The neuroprotective effect of lamotrigine against glutamate excitotoxicity in SH-SY5Y human neuroblastoma cells

Year 2020, Volume: 33 Issue: 3, 146 - 152, 23.10.2020

Berna Terzıoglu Bebıtoglu Elif Oguz Nazife Gokce Acet Ajla Hodzıc Fatime Temel Saniye Ada Andac Kılıckap

https://doi.org/10.5472/marumj.816319

Cited By: 3

Abstract

Objective: Glutamate-induced excitotoxicity has a role in the pathophysiology of neurodegenerative disorders. Lamotrigine, an
antiepileptic drug, also used to treat bipolar disorders, may be protective against excitotoxic insult. The aim of the study was to
investigate the neuroprotective effect of lamotrigine against the glutamate excitotoxicity in SH-SY5Y cell line.
Materials and Methods: SH-SY5Y human neuroblastoma cells were pre-treated with lamotrigine (50-100-150 μM) prior to exposure
to 15 mM glutamate. The 3-(4,5-dimethythiazol – 2-yl)-2,5 – diphenyl tetrazolium bromide (MTT) assay was performed to determine
cell viability. The anti-oxidant effect of lamotrigine and the role of inflammatory parameters were determined by measuring superoxide
dismutase (SOD), hydrogen peroxide (H2O2), IL-1β, IL-6 and TNF-α.
Results: Intracellular calcium levels and lactate dehydrogenase (LDH) activity increased in glutamate exposed cells. Pre-treatment of
cells with MK-801 showed no protective features against glutamate excitotoxicity. Treatment with 100 μM lamotrigine was effective
in increasing the viability of glutamate exposed cells and in reducing H2O2 increase in these cells. The SOD activity increased by
lamotrigine treated cells exposed to glutamate. IL-1β, IL-6 and TNF-α levels increased after induction with glutamate and attenuated
by lamotrigine.
Conclusion: Overall, our results confirmed the critical role of inflammation and oxidative stress in glutamate-induced excitotoxicity
and lamotrigine may exert a protective effect.
Keywords: Lamotrigine, Glutamate excitotoxicity,

Keywords

Lamotrigine, Glutamate excitotoxicity, SH-SY5Y, Oxidative stress parameter, Cytokines, MK-801

References

• Bhagwagar Z, Goodwin GM. Lamotrigine in the treatment of bipolar disorder. Expert Opin Pharmacother 2005;6:1401-8. doi:10.1517/14656566.6.8.1401
• Bowden CL. Acute and maintenance treatment with mood stabilizers. Int J Neuropsychopharmacol 2003;6:269-75. doi:10.1017/S146.114.5703003535
• Cook AM, Bensalem-Owen MK. Mechanisms of action of antiepileptic drugs. Therapy 2011;8:307-13
• Mantegazza M, Curia G, Biagini G, Ragsdale DS, Avoli M. Voltage-gated sodium channels as therapeutic targets in epilepsy and other neurological disorders. Lancet Neurol 2010;9:413-24. doi: 10.1016/S1474-4422(10)70059-4
• Rothman SM, Olney JW. Glutamate and the pathophysiology of hypoxic—ischemic brain damage. Ann Neurol 1986;19:105- 11.
• Bleich S, Romer K, Wiltfang J, Kornhuber J. Glutamate and the glutamate receptor system: a target for drug action. Int J Geriatr Psychiatry 2003;18(Suppl 1):S33-40.
• Halonen T, Nissinen J, Pitkänen A. Effect of lamotrigine treatment on status epilepticus-induced neuronal damage and memory impairment in rat. Epilepsy Res 2001;46: 205-23. doi: 10.1016/s0920-1211(01)00278-9.
• Calabresi P, Picconi B, Saulle E, Centonze D, Hainsworth AH, Bernardi G. Is pharmacological neuroprotection dependent on reduced glutamate release? Stroke 2000;31:766-72. doi: 10.1161/01.str.31.3.766
• Papazisis G, Kallaras K, Kaiki-Astara A, et al. Neuroprotection by lamotrigine in a rat model of neonatal hypoxic–ischaemic encephalopathy. Int J Neuropsychopharmacol 2008;11:321-9. doi: 10.1017/S146.114.5707008012.
• Belov Kirdajova D, Kriska J, Tureckova J, Anderova M. Ischemia-triggered glutamate excitotoxicity from the perspective of glial cells. Front Cell Neurosci 2020;14:51. doi:10.3389/fncel.2020.00051.
• Chen WW, Zhang X, Huang WJ. Role of neuroinflammation in neurodegenerative diseases (Review). Mol Med Rep 2016;13:3391-96. doi:10.3892/mmr.2016.4948
• Ward RJ, Dexter DT, Crichton RR. Ageing, neuroinflammation and neurodegeneration. Front Biosci (Schol Ed) 2015;7:189- 204.
• Walker MC, Tong X, Perry H, Alavijeh MS, Patsalos PN. Comparison of serum, cerebrospinal fluid and brain extracellular fluid pharmacokinetics of lamotrigine. Br J Pharmacol 2000;130:242–48. doi:10.1038/sj.bjp.0703337
• Leng Y, Fessler EB, Chuang DM. Neuroprotective effects of the mood stabilizer lamotrigine against glutamate excitotoxicity: Roles of chromatin remodelling and Bcl-2 induction. Int J Neuropsychopharmacol 2013;16:607-20. doi:10.1017/ S146.114.5712000429.
• Johannessen SI, Battino D, Berry DJ, et al. Therapeutic drug monitoring of the newer antiepileptic drugs. Ther Drug Monit 2003;25:347-63. doi:10.1097/00007.691.200306000-00016
• Naarala J, Nykvist P, Tuomala M, Savolainen K. Excitatory amino acid-induced slow biphasic responses of free intracellular calcium in human neuroblastoma cells. FEBS Lett 1993;330:222-6. doi:10.1016/0014-5793(93)80278-3.
• Nair VD, Niznik HB, Mishra RK. Interaction of NMDA and dopamine D2 receptors in human neuroblastoma SH-SY5Ycells. J. Neurochem 1996;66:2390-93. doi:10.1046/j.1471-4159.1996.660.62390.
• Sun ZW, Zhang L, Zhu SJ, Chen WC, Mei B. Excitotoxicity effects of glutamate on human neuroblastoma SH-SY5Y cells via oxidative damage. Neurosci Bull 2010;26:8-16. doi:10.1007/ s12264.010.0813-7
• Xie HR, Hu LS, Li GY. SH-SY5Y human neuroblastoma cell line: in vitro cell model of dopaminergic neurons in Parkinson’s disease. Chin Med J (Engl) 2010;123:1086-92.
• Hanada T. Ionotropic glutamate receptors in epilepsy: A review focusing on AMPA and NMDA receptors. Biomolecules 2020;10(3):464:1-22. doi:10.3390/biom10030464
• Schubert D, Piasecki D. Oxidative glutamate toxicity can be a component of the excitotoxicity cascade. J Neurosci 2001;21:7455-62. doi:10.1523/JNEUROSCI.21-19-07455.2001
• Gudiño-Cabrera G, Ureña-Guerrero ME, Rivera-Cervantes MC, Feria-Velasco AI, Beas-Zárate C. Excitotoxicity triggered by neonatal monosodium glutamate treatment and bloodbrain barrier function. Arch Med Res 2014;45:653-9. doi:10.1016/j.arcmed.2014.11.014
• Parpura V, Grubišić V, Verkhratsky A. Ca(2+) sources for the exocytotic release of glutamate from astrocytes. Biochim Biophys Acta 2011;1813:984-91. doi:10.1016/j. bbamcr.2010.11.006
• Hamadi A, Giannone G, Takeda K, Rondé P. Glutamate involvement in calcium-dependent migration of astrocytoma cells. Cancer Cell Int 2014;14:42. doi:10.1186/1475-2867-14- 42
• Friedman LK. Calcium: a role for neuroprotection and sustained adaptation. Mol Interv 2006;6:315-29. doi:10.1124/ mi.6.6.5
• Choi DW. Glutamate neurotoxicity in cortical cell culture is calcium dependent. Neurosci Lett 1985;58:293-7. doi:10.1016/0304-3940(85)90069-2
• Von Wegerer J, Hesslinger B, Berger M, Walden J. A calcium antagonistic effect of the new antiepileptic drug lamotrigine. Eur Neuropsychopharmacol 1997;7:77-81. doi:10.1016/s0924- 977x(96)00384-7
• Song JH, Kang KS, Choi YK. Protective effect of casuarinin against glutamate-induced apoptosis in HT22 cells through inhibition of oxidative stress-mediated MAPK phosphorylation. Bioorg Med Chem Lett 2017;27:5109-13. doi:10.1016/j.bmcl.2017.10.075
• Sies H. Hydrogen peroxide as a central redox signaling molecule in physiological oxidative stress: Oxidative eustress. Redox Biol 2017;11:613-19. doi:10.1016/j.redox.2016.12.035
• Ha JS, Lim HM, Park SS. Extracellular hydrogen peroxide contributes to oxidative glutamate toxicity. Brain Res 2010;1359:291-97. doi:10.1016/j.brainres.2010.08.086
• Lobysheva NV, Selin AA, Vangeli IM, Byvshev IM, Yaguzhinsky LS, Nartsissov YR. Glutamate induces H2O2 synthesis in nonsynaptic brain mitochondria. Free Radic Biol Med 2013;65:428-35. doi:10.1016/j.freeradbiomed.2013.07.030
• Lee HJ, Spandidos DA, Tsatsakis A, Margina D, Izotov BN, Yang SH. Neuroprotective effects of Scrophularia buergeriana extract against glutamate-induced toxicity in SH-SY5Y cells. Int J Mol Med 2019;43:2144-52. doi:10.3892/ijmm.2019.4139
• He L, He T, Farrar S, Ji L, Liu T, Ma X. Antioxidants maintain cellular redox homeostasis by elimination of reactive oxygen species. Cell Physiol Biochem 2017;44:532-53. doi:10.1159/000485089
• Kasperczyk S, Birkner E, Kasperczyk A, Zalejska-Fiolka J. Activity of superoxide dismutase and catalase in people protractedly exposed to lead compounds. Ann Agric Environ Med 2004;11:291-96.
• Kamal SM. Possible anti-oxidant effect of lamotrigine in nucleus accumbens of mice exposed to picrotoxin. J Neurol Disord 2013;1:108:1-5 doi: 10.4172/2329-6895.100.0108
• Eren I, Naziroğlu M, Demirdaş A. Protective effects of lamotrigine, aripiprazole and escitalopram on depressioninduced oxidative stress in rat brain. Neurochem Res. 2007;32:1188-95. doi:10.1007/s11064.007.9289-x
• Xu J, Wu W, Zhang H, Yang L. Berberine alleviates amyloid β25- 35-induced inflammatory response in human neuroblastoma cells by inhibiting proinflammatory factors. Exp Ther Med 2018;16:4865-72. doi:10.3892/etm.2018.6749
• Li N, Song J, Kong L, et al. Neuroprotection of TSG against mechanical trauma injury through an anti-inflammatory mechanism in human neuroblastoma SH-SY5Y cells. Int J Pharmacol 2016;12:789-800. doi:10.3923/ijp.2016.789.800
• Teeling JL, Perry VH. Systemic infection and inflammation in acute CNS injury and chronic neurodegeneration: underlying mechanisms. Neuroscience 2009;158:1062-73. doi:10.1016/j. neuroscience.2008.07.031
• Rosales-Corral S, Reiter RJ, Tan DX, Ortiz GG, Lopez- Armas G. Functional aspects of redox control during neuroinflammation. Antioxid Redox Signal 2010;13:193-247. doi:10.1089/ars.2009.2629
• Abu-Rish EY, Elhayek SY, Mohamed YS, Hamad I, Bustanji Y. Evaluation of immunomodulatory effects of lamotrigine in BALB/c mice. Acta Pharm 2017;67:543-55. doi:10.1515/acph- 2017-0035
• Abu-Rish EY, Dahabiyeh LA, Bustanji Y, Mohamed YS, Browning MJ. Effect of lamotrigine on in vivo and in vitro cytokine secretion in murine model of inflammation. J Neuroimmunol 2018;322:36-45. doi:10.1016/j.jneuroim.2018.06.008
• Himmerich H, Bartsch S, Hamer H, et al. Impact of mood stabilizers and antiepileptic drugs on cytokine production in-vitro. J Psychiatr Res 2013;47:1751-59. doi:10.1016/j. jpsychires.2013.07.026
• Himmerich H, Bartsch S, Hamer H, et al. Modulation of cytokine production by drugs with antiepileptic or mood stabilizer properties in anti-CD3 – and anti-Cd40-stimulated blood in vitro. Oxid Med Cell Longev 2014;2014:806162. doi:10.1155/2014/806162