The Antiepileptic Drug Levetiracetam Protects Against Quinolinic Acid-Induced Toxicity in the Rat Striatum

Abstract

Levetiracetam (LVT) is a relatively novel antiepileptic drug (AED) known to act through binding with the synaptic vesicular 2A (SV2A) protein, thus modulating the presynaptic neurotransmitter release. The tryptophan metabolite quinolinic acid (QUIN) acts as an excitotoxin when its brain concentrations reach toxic levels under pathological conditions. Since increased neuronal excitability induced by QUIN recruits degenerative events in the brain, and novel AED is also expected to exert neuroprotective effects in their pharmacological profiles, in this work the effect of LVT (54 mg/kg, i.p., administered for seven consecutive days) was tested as a pretreatment against the toxicity evoked by the bilateral intrastriatal injection of QUIN (60 nmol/μl) to adult rats. QUIN increased the striatal levels of peroxidized lipids and carbonylated proteins as indexes of oxidative damage 24 h after its infusion. In addition, in synaptosomal fractions isolated from QUIN-lesioned rats 24 h after the toxin infusion, γ-aminobutyric acid (GABA) release was decreased, whereas glutamate (Glu) release was increased. QUIN also decreased motor activity and augmented the rate of cell damage at 7 days post-lesion. All these alterations were significantly prevented by pretreatment of rats with LVT. The results of this study show a neuroprotective role and antioxidant action of LVT against the brain damage induced by excitotoxic events.

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References

  1. Abdel-Wahab BA, Shaikh IA, Khateeb MM, Habeeb SM (2015) Omega 3 polyunsaturated fatty acids enhance the protective effect of levetiracetam against seizures, cognitive impairment and hippocampal oxidative DNA damage in young kindled rats. Pharmac Biochem Behav 135:105–113

    CAS  Article  Google Scholar 

  2. Bajjalieh SM, Frantz GD, Weimann JM, McConnell SK, Scheller RH (1994) Differential expression of synaptic vesicle protein 2 (SV2) isoforms. J Neurosci 14:5223–5235

    CAS  Article  PubMed  Google Scholar 

  3. Bannai S, Tateishi N (1986) Role of membrane transport in metabolism and function of glutathione in mammals. J Membr Biol 89:1–8

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  5. CINAPS Compound Dossiers (2017) Levetiracetam. National Institute of Neurological Disorders and Stroke, USA

    Google Scholar 

  6. Crowder KM, Gunther JM, Jones TA, Hale BD, Zhang HZ, Petersen MR, Scheller RH, Chavkin C, Bajjalieh SM (1999) Abnormal neurotransmission in mice lacking synaptic vesicle protein 2A (SV2A). PNAS (USA) 6:15268–15273

    Article  Google Scholar 

  7. de Tommaso M, Di Fruscolo O, Sciruicchio V, Specchio N, Cormio C, De Caro MF, Livrea P (2005) Efficacy of levetiracetam in Huntington disease. Clin Neuropharmacol 28:280–284

    Article  PubMed  Google Scholar 

  8. Dubovsky SL, Daurignac E, Leonard K, Serotte JC (2001) Levetiracetam, calcium antagonism, and bipolar disorder. Seizure 10:287–293

    Article  Google Scholar 

  9. El-Aal HAHMA (2012) Chapter 3: lipid peroxidation end-products as a key of oxidative stress: effect of antioxidant on their production and transfer of free radicals. In: Catala A (ed) Biochemistry, genetics and molecular biology “lipid peroxidation”. InTechOpen, Rijeka, pp 63–88

  10. Guillemin GJ (2012) Quinolinic acid: the inescapable neurotoxin. FEBS J 279:1356–1365

    CAS  Article  PubMed  Google Scholar 

  11. Hanon E, Klitgaard H (2001) Neuroprotective properties of the novel antiepileptic drug levetiracetam in the rat middle cerebral artery occlusion model of focal cerebral ischemia. Seizure 10:287–293

    CAS  Article  PubMed  Google Scholar 

  12. Harada S, Tanaka S, Takahashi Y, Matsumura H, Shimamoto C, Nakano T, Kuwabara H, Sawabe Y, Nakahari T (2013) Inhibition of Ca(2+)-regulated exocytosis by levetiracetam, a ligand for SV2A, in antral mucous cells of guinea pigs. Eur J Pharmacol 721:185–192

  13. Janz R, Goda Y, Geppert M, Missler M, Südhof TC (1999) SV2A and SV2B function as redundant Ca2+ regulators in neurotransmitter release. Neuron 24:1003–1016

    CAS  Article  PubMed  Google Scholar 

  14. Janz R, Südhof TC (1999) SV2C is a synaptic vesicle protein with an unusually restricted localization: anatomy of a synaptic vesicle protein family. Neuroscience 94:1279–1290

    CAS  Article  PubMed  Google Scholar 

  15. Jhamandas KH, Boegman RJ, Beninger RJ, Miranda AE, Lipic KA (2000) Excitotoxicity of quinolinic acid: modulation by endogenous antagonists. Neurotox Res 2:139–155

    CAS  Article  PubMed  Google Scholar 

  16. Lukyanetz EA, Shkryl VM, Kostyuk PG (2002) Selective blockade of N-type calcium channels by levetiracetam. Epilepsia 43:9–18

    CAS  Article  PubMed  Google Scholar 

  17. Marini H, Costa C, Passaniti M, Esposito M, Campo GM, Ientile R, Adamo EB, Marini R, Calabresi P, Altavilla D, Minutoli L, Pisani F, Squadrito F (2004) Levetiracetam protects against kainic acid-induced toxicity. Life Sci 74:1253–1264

    CAS  Article  PubMed  Google Scholar 

  18. Martínez-Flórez S, González-Gallego J, Culabras JM, Tuñón MJ (2002) Los flavonoides: propiedades y acciones antioxidantes. Nutr Hosp (Nutrición Hospitalaria), Madrid XVII: 271–278

  19. Mattson MP (2003) Excitotoxic and excitoprotective mechanisms: abundant targets for the prevention and treatment of neurodegenerative disorders. NeuroMolecular Med 3:65–94

    CAS  Article  PubMed  Google Scholar 

  20. 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 28:31–42

    CAS  Article  PubMed  Google Scholar 

  21. Miyazaki I, Murakami S, Torigoe N, Kitamura Y, Asanuma M (2016) Neuroprotective effects of levetiracetam target xCT in astrocytes in parkinsonian mice. J Neurochem 136:194–204

    CAS  Article  PubMed  Google Scholar 

  22. Oliveira AA, Almeida JP, Freitas RM, Nascimento VS, Aguiar LM, Júnior HV, Fonseca FN, Viana GS, Sousa FC, Fonteles MM (2007) Effects of levetiracetam in lipid peroxidation level, nitrite-nitrate formation and antioxidant enzymatic activity in mice brain after pilocarpine-induced seizures. Cell Mol Neurobiol 27:395–406

    CAS  Article  PubMed  Google Scholar 

  23. Patel SA, Warren BA, Rhoderick JF, Bridges RJ (2004) Differentiation of substrate and non-substrate inhibitors of transport system xc(−): an obligate exchanger of L-glutamate and L-cystine. Neuropharmacology 46:273–284

    CAS  Article  PubMed  Google Scholar 

  24. Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. USA. Academic Press Inc., San Diego

    Google Scholar 

  25. Pérez-De La Cruz V, Carrillo-Mora P, Santamaría A (2012) Quinolinic acid, an endogenous molecule combining excitotoxicity, oxidative stress and other toxic mechanisms. Int J Tryptophan Res 5:1–8

    PubMed  PubMed Central  Google Scholar 

  26. Pierozan P, Zamoner A, Soska AK, Silvestrin RB, Loureiro SO, Heimfarth L, Mello e Souza T, Wajner M, Pessoa-Pureur R (2010) Acute intrastriatal administration of quinolinic acid provokes hyperphosphorylation of cytoskeletal intermediate filament proteins in astrocytes and neurons of rats. Exp Neurol 224:188–196

    CAS  Article  PubMed  Google Scholar 

  27. Pyle RA, Schivell AE, Hidaka H, Bajjalieh SM (2000) Phosphorylation of synaptic vesicle protein 2 modulates binding to synaptotagmin. J Biol Chem 275:17195–17200

    CAS  Article  PubMed  Google Scholar 

  28. Rangel-López E, Colín-González AL, Paz-Loyola AL, Pinzón E, Torres I, Serratos IN, Castellanos P, Wajner M, Souza DO, Santamaría A (2015) Cannabinoid receptor agonists reduce the short-term mitochondrial dysfunction and oxidative stress linked to excitotoxicity in the rat brain. Neuroscience 285:97–106

    Article  PubMed  Google Scholar 

  29. Schwarcz R, Stone TW (2017) The kynurenine pathway and the brain: challenges, controversies and promises. Neuropharmacology 112:237–247

    CAS  Article  PubMed  Google Scholar 

  30. Silva-Adaya D, Pérez-De La Cruz V, Herrera-Mundo MN, Mendoza-Macedo K, Villeda-Hernández J, Binienda Z, Ali SF, Santamaría A (2008) Excitotoxic damage, disrupted energy metabolism, and oxidative stress in the rat brain: antioxidant and neuroprotective effects of L-carnitine. J Neurochem 105:677–689

    CAS  Article  PubMed  Google Scholar 

  31. Tavares RG, Tasca CI, Santos CE, Alves LB, Porciúncula LO, Emanuelli T, Souza DO (2002) Quinolinic acid stimulates synaptosomal glutamate release and inhibits glutamate uptake into astrocytes. Neurochem Int 40:621–627

    CAS  Article  PubMed  Google Scholar 

  32. Tobón-Velasco JC, Silva-Adaya D, Carmona-Aparicio L, García E, Galván-Arzate S, Santamaría A (2010) Early toxic effect of 6-hydroxydopamine on extracellular concentrations of neurotransmitters in the rat striatum: an in vivo microdialysis study. Neurotoxicology 31:715–723

    Article  PubMed  Google Scholar 

  33. Ueda Y, Doi T, Takaki M, Nagatomo K, Nakajima A, Willmore LJ (2009) Levetiracetam enhances endogenous antioxidant in the hippocampus of rats: in vivo evaluation by brain microdialysis combined with ESR spectroscopy. Brain Res 1266:1–7

    CAS  Article  PubMed  Google Scholar 

  34. Wang H, Gao J, Lassiter TF, McDonagh DL, Sheng H, Warner DS, Lynch JR, Laskowitz DT (2006) Levetiracetam is neuroprotective in murine models of closed head injury and subarachnoid hemorrhage. Neurocrit Care 5:71–78

    CAS  Article  PubMed  Google Scholar 

  35. Winden KD, Karsten SL, Bragin A, Kudo LC, Gehman L, Ruidera J, Geschwind DH, Engel J Jr (2011) A systems level, functional genomics analysis of chronic epilepsy. PLoS One 6:e20763

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Correspondence to Abel Santamaría.

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The experimental protocols were approved by the Ethics Committee of the INNN.

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Dircio-Bautista, M., Colín-González, A.L., Aguilera, G. et al. The Antiepileptic Drug Levetiracetam Protects Against Quinolinic Acid-Induced Toxicity in the Rat Striatum. Neurotox Res 33, 837–845 (2018). https://doi.org/10.1007/s12640-017-9836-4

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Keywords

  • Excitotoxicity
  • Neurotransmitter release
  • Oxidative damage
  • Motor alterations
  • Brain tissue damage
  • Antiepileptic drug