Skip to main content
SpringerLink
Log in

The Anti-Seizure Effect of Liraglutide on Ptz-Induced Convulsions Through its Anti-Oxidant and Anti-Inflammatory Properties

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Epilepsy is a prevalent and frequently devastating neurological disorder defined by recurring spontaneous seizures caused by aberrant electrical activity in the brain. Over ten million people worldwide suffer from drug-resistant epilepsy. This severe condition requires novel treatment approaches. Both oxidative and nitrosative stress are thought to have a role in the etiology of epilepsy. Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue that is used to treat type-2 diabetes mellitus. According to recent studies, Liraglutide also shows neuroprotective properties, improving memory retention and total hippocampus pyramidal neuronal population in mice. The purpose of this investigation was to determine the anti-seizure and anti-oxidative effects of liraglutide in a pentylenetetrazole (PTZ)-induced rat model of epilepsy. 48 rats were randomly assigned to two groups: those who had electroencephalography (EEG) recordings and those who underwent behavioral assessment. Rats received either intraperitoneal (IP) liraglutide at two different dosages (3–6 mg/kg) or a placebo, followed by pentylenetetrazole (IP). To determine if liraglutide has anti-seizure characteristics, we examined seizure activity in rats using EEG, the Racine convulsion scale (RCS), the time of first myoclonic jerk (FMJ), and MDA, SOD, TNF-α, IL-1β and GAD-67 levels. The mean EEG spike wave percentage score was reduced from 75.8% (placebo) to 59.4% (lower-dose) and 41.5% (higher-dose). FMJ had increased from a mean of 70.6 s (placebo) to 181.2 s (lower-dose) and 205.2 s (higher-dose). RCS was reduced from a mean of 5.5 (placebo) to 2.7 (lower-dose) and 2.4 (higher-dose). Liraglutide (3 and 6 mg/kg i.p.) successfully decreased the spike percentages and RCS associated with PTZ induced epilepsy, as well as considerably decreased MDA, TNF-α, IL-1β and elevated SOD, GAD-67 levels in rat brain. Liraglutide significantly decreased seizure activity at both dosages when compared to control, most likely due to its anti-oxidant and anti-inflammatory properties. The potential clinical role of liraglutide as an anti-seizure medication should be further explored.

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

Similar content being viewed by others

Data Availability

Enquiries about data availability should be directed to the authors.

References

  1. Mendez-Armenta M, Nava-Ruiz C, Juarez-Rebollar D, Rodriguez-Martinez E, Gomez PY (2014) Oxidative stress associated with neuronal apoptosis in experimental models of epilepsy. Oxid Med Cell Longev 2014:293689

    Article  Google Scholar 

  2. Ngugi AK, Bottomley C, Kleinschmidt I, Sander JW, Newton CR (2010) Estimation of the burden of active and life-time epilepsy: a meta-analytic approach. Epilepsia 51:883–890

    Article  Google Scholar 

  3. Avoli M et al (2002) Network and pharmacological mechanisms leading to epileptiform synchronization in the limbic system in vitro. Prog Neurobiol 68:167–207

    Article  CAS  Google Scholar 

  4. Aminoff MJ, Simon RP (1980) Status epilepticus: causes, clinical features and consequences in 98 patients. Am J Med 69(5):657–666

    Article  CAS  Google Scholar 

  5. Trinka E, Hofler J, Leitinger M, Brigo F (2015) Pharmacotherapy for status epilepticus. Drugs 75:1499–1521

    Article  CAS  Google Scholar 

  6. Fisher RS, van Emde Boas W, Blume W, Elger C, Genton P, Lee P, Engel J Jr (2005) Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 46:470–472

    Article  Google Scholar 

  7. Si PP, Zhen JL, Cai YL, Wang WJ, Wang WP (2016) Salidroside protects against kainic acid-induced status epilepticus via suppressing oxidative stress. Neurosci Lett 618:19–24

    Article  CAS  Google Scholar 

  8. Costa AM, Lucchi C, Malkoç A, Rustichelli C, Biagini G (2021) Relationship between delta rhythm, seizure occurrence and allopregnanolone hippocampal levels in epileptic rats exposed to the rebound effect. Pharmaceuticals 14(2):127

    Article  CAS  Google Scholar 

  9. Devinsky O, Vezzani A, Najjar S, De Lanerolle NC, Rogawski MA (2013) Glia and epilepsy: excitability and inflammation. Trends Neurosci 36:174–184

    Article  CAS  Google Scholar 

  10. Frantseva MV, Perez Velazquez JL, Tsoraklidis G (2000) Oxidative stress is involved in seizure–induced neurodegeneration in the kindling model of epilepsy. Neuroscience 97:431–435

    Article  CAS  Google Scholar 

  11. Gluck MR, Jayatilleke E, Shaw S, Rowan AJ, Haroutunian V (2000) CNS oxidative stress associated with the kainic acid rodent model of experimental epilepsy. Epilepsy Res 39:63–71

    Article  CAS  Google Scholar 

  12. Patsokis N, Zervoudakis G, Panagopoulos NT (2004) Thiol redox state (TRS) and oxidative stres in the mouse hippocampus after pentylenetetrazol-induced epileptic seizure. Neurosci Lett 357:83–86

    Article  Google Scholar 

  13. Patsokis NG, Zervoudakis C, Georgiou D (2004) Effect of pentylenetetrazol-induced epileptic seizure on thiol redox state in the mouse cerebral cortex. Epilepsy Res 62:65–74

    Article  Google Scholar 

  14. Atmaca M, Fry JR (1996) Adenosine-mediated inhibition of glutathione synthesis in rat isolated hepatocytes. Biochem Pharmocol 52:1423–1428

    Article  CAS  Google Scholar 

  15. Sudha K, Rao AV, Rao A (2001) Oxidative stress and antioxidants in epilepsy. Clin Chim Acta 303:19–24

    Article  CAS  Google Scholar 

  16. Oliver CN, Starke-Reed PE, Stadtman ER, Lin GJ, Correy JM, Floyd RA (1990) Oxidative damage to brain proteins, loss of glutamine synthetase activity and production of free radicals during ischemia/reperfusion induced injury to gerbil brain. Proc Natl Acad Sci USA 87:5144–5147

    Article  CAS  Google Scholar 

  17. Koshal P, Kumar P (2016) Neurochemical modulation involved in the beneficial effect of liraglutide, GLP-1 agonist on PTZ kindling epilepsy-induced comorbidities in mice. Mol Cell Biochem 415(1–2):77–87

    Article  CAS  Google Scholar 

  18. Knauf C, Cani PD, Kim D-H, Iglesias MA, Chabo C, Waget A et al (2008) Role of central nervous system glucagon-like peptide-1 receptors in enteric glucose sensing. Diabetes 57:2603–2612

    Article  CAS  Google Scholar 

  19. Yoshino Y, Ishisaka M, Tsujii S, Shimazawa M, Hara H (2015) Glucagon-like peptide-1 protects the murine hippocampus against stressors via Akt and ERK1/2 signaling. Biochem Biophys Res Commun 458:274–279

    Article  CAS  Google Scholar 

  20. During MJ, Cao L, Zuzga DS, Francis JS, Fitzsimons HL, Jiao X et al (2003) Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med 9:1173–1179

    Article  CAS  Google Scholar 

  21. Harkavyi A, Whitton PS (2010) Glucagon-like peptide 1 receptor stimulation as a means of neuroprotection. Br J Pharmacol 159:495–501

    Article  CAS  Google Scholar 

  22. Ladenheim EE (2015) Liraglutide and obesity: a review of the data so far. Drug Des Devel Ther 9:1867

    Article  CAS  Google Scholar 

  23. Hansen HH, Fabricius K, Barkholt P, Niehoff ML, Morley JE, Jelsing J et al (2015) The GLP-1 receptor agonist liraglutide improves memory function and increases hippocampal CA1 neuronal numbers in a senescence-accelerated mouse model of Alzheimer’s disease. J Alzheimers Dis 46(4):877–888

    Article  CAS  Google Scholar 

  24. Kim DI, Park SH (2015) Glucagon peptide-like 1 receptor (GLP-1R) expression per se: a new insight into neurodegenerative disease? Neural Regen Res 10(7):1055

    Article  CAS  Google Scholar 

  25. Holscher C (2014) The incretin hormones glucagonlike peptide 1 and glucose-dependent insulinotropic polypeptide are neuroprotective in mouse models of Alzheimer’s disease. Alzheimers Dement 10:S47-54

    Article  Google Scholar 

  26. Darsalia V, Mansouri S, Ortsater H, Olverling A, Nozadze N, Kappe C, Iverfeldt K, Tracy LM, Grankvist N, Sjoholm A, Patrone C (2012) Glucagon-like peptide-1 receptor activation reduces ischaemic brain damage following stroke in Type 2 diabetic rats. Clin Sci (Lond) 122:473–483

    Article  CAS  Google Scholar 

  27. Faivre E, Hölscher C (2013) Neuroprotective effects of D-Ala2GIP on Alzheimer’s disease biomarkers in an APP/PS1 mouse model. Alzheimers Res Ther 5:20

    Article  CAS  Google Scholar 

  28. Solmaz V, Çınar BP, Yiğittürk G, Çavuşoğlu T, Taşkıran D, Erbaş O (2015) Exenatide reduces TNF-α expression and improves hippocampal neuron numbers and memory in streptozotocin treated rats. Eur J Pharmacol 765:482–487

    Article  CAS  Google Scholar 

  29. Aksoy D, Solmaz V, Çavuşoğlu T, Meral A, Ateş U, Erbaş O (2017) Neuroprotective effects of eexenatide in a rotenone-induced rat model of Parkinson’s disease. Am J Med Sci 354(3):319–324

    Article  Google Scholar 

  30. Erdogan MA, Yusuf D, Christy J, Solmaz V, Erdogan A, Taskiran E, Erbas O (2018) Highly selective SGLT2 inhibitor dapagliflozin reduces seizure activity in pentylenetetrazol-induced murine model of epilepsy. BMC Neurol 18(1):1–8

    Article  Google Scholar 

  31. Erdogan A, Erdogan MA, Atasoy O et al (2021) Effects of the calcium channel blocker otilonium bromide on seizure activity in rats with pentylenetetrazole-induced convulsions. Neurochem Res 46:1717–1724. https://doi.org/10.1007/s11064-021-03310-4

    Article  CAS  Google Scholar 

  32. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72(1–2):248–254

    Article  CAS  Google Scholar 

  33. Genkova-Papazova M, Petkova B, Shishkova N, Lazarova-Bakarova M (2000) The GABA-B antagonist CGP 36742 prevent PTZ-kindling-provoked amnesia in rats. Eur Neuropsychopharmacol 10:273–278

    Article  CAS  Google Scholar 

  34. Agarwal NB, Agarwal NK, Mediratta PK, Sharma KK (2011) Effect of lamotrigine, oxcarbazepine and topiramate on cognitive functions and oxidative stress in PTZ-kindled mice. Seizure 20:257–262

    Article  Google Scholar 

  35. Gupta Y, Kumar MV, Srivastava A (2003) Effect of Centella asiatica on pentylenetetrazole-induced kindling, cognition and oxidative stress in rats. Pharmacol Biochem Behav 74:579–585

    Article  CAS  Google Scholar 

  36. Mehla J, Reeta K, Gupta P, Gupta YK (2010) Protective effect of curcumin against seizures and cognitive impairment in a pentylenetetrazole-kindled epileptic rat model. Life Sci 87:596–603

    Article  CAS  Google Scholar 

  37. Dhir A, Naidu PS, Kulkarni SK (2007) Neuroprotective effect of nimesulide, a preferential COX-2 inhibitor, against pentylenetetrazol (PTZ)-induced chemical kindling and associated biochemical parameters in mice. Seizure 16:691–697

    Article  Google Scholar 

  38. Sehar N, Agarwal NB, Vohora D, Raisuddin S (2015) Atorvastatin prevents development of kindling by modulating hippocampal levels of dopamine, glutamate, and GABA in mice. Epilepsy Behav 42:48–53

    Article  Google Scholar 

  39. Vezzani A, Ravizza T, Balosso S, Aronica E (2008) Glia as a source of cytokines: implications for neuronal excitability and survival. Epilepsia 49(Suppl 2):24–32

    Article  CAS  Google Scholar 

  40. Volterra A, Meldolesi J (2005) Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci 6:626–640

    Article  CAS  Google Scholar 

  41. Curia G, Lucchi C, Vinet J, Gualtieri F, Marinelli C, Torsello A, Biagini G (2014) Pathophysiogenesis of mesial temporal lobe epilepsy: is prevention of damage antiepileptogenic? Curr Med Chem 21(6):663–688

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  43. Vezzani A, Friedman A, Dingledine RJ (2013) The role of inflammation in epileptogenesis. Neuropharmacology 69:16–24

    Article  CAS  Google Scholar 

  44. Cardenas-Rodriguez N, Huerta-Gertrudis B, Rivera-Espinosa L, Montesinos-Correa H, Bandala C, Carmona-Aparicio L, Coballase-Urrutia E (2013) Role of oxidative stress in refractory epilepsy: evidence in patients and experimental models. Int J Mol Sci 14:1455–1476

    Article  Google Scholar 

  45. Shin EJ, Jeong JH, Chung YH, Kim WK, Ko KH, Bach JH, Hong JS, Yoneda Y, Kim HC (2011) Role of oxidative stress in epileptic seizures. Neurochem Int 59:122–137

    Article  CAS  Google Scholar 

  46. Chen SD, Chang AY, Chuang YC (2010) The potential role of mitochondrial dysfunction in seizure-associated cell death in the hippocampus and epileptogenesis. J Bioenerg Biomembr 42:461–465

    Article  CAS  Google Scholar 

  47. Viviani B, Bartesaghi S, Gardoni F, Vezzani A, Behrens MM, Bartfai T, Binaglia M, Corsini E, Di Luca M, Galli CL, Marinovich M (2003) Interleukin-1β Enhances NMDA Receptor-Mediated Intracellular Calcium Increase through Activation of the Src Family of Kinases. J Neurosci 23:8692–8700. https://doi.org/10.1523/JNEUROSCI.23-25-08692.2003

    Article  CAS  Google Scholar 

  48. Iwai T, Ito S, Tanimitsu K, Udagawa S, Oka JI (2006) Glucagon-like peptide-1 inhibits LPS-induced IL-1β production in cultured rat astrocytes. Neurosci Res 55(4):352–360

    Article  CAS  Google Scholar 

  49. Perry T, Haughey NJ, Mattson MP, Egan JM, Greig NH (2002) Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4. J Pharmacol Exp Ther 302:881–888

    Article  CAS  Google Scholar 

  50. Hamilton A, Holscher C (2009) Receptors for the incretin glucagon-like peptide-1 are expressed on neurons in the central nervous system. NeuroReport 20:1161–1166

    Article  CAS  Google Scholar 

  51. Abbas T, Faivre E, Ho¨lscher C, (2009) Impairment of synaptic plasticity and memory formation in GLP-1 receptor KO mice: interaction between type 2 diabetes and Alzheimer’s disease. Behav Brain Res 205:265–271

    Article  CAS  Google Scholar 

  52. Gilman CP, Perry T, Furukawa K, Grieg NH, Egan JM, Mattson MP (2003) Glucagon-like peptide 1 modulates calcium responses to glutamate and membrane depolarization in hippocampal neurons. J Neurochem 87:1137–1144

    Article  CAS  Google Scholar 

  53. Mazhar F, Malhi SM, Simjee SU (2017) Comparative studies on the effects of clinically used anticonvulsants on the oxidative stress biomarkers in pentylenetetrazole-induced kindling model of epileptogenesis in mice. J Basic Clin Physiol Pharmacol 28(1):31–42

    Article  CAS  Google Scholar 

  54. Jain S et al (2011) Anticonvulsant and antioxidant actions of trimetazidine in pentylenetetrazole-induced kindling model in mice, Naunyn. Schmiedebergs. Arch Pharmacol 383:385–392

    Article  CAS  Google Scholar 

  55. Korol SV, Jin Z, Babateen O, Birnir B (2015) GLP-1 and exendin-4 transiently enhance GABAA receptor-mediated synaptic and tonic currents in rat hippocampal CA3 pyramidal neurons. Diabetes 64:79–89

    Article  CAS  Google Scholar 

  56. Feldblum S, Ackermann RF, Tobin AJ (1990) Long term increase of glutamate decarboxylase mRNA in a rat model of temporal lobe epilepsy. Neuron 5(3):361–371

    Article  CAS  Google Scholar 

  57. Martin DL, Rimvall K (1993) Regulation of γ-aminobutyric acid synthesis in the brain. J Neurochem 60(2):395–407

    Article  CAS  Google Scholar 

  58. Najlerahim A, Harrison PJ, Barton AJL, Heffernan J, Pearson RCA (1990) Distribution of messenger RNAs encoding the enzymes glutaminase, aspartate aminotransferase and glutamic acid decarboxylase in rat brain. Mol Brain Res 7(4):317–333

    Article  CAS  Google Scholar 

  59. He X, Wang W, Ruan X, Li W, Zhang L (2002) Effects of antisense glutamic aciddecarboxylase oligodeoxynucleotide on epileptic rats induced by pentylenetetrazol. Chin Med J 115(03):425–429

    CAS  Google Scholar 

  60. Wang C, Mao R, Van De Casteele M, Pipeleers D, Ling Z (2007) Glucagon-like peptide-1 stimulates GABA formation by pancreatic β-cells at the level of glutamate decarboxylase. Am J Phy Endocrinol Metab 292(4):E1201–E1206

    Article  CAS  Google Scholar 

Download references

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or non-for-profit sectors.

Author information

Authors and Affiliations

  1. Department of Physiology, Faculty of Medicine, Izmir Katip Celebi University, Izmir, Turkey

    Mumin Alper Erdogan

  2. Department of Emergency Medicine, Izmir Bakırcay University Cigli Education and Research Hospital, Izmir, Turkey

    Arife Erdogan

  3. Department of Physiology, Faculty of Medicine, Istanbul Demiroglu Bilim University, Istanbul, Turkey

    Oytun Erbas

Authors
  1. Mumin Alper Erdogan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arife Erdogan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Oytun Erbas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mumin Alper Erdogan.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical Approval

The Animal Ethics Committee of Demiroglu Science University authorized the experimental procedures used in this study (Approval no: 13210223).

Additional information

Publisher's Note

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

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Erdogan, M.A., Erdogan, A. & Erbas, O. The Anti-Seizure Effect of Liraglutide on Ptz-Induced Convulsions Through its Anti-Oxidant and Anti-Inflammatory Properties. Neurochem Res 48, 188–195 (2023). https://doi.org/10.1007/s11064-022-03736-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-022-03736-4

Keywords

Search

Navigation