini F, Betto G, Batra A, Carlton E et al (2009) Antagonism of peripheral inflammation reduces the severity of status epilepticus. Neurobiol Dis 33:171–181

    Article  CAS  PubMed  Google Scholar 

  38. Chawla A, Barak Y, Nagy L, Liao D, Tontonoz P, Evans RM (2001) PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat Med 7:48–52

    Article  CAS  PubMed  Google Scholar 

  39. Park EJ, Park SY, Joe E, Jou I (2003) 15d-PGJ2 and rosiglitazone suppress Janus kinase-STAT inflammatory signaling through induction of suppressor of cytokine signaling 1 (SOCS1) and SOCS3 in glia. J Biol Chem 278:14747–14752

    Article  CAS  PubMed  Google Scholar 

  40. Asano M, Nakajima T, Iwasawa K, Morita T, Nakamura F, Imuta H, Chisaki K, Yamada N et al (1999) Troglitazone and pioglitazone attenuate agonist-dependent Ca2+ mobilization and cell proliferation in vascular smooth muscle cells. Br J Pharmacol 128:673–683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhang F, Sowers JR, Ram JL, Standley PR, Peuler JD (1994) Effects of pioglitazone on calcium channels in vascular smooth muscle. Hypertension 24:170–175

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported in part by grants from the Taiwan National Science Council (NSC-102-2314-B-006-051-MY3), Ministry of Science and Technology, ROC, (105-2314-B-006-013, 106-2314-B-006-034, 106-2320-B-006-055, 107-2314-B-006-018, 107-2320-B-006-019), National Cheng Kung University Hospital (20180254), and Chi-Mei Medical Center (CMNCKU10303). Part of this abstract was presented at the Taiwan Neurological Society Annual Meeting, 2013.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Chi-Mei Medical Center, Tainan, Taiwan

    Te-Yu Hung

  2. Institute of Clinical Medicine, National Cheng Kung University College of Medicine, Tainan, Taiwan

    Fang-Liang Chu

  3. Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan

    Dong Chuan Wu

  4. Translational Medicine Research Center, China Medical University Hospital, Taichung, Taiwan

    Dong Chuan Wu

  5. Department of Physiology, National Cheng Kung University College of Medicine, Tainan, Taiwan

    Sheng-Nan Wu

  6. Department of Neurology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Chin-Wei Huang

Authors
  1. Te-Yu Hung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fang-Liang Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dong Chuan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sheng-Nan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chin-Wei Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chin-Wei Huang.

Ethics declarations

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hung, TY., Chu, FL., Wu, D.C. et al. The Protective Role of Peroxisome Proliferator-Activated Receptor-Gamma in Seizure and Neuronal Excitotoxicity. Mol Neurobiol 56, 5497–5506 (2019). https://doi.org/10.1007/s12035-018-1457-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-018-1457-2

Keywords

Search

Navigation