Abstract
The anticonvulsants that are currently available modulate the activity of neuronal receptors and ion channels, which are equally involved in apoptotic pathways. We investigated the hypothesis that gabapentin (GP), an anticonvulsant without effect on glutamate receptors acting as GABA analog, has neuroprotective properties. For comparison, we chose topiramate (TPM), which has been reported to be neuroprotective via AMPA receptors blockade. For this purpose, we used rat cerebellar granule neuron (CGN) cultures and we triggered apoptosis independent of glutamate receptors with staurosporine, a broad-spectrum protein kinase inhibitor. GP at therapeutic range concentration significantly increased cell viability in CGN cultures maintained in physiological KCl concentration and reversed apoptosis induced by staurosporine. Blockade of NMDA or AMPA receptors by MK801 or NBQX, respectively, did not alter GP neuroprotection, which was reversed instead by GABA. In contrast, protective effect of TPM on STS-treated CGN cultures was annihilated by NBQX, and not altered by MK801 or GABA. Treatments with neuroprotective concentrations of GP or TPM did not modify the expression of neuronal cell adhesion molecule or synaptophysin or the morphological aspect of neuronal endings. In summary, we report that GP is neuroprotective through glutamate-receptor independent mechanisms and without alteration of neuronal plasticity markers, which makes it a possible candidate for clinical neuroprotection trials.
[1] Bredesen D.E., Rao R.V., Mehlen P., Cell death in the nervous system, Nature, 2006, 443, 796–802 http://dx.doi.org/10.1038/nature0529310.1038/nature05293Search in Google Scholar PubMed PubMed Central
[2] Almeida A., Genetic determinants of neuronal vulnerability to apoptosis, Cell. Mol. Life Sci., 2013, 70, 71–88 http://dx.doi.org/10.1007/s00018-012-1029-y10.1007/s00018-012-1029-ySearch in Google Scholar PubMed
[3] Martinez-Vila E., Irimia P., The cost of stroke, Cerebrovasc. Dis., 2004, 17Suppl. 1, 124–129 http://dx.doi.org/10.1159/00007480410.1159/000074804Search in Google Scholar PubMed
[4] Muresanu D.F., Buzoianu A., Florian S.I., von Wild T., Towards a roadmap in brain protection and recovery, J. Cell. Mol. Med., 2012, 16, 2861–2871 http://dx.doi.org/10.1111/j.1582-4934.2012.01605.x10.1111/j.1582-4934.2012.01605.xSearch in Google Scholar PubMed PubMed Central
[5] Rahn K.A., Slusher B.S., Kaplin A.I., Glutamate in CNS neurodegeneration and cognition and its regulation by GCPII inhibition, Curr. Med. Chem., 2012, 19, 1335–1345 http://dx.doi.org/10.2174/09298671279946264910.2174/092986712799462649Search in Google Scholar PubMed
[6] Johannessen Landmark C., Antiepileptic drugs in non-epilepsy disorders: relations between mechanisms of action and clinical efficacy, CNS Drugs, 2008, 22, 27–47 http://dx.doi.org/10.2165/00023210-200822010-0000310.2165/00023210-200822010-00003Search in Google Scholar PubMed
[7] Pitkänen A., Kubova H., Antiepileptic drugs in neuroprotection, Expert Opin. Pharmacother., 2004, 5, 777–798 http://dx.doi.org/10.1517/14656566.5.4.77710.1517/14656566.5.4.777Search in Google Scholar PubMed
[8] Latini G., Verrotti A., Manco R., Scardapane A., Del Vecchio A., Chiarelli F., Topiramate: its pharmacological properties and therapeutic efficacy in epilepsy, Mini Rev. Med. Chem., 2008, 8, 10–23 http://dx.doi.org/10.2174/13895570878333156810.2174/138955708783331568Search in Google Scholar PubMed
[9] Sills G.J., The mechanisms of action of gabapentin and pregabalin, Curr. Opin. Pharmacol., 2006, 6, 108–113 http://dx.doi.org/10.1016/j.coph.2005.11.00310.1016/j.coph.2005.11.003Search in Google Scholar PubMed
[10] Thorpe A.J., Offord J., The alpha2-delta protein: an auxiliary subunit of voltage-dependent calcium channels as a recognized drug target, Curr. Opin. Investig. Drugs, 2010, 11, 761–770 Search in Google Scholar
[11] Lagrèze W.A., Müller-Velten R., Feurstein T.J., The neuroprotective properties of gabapentin-lactam, Graef. Arch. Clin. Exp. Ophthalmol., 2001, 239, 845–849 http://dx.doi.org/10.1007/s00417-001-0383-510.1007/s00417-001-0383-5Search in Google Scholar PubMed
[12] Pitkänen A., Efficacy of current antiepileptics to prevent neurodegeneration in epilepsy models, Epilepsy Res., 2002, 50, 141–160 http://dx.doi.org/10.1016/S0920-1211(02)00076-110.1016/S0920-1211(02)00076-1Search in Google Scholar
[13] Trojnar M.K., Malek R., Chroscinska M., Nowak S., Blaszczyk B., Czuczwar S.J., Neuroprotective effects of antiepileptic drugs, Pol. J. Pharmacol., 2002, 54, 557–566 Search in Google Scholar
[14] Baydas G., Sonkaya E., Tuzcu M., Yasar A., Donder E., Novel role for gabapentin in neuroprotection of central nervous system in streptozotocine-induced diabetic rats, Acta Pharmacol. Sin., 2005, 26, 417–422 http://dx.doi.org/10.1111/j.1745-7254.2005.00072.x10.1111/j.1745-7254.2005.00072.xSearch in Google Scholar
[15] Kale A., Börcek A.Ö., Emmez H., Yildirim Z., Durdağ E., Lortlar N., et al., Neuroprotective effects of gabapentin on spinal cord ischemiareperfusion injury in rabbits, J. Neurosurg. Spine, 2011, 15, 228–237 http://dx.doi.org/10.3171/2011.4.SPINE1058310.3171/2011.4.SPINE10583Search in Google Scholar
[16] Rekling J.C., Neuroprotective effects of anticonvulsants in rat hippocampal slice cultures exposed to oxygen/glucose deprivation, Neurosci. Lett., 2003, 335, 167–170 http://dx.doi.org/10.1016/S0304-3940(02)01193-X10.1016/S0304-3940(02)01193-XSearch in Google Scholar
[17] Williams A.J., Bautista C.C., Chen R.W., Dave J.R., Lu X.C., Tortella F.C., et al., Evaluation of gabapentin and ethosuximide for treatment of acute nonconvulsive seizures following ischemic brain injury in rats, J. Pharmacol. Exp. Ther., 2006, 318, 947–955 http://dx.doi.org/10.1124/jpet.106.10599910.1124/jpet.106.105999Search in Google Scholar PubMed
[18] Frisch C., Kudin A.P., Elger C.E., Kunz W.S., Helmstaedter C., Amelioration of water maze performance deficits by topiramate applied during pilocarpine-induced status epilepticus is negatively dose-dependent, Epilepsy Res., 2006, 73, 173–180 http://dx.doi.org/10.1016/j.eplepsyres.2006.10.00110.1016/j.eplepsyres.2006.10.001Search in Google Scholar PubMed
[19] Francois J., Koning E., Ferrandon A., Nehlig A., The combination of topiramate and diazepam is partially neuroprotective in the hippocampus but not antiepileptogenic in the lithium-pilocarpine model of temporal lobe epilepsy, Epilepsy Res., 2006, 72, 147–163 http://dx.doi.org/10.1016/j.eplepsyres.2006.07.01410.1016/j.eplepsyres.2006.07.014Search in Google Scholar PubMed
[20] Schubert S., Brandl U., Brodhun M., Ulrich C., Spaltmann J., Fiedler N., et al., Neuroprotective effects of topiramate after hypoxia-ischemia in newborn piglets, Brain Res., 2005, 1058, 129–136 http://dx.doi.org/10.1016/j.brainres.2005.07.06110.1016/j.brainres.2005.07.061Search in Google Scholar PubMed
[21] Costa C., Martella G., Picconi B., Prosperetti C., Pisani A., Di Filippo M., et al., Multiple mechanisms underlying the neuroprotective effects of antiepileptic drugs against in vitro ischemia, Stroke, 2006, 37, 1319–1326 http://dx.doi.org/10.1161/01.STR.0000217303.22856.3810.1161/01.STR.0000217303.22856.38Search in Google Scholar PubMed
[22] Contestabile A., Cerebellar granule cells as a model to study mechanisms of neuronal apoptosis or survival in vivo and in vitro, Cerebellum, 2002, 1, 41–55 http://dx.doi.org/10.1080/14734220275320308710.1080/147342202753203087Search in Google Scholar PubMed
[23] Koh J.Y., Wie M.B., Gwag B.J., Sensi S.L., Canzoniero L.M., Demaro J., et al., Staurosporine-induced neuronal apoptosis, Exp. Neurol., 1995, 135, 153–159 http://dx.doi.org/10.1006/exnr.1995.107410.1006/exnr.1995.1074Search in Google Scholar
[24] Follett P.L., Deng W., Dai W., Talos D.M., Massillon L.J., Rosenberg P.A., et al., Glutamate receptor-mediated oligodendrocyte toxicity in periventricular leukomalacia: a protective role for topiramate, J. Neurosci., 2004, 24, 4412–4420 http://dx.doi.org/10.1523/JNEUROSCI.0477-04.200410.1523/JNEUROSCI.0477-04.2004Search in Google Scholar
[25] Gerrow K., El-Husseini A., Cell adhesion molecules at the synapse, Front. Biosci., 2006, 11, 2400–2419 http://dx.doi.org/10.2741/197810.2741/1978Search in Google Scholar
[26] Rao J.S., Kellom M., Kim H.W., Rapoport S.I., Reese E.A., Neuroinflammation and synaptic loss, Neurochem. Res., 2012, 37, 903–910 http://dx.doi.org/10.1007/s11064-012-0708-210.1007/s11064-012-0708-2Search in Google Scholar
[27] Popescu A.T., Vidulescu C., Stanciu C.L., Popescu B.O., Popescu L.M., Selective protection by phosphatidic acid against staurosporineinduced apoptosis, J. Cell. Mol. Med., 2002, 6, 433–438 http://dx.doi.org/10.1111/j.1582-4934.2002.tb00523.x10.1111/j.1582-4934.2002.tb00523.xSearch in Google Scholar
[28] Gatti G., Ferrari A.R, Guerrini R., Bonanni P., Bonomi I., Perucca E., Plasma gabapentin concentrations in children with epilepsy: influence of age, relationship with dosage, and preliminary observations on correlation with clinical response, Ther. Drug Monit., 2003, 25, 54–60 http://dx.doi.org/10.1097/00007691-200302000-0000810.1097/00007691-200302000-00008Search in Google Scholar
[29] Ferrari A.R., Guerrini R., Gatti G., Alessandri M.G., Bonanni P., Perucca E., Influence of dosage, age, and co-medication on plasma topiramate concentrations in children and adults with severe epilepsy and preliminary observations on correlations with clinical response, Ther. Drug Monit., 2003, 25, 700–708 http://dx.doi.org/10.1097/00007691-200312000-0000810.1097/00007691-200312000-00008Search in Google Scholar
[30] Mosmann T., Rapid colorimetric assay for cellular growth and survival: application to proliferation and citotoxicity assays, J. Immunol. Methods, 1983, 65, 55–63 http://dx.doi.org/10.1016/0022-1759(83)90303-410.1016/0022-1759(83)90303-4Search in Google Scholar
[31] Grayson D.R., Zhu W., Harris B.T., Vicini S., Zheng T., Differentially expressed GABAA-receptor subunits result in structurally and functionally receptor assemblies following excitatory afferent synaptic transmission, Perspect. Dev. Neurobiol., 1998, 5, 193–205 Search in Google Scholar
[32] Gallo V., Kingsbury A., Balázs R., Jørgensen O.S., The role of depolarization in the survival and differentiation of cerebellar granule cells in culture, J. Neurosci., 1987, 7, 2203–2213 10.1523/JNEUROSCI.07-07-02203.1987Search in Google Scholar
[33] Franco-Cea A., Valencia A., Sánchez-Armass S., Domínguez G., Morán J., Role of ionic fluxes in the apoptotic cell death of cultured cerebellar granule neurons, Neurochem. Res., 2004, 29, 227–238 http://dx.doi.org/10.1023/B:NERE.0000010501.25627.0f10.1023/B:NERE.0000010501.25627.0fSearch in Google Scholar
[34] Prehn J.H., Jordán J., Ghadge G.D., Preis E., Galindo M.F., Roos R.P., et al., Ca2+ and reactive oxygen species in staurosporine-induced neuronal apoptosis, J. Neurochem., 1997, 68, 1679–1685 http://dx.doi.org/10.1046/j.1471-4159.1997.68041679.x10.1046/j.1471-4159.1997.68041679.xSearch in Google Scholar
[35] Paoletti P., Bellone C., Zhou Q., NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease, Nat. Rev. Neurosci., 2013, 14, 383–400 http://dx.doi.org/10.1038/nrn350410.1038/nrn3504Search in Google Scholar
[36] Monaco E.A., Vallano M.L., Roscovitine triggers excitotoxicity in cultured granule neurons by enhancing glutamate release, Mol. Pharmacol., 2005, 68, 1331–1342 http://dx.doi.org/10.1124/mol.105.01273210.1124/mol.105.012732Search in Google Scholar
[37] Ikonomovic S., Kharlamov E., Manev H., Ikonomovic M.D., Grayson D.R., GABA and NMDA in the prevention of apoptotic-like cell death in vitro, Neurochem. Int., 1997, 31, 283–290 http://dx.doi.org/10.1016/S0197-0186(96)00159-310.1016/S0197-0186(96)00159-3Search in Google Scholar
[38] Babot Z., Cristòfol R., Suñol C., Excitotoxic death induced by released glutamate in depolarized primary cultures of mouse cerebellar granule cells is dependent on GABAA receptors and niflumic acidsensitive chloride channels, Eur. J. Neurosci., 2005, 21, 103–112 http://dx.doi.org/10.1111/j.1460-9568.2004.03848.x10.1111/j.1460-9568.2004.03848.xSearch in Google Scholar PubMed
[39] Borodinsky L.N., O’Leary D., Neale J.H., Vicini S., Coso O.A., Fiszman M.L., GABA-induced neurite outgrowth of cerebellar granule cells is mediated by GABA(A) receptor activation, calcium influx and CaMKII and erk1/2 pathways, J. Neurochem., 2003, 84, 1411–1420 http://dx.doi.org/10.1046/j.1471-4159.2003.01638.x10.1046/j.1471-4159.2003.01638.xSearch in Google Scholar PubMed
[40] Mirnics Z.K., Yan C., Portugal C., Kim T.W., Saragovi H.U., Sisodia S.S., et al., P75 neurotrophin receptor regulates expression of neural cell adhesion molecule 1, Neurobiol. Dis., 2005, 20, 969–985 http://dx.doi.org/10.1016/j.nbd.2005.06.00410.1016/j.nbd.2005.06.004Search in Google Scholar PubMed
[41] Kolkova K., Stensman H., Berezin V., Bock E., Larsson C., Distinct roles of PKC isoforms in NCAM-mediated neurite outgrowth, J. Neurochem., 2005, 92, 886–894 http://dx.doi.org/10.1111/j.1471-4159.2004.02919.x10.1111/j.1471-4159.2004.02919.xSearch in Google Scholar PubMed
[42] Seidenfaden R., Krauter A., Hildebrandt H., The neural cell adhesion molecule NCAM regulates neuritogenesis by multiple mechanisms of interaction, Neurochem. Int., 2006, 49, 1–11 http://dx.doi.org/10.1016/j.neuint.2005.12.01110.1016/j.neuint.2005.12.011Search in Google Scholar PubMed
[43] Conboy L., Foley A.G., O’Boyle N.M., Lawlor M., Gallagher H.C., Murphy K.J., et al., Curcumin-induced degradation of PKC delta is associated with enhanced dentate NCAM PSA expression and spatial learning in adult and aged Wistar rats Biochem. Pharmacol., 2009, 77, 1254–1265 10.1016/j.bcp.2008.12.011Search in Google Scholar PubMed
[44] Tariot P.N., Loy R., Ryan J.M., Porsteinsson A., Ismail S., Mood stabilizers in Alzheimer’s disease: symptomatic and neuroprotective rationales, Adv. Drug Deliv. Rev., 2002, 54, 1567–1577 http://dx.doi.org/10.1016/S0169-409X(02)00153-910.1016/S0169-409X(02)00153-9Search in Google Scholar
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