Generic placeholder image

CNS & Neurological Disorders - Drug Targets


ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Research Article

Topiramate Decelerates Bicarbonate-Driven Acid-Elimination of Human Neocortical Neurons: Strategic Significance for its Antiepileptic, Antimigraine and Neuroprotective Properties

Author(s): Udo Bonnet* and Martin Wiemann

Volume 19 , Issue 4 , 2020

Page: [264 - 275] Pages: 12

DOI: 10.2174/1871527319666200604173208

Price: $65


Background: Mammalian central neurons regulate their intracellular pH (pHi) strongly and even slight pHi-fluctuations can influence inter-/intracellular signaling, synaptic plasticity and excitability.

Objective: For the first time, we investigated topiramate´s (TPM) influence on pHi-behavior of human central neurons representing a promising target for anticonvulsants and antimigraine drugs.

Methods: In slice-preparations of tissue resected from the middle temporal gyrus of five adults with intractable temporal lobe epilepsy, BCECF-AM-loaded neocortical pyramidal-cells were investigated by fluorometry. The pHi-regulation was estimated by using the recovery-slope from intracellular acidification after an Ammonium-Prepulse (APP).

Results: Among 17 pyramidal neurons exposed to 50 μM TPM, seven (41.24%) responded with an altered resting-pHi (7.02±0.12), i.e., acidification of 0.01-0.03 pH-units. The more alkaline the neurons, the greater the TPM-related acidifications (r=0.7, p=0.001, n=17). The recovery from APPacidification was significantly slowed under TPM (p<0.001, n=5). Further experiments using nominal bicarbonate-free (n=2) and chloride-free (n=2) conditions pointed to a modulation of the HCO3 -- driven pHi-regulation by TPM, favoring a stimulation of the passive Cl-/HCO3 --antiporter (CBT) - an acid-loader predominantly in more alkaline neurons.

Conclusion: TPM modulated the bicarbonate-driven pHi-regulation, just as previously described in adult guinea-pig hippocampal neurons. We discussed the significance of the resulting subtle acidifications for beneficial antiepileptic, antimigraine and neuroprotective effects as well as for unwanted cognitive deficits.

Keywords: Anticonvulsants, epilepsy, transporters, excitability, cognition, neuroprotection.

Graphical Abstract
Landmark CJ. Targets for antiepileptic drugs in the synapse. Med Sci Monit 2007; 13(1): RA1-7.
[PMID: 17179916]
Spritzer SD, Bravo TP, Drazkowski JF. Topiramate for treatment in patients with migraine and epilepsy. Headache 2016; 56(6): 1081-5.
[] [PMID: 27122361]
Sommer BR, Mitchell EL, Wroolie TE. Topiramate: effects on cognition in patients with epilepsy, migraine headache and obesity. Ther Adv Neurol Disord 2013; 6(4): 211-7.
Iyengar S, Johnson KW, Ossipov MH, Aurora SK. CGRP and the trigeminal system in migraine. Headache 2019; 59(5): 659-81.
[] [PMID: 30982963]
Kudin AP, Debska-Vielhaber G, Vielhaber S, Elger CE, Kunz WS. The mechanism of neuroprotection by topiramate in an animal model of epilepsy. Epilepsia 2004; 45(12): 1478-87.
[] [PMID: 15571505]
Dodgson SJ, Shank RP, Maryanoff BE. Topiramate as an inhibitor of carbonic anhydrase isoenzymes. Epilepsia 2000; 41(Suppl. 1): S35-9.
[] [PMID: 10768298]
Herrero AI, Del Olmo N, González-Escalada JR, Solís JM. Two new actions of topiramate: inhibition of depolarizing GABA(A)-mediated responses and activation of a potassium conductance. Neuropharmacology 2002; 42(2): 210-20.
[] [PMID: 11804617]
Cárdenas-Rodríguez N, Coballase-Urrutia E, Rivera-Espinosa L, et al. Modulation of antioxidant enzymatic activities by certain antiepileptic drugs (valproic acid, oxcarbazepine, and topiramate): evidence in humans and experimental models. Oxid Med Cell Longev 2013; 2013: 598493.
[] [PMID: 24454986]
Edmonds HL Jr, Jiang YD, Zhang PY, Shank R. Topiramate as a neuroprotectant in a rat model of global ischemia-induced neurodegeneration. Life Sci 2001; 69(19): 2265-77.
[] [PMID: 11669469]
Schubert S, Brandl U, Brodhun M, et al. Neuroprotective effects of topiramate after hypoxia-ischemia in newborn piglets. Brain Res 2005; 1058(1-2): 129-36.
[] [PMID: 16139822]
Noh MR, Kim SK, Sun W, et al. Neuroprotective effect of topiramate on hypoxic ischemic brain injury in neonatal rats. Exp Neurol 2006; 201(2): 470-8.
[] [PMID: 16884714]
Mao XY, Cao YG, Ji Z, Zhou HH, Liu ZQ, Sun HL. Topiramate protects against glutamate excitotoxicity via activating BDNF/TrkB-dependent ERK pathway in rodent hippocampal neurons. Prog Neuropsychopharmacol Biol Psychiatry 2015; 60: 11-7.
[] [PMID: 25661849]
Motaghinejad M, Motevalian M, Fatima S. Mediatory role of NMDA, AMPA/kainate, GABAA and Alpha2 receptors in topiramate neuroprotective effects against methylphenidate induced neurotoxicity in rat. Life Sci 2017; 179: 37-53.
[] [PMID: 28082019]
Leniger T, Thöne J, Wiemann M. Topiramate modulates pH of hippocampal CA3 neurons by combined effects on carbonic anhydrase and Cl-/HCO3- exchange. Br J Pharmacol 2004; 142(5): 831-42.
[] [PMID: 15197104]
Ruffin VA, Salameh AI, Boron WF, Parker MD. Intracellular pH regulation by acid-base transporters in mammalian neurons. Front Physiol 2014; 5: 43.
[] [PMID: 24592239]
Xiong ZQ, Saggau P, Stringer JL. Activity-dependent intracellular acidification correlates with the duration of seizure activity. J Neurosci 2000; 20(4): 1290-6.
[] [PMID: 10662818]
Chesler M. Regulation and modulation of pH in the brain. Physiol Rev 2003; 83(4): 1183-221.
[] [PMID: 14506304]
Bonnet U, Wiemann M. Verapamil and ethacrynic acid are associated with neuronal acidification in hippocampal CA3-neurons (slice preparation, guinea pig): contribution to their anti-seizure potency? Pharmacol Res 2016; 110: 50-1.
[] [PMID: 27180009]
Xiang Z, Bergold PJ. Synaptic depression and neuronal loss in transiently acidic hippocampal slice cultures. Brain Res 2000; 881(1): 77-87.
[] [PMID: 11033097]
Bonnet U, Bingmann D, Speckmann EJ, Wiemann M. Levetiracetam mediates subtle pH-shifts in adult human neocortical pyramidal cells via an inhibition of the bicarbonate-driven neuronal pHregulation - implications for excitability and plasticity modulation. Brain Res 2019; 1710: 146-56.
[] [PMID: 30590026]
Hwang SM, Koo NY, Jin M, et al. Intracellular acidification is associated with changes in free cytosolic calcium and inhibition of action potentials in rat trigeminal ganglion. J Biol Chem 2011; 286(3): 1719-29.
[] [PMID: 21068392]
Vause C, Bowen E, Spierings E, Durham P. Effect of carbon dioxide on calcitonin gene-related peptide secretion from trigeminal neurons. Headache 2007; 47(10): 1385-97.
[] [PMID: 18052948]
Tombaugh GC, Somjen GG. Differential sensitivity to intracellular pH among high- and low-threshold Ca2+ currents in isolated rat CA1 neurons. J Neurophysiol 1997; 77(2): 639-53.
[] [PMID: 9065837]
Bonnet U, Bingmann D, Wiltfang J, Scherbaum N, Wiemann M. Modulatory effects of neuropsychopharmaca on intracellular pH of hippocampal neurones in vitro. Br J Pharmacol 2010; 159(2): 474-83.
[] [PMID: 20015293]
Pedersen SF, Counillon L. The SLC9A-C mammalian Na+/H+ Exchanger family: molecules, mechanisms, and physiology. Physiol Rev 2019; 99(4): 2015-113.
[] [PMID: 31507243]
Jha MK, Morrison BM. Glia-neuron energy metabolism in health and diseases: new insights into the role of nervous system metabolic transporters. Exp Neurol 2018; 309: 23-31.
[] [PMID: 30044944]
Bonnet U, Bingmann D, Speckmann EJ, Wiemann M. Small intraneuronal acidification via short-chain monocarboxylates: first evidence of an inhibitory action on over-excited human neocortical neurons. Life Sci 2018; 204: 65-70.
[] [PMID: 29730171]
Uchitel OD, González Inchauspe C, Weissmann C. Synaptic signals mediated by protons and acid-sensing ion channels. Synapse 2019; 73(10): e22120.
[] [PMID: 31180161]
Vullo S, Kellenberger S. A molecular view of the function and pharmacology of acid-sensing ion channels. Pharmacol Res 2019. [Epub ahead of print]
[PMID: 30731197]
Trudeau LE, Parpura V, Haydon PG. Activation of neurotransmitter release in hippocampal nerve terminals during recovery from intracellular acidification. J Neurophysiol 1999; 81(6): 2627-35.
[] [PMID: 10368383]
Shono Y, Kamouchi M, Kitazono T, et al. Change in intracellular pH causes the toxic Ca2+ entry via NCX1 in neuron- and gliaderived cells. Cell Mol Neurobiol 2010; 30(3): 453-60.
[] [PMID: 19830548]
Stempel AV, Stumpf A, Zhang HY, et al. Cannabinoid type 2 receptors mediate a cell type-specific plasticity in the hippocampus. Neuron 2016; 90(4): 795-809.
[] [PMID: 27133464]
Kazuno AA, Munakata K, Nagai T, et al. Identification of mitochondrial DNA polymorphisms that alter mitochondrial matrix pH and intracellular calcium dynamics. PLoS Genet 2006; 2(8): e128.
[] [PMID: 16895436]
Chang JC, Oude-Elferink RP. Role of the bicarbonate-responsive soluble adenylyl cyclase in pH sensing and metabolic regulation. Front Physiol 2014; 5: 42.
[] [PMID: 24575049]
Huang Z, Cai L, Tu BP. Dietary control of chromatin. Curr Opin Cell Biol 2015; 34: 69-74.
[] [PMID: 26094239]
Jiang XW, Lu HY, Xu Z, et al. In silico analyses for key genes and molecular genetic mechanism in epilepsy and Alzheimer’s disease. CNS Neurol Disord Drug Targets 2018; 17(8): 608-17.
[] [PMID: 30047339]
Salameh AI, Hübner CA, Boron WF. Role of Cl- -HCO3- exchanger AE3 in intracellular pH homeostasis in cultured murine hippocampal neurons, and in crosstalk to adjacent astrocytes. J Physiol 2017; 595(1): 93-124.
[] [PMID: 27353306]
Francis D, Stergiopoulos K, Ek-Vitorín JF, Cao FL, Taffet SM, Delmar M. Connexin diversity and gap junction regulation by pHi. Dev Genet 1999; 24(1-2): 123-36.
[<123:AIDDVG12>3.0.CO;2-H] [PMID: 10079516]
Ruusuvuori E, Kaila K. Carbonic anhydrases and brain pH in the control of neuronal excitability. Subcell Biochem 2014; 75: 271-90.
[] [PMID: 24146384]
Ruusuvuori E, Kirilkin I, Pandya N, Kaila K. Spontaneous network events driven by depolarizing GABA action in neonatal hippocampal slices are not attributable to deficient mitochondrial energy metabolism. J Neurosci 2010; 30(46): 15638-42.
[] [PMID: 21084619]
Jinadasa T, Szabó EZ, Numat M, Orlowski J. Activation of AMP-activated protein kinase regulates hippocampal neuronal pH by recruiting Na(+)/H(+) exchanger NHE5 to the cell surface. J Biol Chem 2014; 289(30): 20879-97.
[] [PMID: 24936055]
Witkin JM, Schober DA, Gleason SD, et al. Targeted blockade of TARP-γ8-associated AMPA receptors: anticonvulsant activity with the selective antagonist LY3130481 (CERC-611). CNS Neurol Disord Drug Targets 2017; 16(10): 1099-110.
[] [PMID: 29090671]
Xu H, Cui N, Yang Z, et al. Direct activation of cloned K(ATP) channels by intracellular acidosis. J Biol Chem 2001; 276(16): 12898-902.
[] [PMID: 11278532]
Zang K, Zhang Y, Hu J, Wang Y. The large conductance calcium and voltage-activated potassium channel (BK) and epilepsy. CNS Neurol Disord Drug Targets 2018; 17(4): 248-54.
[] [PMID: 29623857]
Zhu Y, Zhang S, Feng Y, Xiao Q, Cheng J, Tao J. The Yin and Yang of BK channels in epilepsy. CNS Neurol Disord Drug Targets 2018; 17(4): 272-9.
[] [PMID: 29437015]
Nordström T, Andersson LC, Åkerman KEO. Regulation of intracellular pH by electrogenic Na+/HCO3- co-transporters in embryonic neural stem cell-derived radial glia-like cells. Biochim Biophys Acta Biomembr 2019; 1861(6): 1037-48.
[] [PMID: 30890468]
Qu S, Liu W, Yang H, et al. Clinical observation of electroencephalographic changes and risk of convulsion occurrence in children receiving neural precursor cell transplantation. CNS Neurol Disord Drug Targets 2018; 17(3): 233-9.
[] [PMID: 29692269]
Singh H, Velamakanni S, Deery MJ. Howard J, Wei SL, van Veen HW. ATP-dependent substrate transport by the ABC transporter MsbA is proton-coupled. Nat Commun 2016; 7: 12387.
[] [PMID: 27499013]
Deng X, Xie Y, Chen Y. Effect of neuroinflammation on ABC transporters: possible contribution to refractory epilepsy. CNS Neurol Disord Drug Targets 2018; 17(10): 728-35.
[] [PMID: 30152292]
Tyrtyshnaia AA, Lysenko LV, Madamba F, Manzhulo IV, Khotimchenko MY, Kleschevnikov AM. Acute neuroinflammation provokes intracellular acidification in mouse hippocampus. J Neuroinflammation 2016; 13(1): 283.
[] [PMID: 27809864]
Cordero-Arreola J, West RM, Mendoza-Torreblanca J, et al. The role of innate immune system receptors in epilepsy research. CNS Neurol Disord Drug Targets 2017; 16(7): 749-62.
[] [PMID: 28745241]
Gusev EY, Zotova NV. Cellular stress and general pathological processes. Curr Pharm Des 2019; 25(3): 251-97.
[] [PMID: 31198111]
Bonnet U. The sour side of vitamin C might mediate neuroprotective, anticonvulsive and antidepressant-like effects. Med Hypotheses 2019; 131: 109320.
[] [PMID: 31443769]
Levin LR, Buck J. Physiological roles of acid-base sensors. Annu Rev Physiol 2015; 77: 347-62.
[] [PMID: 25340964]
Wiemann M, Splettstoesser F, Pannek HW, Behne F, Speckmann EJ, Bingmann D. Effects of levetiracetam and topiramate on pHi regulation of human neocortical brain slices Acta Physiol 2006; 186:126(Supplement 650): PM03P-6
Köhling R, Lücke A, Straub H, Speckmann E-J. A portable chamber for long-distance transport of surviving human brain slice preparations. J Neurosci Methods 1996; 67(2): 233-6.
[] [PMID: 8872890]
Bonnet U, Wiemann M, Bingmann D. CO2/HCO3(-)-withdrawal from the bath medium of hippocampal slices: biphasic effect on intracellular pH and bioelectric activity of CA3-neurons. Brain Res 1998; 796(1-2): 161-70.
[] [PMID: 9689466]
Bonnet U, Wiemann M. Ammonium prepulse: effects on intracellular pH and bioelectric activity of CA3-neurones in guinea pig hippocampal slices. Brain Res 1999; 840(1-2): 16-22.
[] [PMID: 10517948]
Bonnet U, Bingmann D, Wiemann M. Intracellular pH modulates spontaneous and epileptiform bioelectric activity of hippocampal CA3-neurones. Eur Neuropsychopharmacol 2000; 10(2): 97-103.
[] [PMID: 10706990]
Bonnet U, Leniger T, Wiemann M. Alteration of intracellular pH and activity of CA3-pyramidal cells in guinea pig hippocampal slices by inhibition of transmembrane acid extrusion. Brain Res 2000; 872(1-2): 116-24.
[] [PMID: 10924683]
Boron WF, Chen L, Parker MD. Modular structure of sodiumcoupled bicarbonate transporters. J Exp Biol 2009; 212(Pt 11): 1697-706.
[] [PMID: 19448079]
Svichar N, Waheed A, Sly WS, Hennings JC, Hübner CA, Chesler M. Carbonic anhydrases CA4 and CA14 both enhance AE3-mediated Cl--HCO3- exchange in hippocampal neurons. J Neurosci 2009; 29(10): 3252-8.
[] [PMID: 19279262]
Perland E, Fredriksson R. Classification systems of secondary active transporters. Trends Pharmacol Sci 2017; 38(3): 305-15.
[] [PMID: 27939446]
Alper SL. Molecular physiology and genetics of Na+-independent SLC4 anion exchangers. J Exp Biol 2009; 212(Pt 11): 1672-83.
[] [PMID: 19448077]
Raley-Susman KM, Sapolsky RM, Kopito RRCl. Cl-/HCO3- exchange function differs in adult and fetal rat hippocampal neurons. Brain Res 1993; 614(1-2): 308-14.
[] [PMID: 8348323]
Brett CL, Kelly T, Sheldon C, Church J. Regulation of Cl--HCO3- exchangers by cAMP-dependent protein kinase in adult rat hippocampal CA1 neurons. J Physiol 2002; 545(3): 837-53.
[] [PMID: 12482890]
Schwartz GJ, Tsuruoka S, Vijayakumar S, Petrovic S, Mian A, Al-Awqati Q. Acid incubation reverses the polarity of intercalated cell transporters, an effect mediated by hensin. J Clin Invest 2002; 109(1): 89-99.
[] [PMID: 11781354]
Bevensee MO, Cummins TR, Haddad GG, Boron WF, Boyarsky G. pH regulation in single CA1 neurons acutely isolated from the hippocampi of immature and mature rats. J Physiol 1996; 494(Pt 2): 315-28.
[] [PMID: 8841993]
Sulis Sato S, Artoni P, Landi S, et al. Simultaneous two-photon imaging of intracellular chloride concentration and pH in mouse pyramidal neurons in vivo. Proc Natl Acad Sci USA 2017; 114(41): E8770-9.
[] [PMID: 28973889]
Tantama M, Hung YP, Yellen G. Imaging intracellular pH in live cells with a genetically encoded red fluorescent protein sensor. J Am Chem Soc 2011; 133(26): 10034-7.
[] [PMID: 21631110]
Garcia PA, Laxer KD, van der Grond J, Hugg JW, Matson GB, Weiner MW. Phosphorus magnetic resonance spectroscopic imaging in patients with frontal lobe epilepsy. Ann Neurol 1994; 35(2): 217-21.
[] [PMID: 8109902]
Hugg JW, Laxer KD, Matson GB, Maudsley AA, Husted CA, Weiner MW. Lateralization of human focal epilepsy by 31P magnetic resonance spectroscopic imaging. Neurology 1992; 42(10): 2011-8.
[] [PMID: 1407585]
Tønnessen TI, Sandvig K, Olsnes S. Role of Na(+)-H+ and Cl(-)-HCO3- antiports in the regulation of cytosolic pH near neutrality. Am J Physiol 1990; 258(6 Pt 1): C1117-26.
[] [PMID: 2163200]
Leniger T, Wiemann M, Bingmann D, Widman G, Hufnagel A, Bonnet U. Carbonic anhydrase inhibitor sulthiame reduces intracellular pH and epileptiform activity of hippocampal CA3 neurons. Epilepsia 2002; 43(5): 469-74.
[] [PMID: 12027906]
Witzel D. Pharmakologische beeinflussung der pH-regulation kardialer fibroblasten dissertation University of Marburg Germany 2003 Available from. .
Doyon N, Vinay L, Prescott SA, De Koninck Y. Chloride regulation: a dynamic equilibrium crucial for synaptic inhibition. Neuron 2016; 89(6): 1157-72.
[] [PMID: 26985723]
Jentsch TJ, Pusch M. CLC chloride channels and transporters: structure, function, physiology, and disease. Physiol Rev 2018; 98(3): 1493-590.
[] [PMID: 29845874]
Packer M. Activation and inhibition of sodium-hydrogen exchanger is a mechanism that links the pathophysiology and treatment of diabetes mellitus with that of heart failure. Circulation 2017; 136(16): 1548-59.
[] [PMID: 29038209]
Touret N, Tanneur V, Godart H, et al. Characterization of sabiporide, a new specific NHE-1 inhibitor exhibiting slow dissociation kinetics and cardioprotective effects. Eur J Pharmaco 2003; 17:459(2-3): 151-8.
Ali A, Ahmad FJ, Pillai KK, Vohora D. Evidence of the antiepileptic potential of amiloride with neuropharmacological benefits in rodent models of epilepsy and behavior. Epilepsy Behav 2004; 5(3): 322-8.
[] [PMID: 15145301]
Angehagen M, Ben-Menachem E, Shank R, Rönnbäck L, Hansson E. Topiramate modulation of kainate-induced calcium currents is inversely related to channel phosphorylation level. J Neurochem 2004; 88(2): 320-5.
[] [PMID: 14690520]
Trapp S, Lückermann M, Kaila K, Ballanyi K. Acidosis of hippocampal neurones mediated by a plasmalemmal Ca2+/H+ pump. Neuroreport 1996; 7(12): 2000-4.
[] [PMID: 8905712]
Sun MK, Alkon DL. Carbonic anhydrase gating of attention: memory therapy and enhancement. Trends Pharmacol Sci 2002; 23(2): 83-9.
[] [PMID: 11830265]
Edelmann E, Cepeda-Prado E, Leßmann V. Coexistence of multiple types of synaptic plasticity in individual hippocampal CA1 pyramidal neurons. Front Synaptic Neurosci 2017; 9: 7.
[] [PMID: 28352224]
Marunaka Y, Yoshimoto K, Aoi W, Hosogi S, Ikegaya H. Low pH of interstitial fluid around hippocampus of the brain in diabetic OLETF rats. Mol Cell Ther 2014; 2: 6.
[] [PMID: 26056575]
Price TO, Farr SA, Niehoff ML, Ercal N, Morley JE, Shah GN. Protective effect of topiramate on hyperglycemia-induced cerebral oxidative stress, pericyte loss and learning behavior in diabetic mice. Int Libr Diabetes Metab 2015; 1(1): 6-12.
[PMID: 26120599]
Baker A. Quantitative parsimony and explanatory pzower. Br J Philos Sci 2003; 54: 245-59.
Watson PL, Weiner JL, Carlen PL. Effects of variations in hippocampal slice preparation protocol on the electrophysiological stability, epileptogenicity and graded hypoxia responses of CA1 neurons. Brain Res 1997; 775(1-2): 134-43.
[] [PMID: 9439837]
Huang S, Uusisaari MY. Physiological temperature during brain slicing enhances the quality of acute slice preparations. Front Cell Neurosci 2013; 7: 48.
[] [PMID: 23630465]
Inoue M, Iwai R, Yamanishi E, et al. Deletion of Prdm8 impairs development of upper-layer neocortical neurons Genes Cells 2015; 20(9): 758-0.
[] [PMID: 26283595]
Köhling R, Höhling JM, Straub H, et al. Optical monitoring of neuronal activity during spontaneous sharp waves in chronically epileptic human neocortical tissue. J Neurophysiol 2000; 84(4): 2161-5.
Straub H, Kuhnt U, Höhling JM, et al. Stimulus-induced patterns of bioelectric activity in human neocortical tissue recorded by a voltage sensitive dye Neuroscience 2003; 121(3): 587-604.
Koch UR, Musshoff U, Pannek HW, et al. Intrinsic excitability, synaptic potentials, and short-term plasticity in human epileptic neocortex. J Neurosci Res 2005; 80(5): 715-26.
Zhang Y, Pak C, Han Y, et al. Rapid single-step induction of functional neurons from human pluripotent stem cells. Neuron 2013; 78(5): 785-98.

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy