Effects of acid-base balance in the brain in epileptogenesis_Journal of Epilepsy

Authors：

LU Qian ^1,2 , ZHANG Qi ^1,2 , WANG Yangyang ² , WANG Qiuhong ^1,2 , DUN Shuo ^1,2 , WANG Jia ^1,2 ,  ZOU Liping ^1,2

1. Medical School of Chinese PLA, Beijing 100853, China;
2. Department of Pediatrics, the First Medical Center of PLA General Hospital, Beijing 100853, China;

Corresponding author：

ZOU Liping, Email: zouliping21@sina.com

Keywords：

Epilepsy; Acid-base balance; Transporter proteins; Neuron

DOI：

10.7507/2096-0247.202306005

Video：

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Abstract Full text Figures/Tables Video References Cited by

The acid-base balance of the brain is critical to the functioning of the nervous system. The mechanisms that maintain acid-base homeostasis in the brain are complex and regulated by a variety of transporter proteins and enzymes. Slight changes in acid-base balance can affect neuronal excitability and even lead to epilepsy. Epilepsy is a common neurological disease with complex pathogenesis and numerous causes. Drug therapy is still the main method, but the treatment effect is limited. Therefore, it is urgent to clarify the pathological mechanism of epilepsy and explore new treatment directions This study provides an overview of the transporter proteins (acid-sensing ion channel, Na⁺/H⁺ exchanger, Na⁺/HCO₃^- cotransporters, anion exchangers, carbonic anhydrases) and the regulation of acid-base balance in the lungs. This study also introduces how these transporters participate in the stable maintenance of brain acid-base balance and their influence in epileptogenesis from both basic and clinical aspects in detail, providing new targets for epilepsy treatment and intervention.

Citation： LU Qian, ZHANG Qi, WANG Yangyang, WANG Qiuhong, DUN Shuo, WANG Jia, ZOU Liping. Effects of acid-base balance in the brain in epileptogenesis. Journal of Epilepsy, 2023, 9(5): 400-405. doi: 10.7507/2096-0247.202306005 Copy

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2.	Duarte CM, Jaremko Ł, Jaremko M. Hypothesis: potentially systemic impacts of elevated CO(2) on the human proteome and health. Frontiers in Public Health, 2020, 8: 543322.
3.	Choudhary A, Mu C, Barrett KT, et al. The link between brain acidosis, breathing and seizures: a novel mechanism of action for the ketogenic diet in a model of infantile spasms. Brain Communications, 2021, 3(4): 189.
4.	Thijs RD, Surges R, O'brien TJ, et al. Epilepsy in adults. Lancet (London, England), 2019, 393(10172): 689-701.
5.	Yang XF, Shi XY, Ju J, et al. 5% CO₂ inhalation suppresses hyperventilation-induced absence seizures in children. Epilepsy Research, 2014, 108(2): 345-348.
6.	Shi XY, Hu LY, Liu MJ, et al. Hypercapnia-induced brain acidosis: Effects and putative mechanisms on acute kainate induced seizures. Life Sciences, 2017, 176: 82-87.
7.	Bonnet U, Bingmann D, Speckmann EJ, et al. Levetiracetam mediates subtle pH-shifts in adult human neocortical pyramidal cells via an inhibition of the bicarbonate-driven neuronal pH-regulation - Implications for excitability and plasticity modulation. Brain Research, 2019, 1710: 146-156.
8.	Obara M, Szeliga M, Albrecht J. Regulation of pH in the mammalian central nervous system under normal and pathological conditions: facts and hypotheses. Neurochemistry International, 2008, 52(6): 905-919.
9.	Zhou RP, Liang HY, Hu WR, et al. Modulators of ASIC1a and its potential as a therapeutic target for age-related diseases. Ageing Research Reviews, 2023, 83: 101785.
10.	Yoder N, Yoshioka C, Gouaux E. Gating mechanisms of acid-sensing ion channels. Nature, 2018, 555(7696): 397-401.
11.	Cheng Y, Zhang W, Li Y, et al. The role of ASIC1a in epilepsy: a potential therapeutic target. Current Neuropharmacology, 2021, 19(11): 1855-64.
12.	Fliegel L. Role of genetic mutations of the Na(+)/H(+) exchanger isoform 1, in human disease and protein targeting and activity. Molecular and Cellular Biochemistry, 2021, 476(2): 1221-1232.
13.	Zhao H, Carney KE, Falgoust L, et al. Emerging roles of Na⁺/H⁺ exchangers in epilepsy and developmental brain disorders. Progress in Neurobiology, 2016, 138-140: 19-35.
14.	Parker MD. Mouse models of SLC4-linked disorders of HCO(3)(-)-transporter dysfunction. American Journal of Physiology Cell Physiology, 2018, 314(5): 569-588.
15.	Ciccone L, Cerri C, Nencetti S, et al. Carbonic anhydrase inhibitors and epilepsy: state of the art and future perspectives. Molecules (Basel, Switzerland), 2021, 26(21): 263-265.
16.	Schuchmann S, Schmitz D, Rivera C, et al. Experimental febrile seizures are precipitated by a hyperthermia-induced respiratory alkalosis. Nature medicine, 2006, 12(7): 817-823.
17.	周马丁. 中间神经元酸敏感离子通道1a在癫痫发生发展中的作用机制. 浙江大学, 2017, 硕士学位论文.
18.	Liang JJ, Huang LF, Chen XM, et al. Amiloride suppresses pilocarpine-induced seizures via ASICs other than NHE in rats. International Journal of Clinical and Experimental Pathology, 2015, 8(11): 14507-14513.
19.	Ievglevskyi O, Isaev D, Netsyk O, et al. Acid-sensing ion channels regulate spontaneous inhibitory activity in the hippocampus: possible implications for epilepsy. Philos Trans R Soc Lond B Biol Sci, 2016, 371(1700): 15021.
20.	Qiao Q, Qu Z, Tian S, et al. Ketogenic diet alleviates hippocampal neurodegeneration possibly via ASIC1a and the mitochondria-mediated apoptotic pathway in a rat model of temporal lobe epilepsy. Neuropsychiatric Disease and Treatment, 2022, 18: 2181-2198.
21.	Yang F, Sun X, Ding Y, et al. Astrocytic acid-sensing ion channel 1a contributes to the development of chronic epileptogenesis. Scientific Reports, 2016, 6: 31581.
22.	Wu H, Wang C, Liu B, et al. Altered expression pattern of acid-sensing ion channel isoforms in piriform cortex after seizures. Molecular Neurobiology, 2016, 53(3): 1782-1793.
23.	Ziemann AE, Schnizler MK, Albert GW, et al. Seizure termination by acidosis depends on ASIC1a. Nature Neuroscience, 2008, 11(7): 816-822.
24.	Odunewu-Aderibigbe A, Fliegel L. Heat shock proteins and the Na(+)/H(+) exchanger. Channels (Austin, Tex), 2017, 11(5): 380-382.
25.	Kang TC, An SJ, Park SK, et al. Alterations in Na+/H+ exchanger and Na+/HCO3- cotransporter immunoreactivities within the gerbil hippocampus following seizure. Brain research Molecular brain research, 2002, 109(1-2): 226-232.
26.	吴旭玲, 董楝, 彭爽, 等. 颞叶外侧癫痫患者脑组织NHE1及凋亡相关蛋白的表达. 中国临床解剖学杂志, 2021, 39(4): 6.
27.	彭爽, 吴旭玲, 于云莉, 等. 钠氢交换体1在氯化锂-匹罗卡品点燃癫痫大鼠模型海马组织内的表达. 贵州医科大学学报, 2021, 46(1): 16-21.
28.	Cengiz P, Kintner DB, Chanana V, et al. Sustained Na+/H+ exchanger activation promotes gliotransmitter release from reactive hippocampal astrocytes following oxygen-glucose deprivation. PLoS One, 2014, 9(1): e84294.
29.	Shi Y, Kim D, Caldwell M, et al. The role of Na(+)/h (+) exchanger isoform 1 in inflammatory responses: maintaining H(+) homeostasis of immune cells. Advances in Experimental Medicine and Biology, 2013, 961: 411-418.
30.	Jacobs S, Ruusuvuori E, Sipilä ST, et al. Mice with targeted Slc4a10 gene disruption have small brain ventricles and show reduced neuronal excitability. Proc Natl Acad Sci U S A, 2008, 105(1): 311-316.
31.	Hentschke M, Wiemann M, Hentschke S, et al. Mice with a targeted disruption of the Cl-/HCO3- exchanger AE3 display a reduced seizure threshold. Molecular and Cellular Biology, 2006, 26(1): 182-191.
32.	Halmi P, Parkkila S, Honkaniemi J. Expression of carbonic anhydrases II, IV, VII, VIII and XII in rat brain after kainic acid induced status epilepticus. Neurochemistry International, 2006, 48(1): 24-30.
33.	Ruusuvuori E, Huebner AK, Kirilkin I, et al. Neuronal carbonic anhydrase VII provides GABAergic excitatory drive to exacerbate febrile seizures. The EMBO Journal, 2013, 32(16): 2275-2286.
34.	Hamidi S, Avoli M. Carbonic anhydrase inhibition by acetazolamide reduces in vitro epileptiform synchronization. Neuropharmacology, 2015, 95: 377-387.
35.	Tolner EA, Hochman DW, Hassinen P, et al. Five percent CO₂ is a potent, fast-acting inhalation anticonvulsant. Epilepsia, 2011, 52(1): 104-114.
36.	Lv RJ, He JS, Fu YH, et al. ASIC1a polymorphism is associated with temporal lobe epilepsy. Epilepsy Research, 2011, 96(1-2): 74-80.
37.	Guo W, Chen X, He JJ, et al. Down-regulated expression of acid-sensing ion channel 1a in cortical lesions of patients with focal cortical dysplasia. Journal of Molecular Neuroscience : MN, 2014, 53(2): 176-182.
38.	Liu X, Xie L, Fang Z, et al. Case Report: Novel SLC9A6 Splicing Variant in a Chinese Boy With Christianson Syndrome With Electrical Status Epilepticus During Sleep. Frontiers in Neurology, 2021, 12: 796283.

1. Richerson GB. Serotonergic neurons as carbon dioxide sensors that maintain pH homeostasis. Nature Reviews Neuroscience, 2004, 5(6): 449-461.
2. Duarte CM, Jaremko Ł, Jaremko M. Hypothesis: potentially systemic impacts of elevated CO(2) on the human proteome and health. Frontiers in Public Health, 2020, 8: 543322.
3. Choudhary A, Mu C, Barrett KT, et al. The link between brain acidosis, breathing and seizures: a novel mechanism of action for the ketogenic diet in a model of infantile spasms. Brain Communications, 2021, 3(4): 189.
4. Thijs RD, Surges R, O'brien TJ, et al. Epilepsy in adults. Lancet (London, England), 2019, 393(10172): 689-701.
5. Yang XF, Shi XY, Ju J, et al. 5% CO₂ inhalation suppresses hyperventilation-induced absence seizures in children. Epilepsy Research, 2014, 108(2): 345-348.
6. Shi XY, Hu LY, Liu MJ, et al. Hypercapnia-induced brain acidosis: Effects and putative mechanisms on acute kainate induced seizures. Life Sciences, 2017, 176: 82-87.
7. Bonnet U, Bingmann D, Speckmann EJ, et al. Levetiracetam mediates subtle pH-shifts in adult human neocortical pyramidal cells via an inhibition of the bicarbonate-driven neuronal pH-regulation - Implications for excitability and plasticity modulation. Brain Research, 2019, 1710: 146-156.
8. Obara M, Szeliga M, Albrecht J. Regulation of pH in the mammalian central nervous system under normal and pathological conditions: facts and hypotheses. Neurochemistry International, 2008, 52(6): 905-919.
9. Zhou RP, Liang HY, Hu WR, et al. Modulators of ASIC1a and its potential as a therapeutic target for age-related diseases. Ageing Research Reviews, 2023, 83: 101785.
10. Yoder N, Yoshioka C, Gouaux E. Gating mechanisms of acid-sensing ion channels. Nature, 2018, 555(7696): 397-401.
11. Cheng Y, Zhang W, Li Y, et al. The role of ASIC1a in epilepsy: a potential therapeutic target. Current Neuropharmacology, 2021, 19(11): 1855-64.
12. Fliegel L. Role of genetic mutations of the Na(+)/H(+) exchanger isoform 1, in human disease and protein targeting and activity. Molecular and Cellular Biochemistry, 2021, 476(2): 1221-1232.
13. Zhao H, Carney KE, Falgoust L, et al. Emerging roles of Na⁺/H⁺ exchangers in epilepsy and developmental brain disorders. Progress in Neurobiology, 2016, 138-140: 19-35.
14. Parker MD. Mouse models of SLC4-linked disorders of HCO(3)(-)-transporter dysfunction. American Journal of Physiology Cell Physiology, 2018, 314(5): 569-588.
15. Ciccone L, Cerri C, Nencetti S, et al. Carbonic anhydrase inhibitors and epilepsy: state of the art and future perspectives. Molecules (Basel, Switzerland), 2021, 26(21): 263-265.
16. Schuchmann S, Schmitz D, Rivera C, et al. Experimental febrile seizures are precipitated by a hyperthermia-induced respiratory alkalosis. Nature medicine, 2006, 12(7): 817-823.
17. 周马丁. 中间神经元酸敏感离子通道1a在癫痫发生发展中的作用机制. 浙江大学, 2017, 硕士学位论文.
18. Liang JJ, Huang LF, Chen XM, et al. Amiloride suppresses pilocarpine-induced seizures via ASICs other than NHE in rats. International Journal of Clinical and Experimental Pathology, 2015, 8(11): 14507-14513.
19. Ievglevskyi O, Isaev D, Netsyk O, et al. Acid-sensing ion channels regulate spontaneous inhibitory activity in the hippocampus: possible implications for epilepsy. Philos Trans R Soc Lond B Biol Sci, 2016, 371(1700): 15021.
20. Qiao Q, Qu Z, Tian S, et al. Ketogenic diet alleviates hippocampal neurodegeneration possibly via ASIC1a and the mitochondria-mediated apoptotic pathway in a rat model of temporal lobe epilepsy. Neuropsychiatric Disease and Treatment, 2022, 18: 2181-2198.
21. Yang F, Sun X, Ding Y, et al. Astrocytic acid-sensing ion channel 1a contributes to the development of chronic epileptogenesis. Scientific Reports, 2016, 6: 31581.
22. Wu H, Wang C, Liu B, et al. Altered expression pattern of acid-sensing ion channel isoforms in piriform cortex after seizures. Molecular Neurobiology, 2016, 53(3): 1782-1793.
23. Ziemann AE, Schnizler MK, Albert GW, et al. Seizure termination by acidosis depends on ASIC1a. Nature Neuroscience, 2008, 11(7): 816-822.
24. Odunewu-Aderibigbe A, Fliegel L. Heat shock proteins and the Na(+)/H(+) exchanger. Channels (Austin, Tex), 2017, 11(5): 380-382.
25. Kang TC, An SJ, Park SK, et al. Alterations in Na+/H+ exchanger and Na+/HCO3- cotransporter immunoreactivities within the gerbil hippocampus following seizure. Brain research Molecular brain research, 2002, 109(1-2): 226-232.
26. 吴旭玲, 董楝, 彭爽, 等. 颞叶外侧癫痫患者脑组织NHE1及凋亡相关蛋白的表达. 中国临床解剖学杂志, 2021, 39(4): 6.
27. 彭爽, 吴旭玲, 于云莉, 等. 钠氢交换体1在氯化锂-匹罗卡品点燃癫痫大鼠模型海马组织内的表达. 贵州医科大学学报, 2021, 46(1): 16-21.
28. Cengiz P, Kintner DB, Chanana V, et al. Sustained Na+/H+ exchanger activation promotes gliotransmitter release from reactive hippocampal astrocytes following oxygen-glucose deprivation. PLoS One, 2014, 9(1): e84294.
29. Shi Y, Kim D, Caldwell M, et al. The role of Na(+)/h (+) exchanger isoform 1 in inflammatory responses: maintaining H(+) homeostasis of immune cells. Advances in Experimental Medicine and Biology, 2013, 961: 411-418.
30. Jacobs S, Ruusuvuori E, Sipilä ST, et al. Mice with targeted Slc4a10 gene disruption have small brain ventricles and show reduced neuronal excitability. Proc Natl Acad Sci U S A, 2008, 105(1): 311-316.
31. Hentschke M, Wiemann M, Hentschke S, et al. Mice with a targeted disruption of the Cl-/HCO3- exchanger AE3 display a reduced seizure threshold. Molecular and Cellular Biology, 2006, 26(1): 182-191.
32. Halmi P, Parkkila S, Honkaniemi J. Expression of carbonic anhydrases II, IV, VII, VIII and XII in rat brain after kainic acid induced status epilepticus. Neurochemistry International, 2006, 48(1): 24-30.
33. Ruusuvuori E, Huebner AK, Kirilkin I, et al. Neuronal carbonic anhydrase VII provides GABAergic excitatory drive to exacerbate febrile seizures. The EMBO Journal, 2013, 32(16): 2275-2286.
34. Hamidi S, Avoli M. Carbonic anhydrase inhibition by acetazolamide reduces in vitro epileptiform synchronization. Neuropharmacology, 2015, 95: 377-387.
35. Tolner EA, Hochman DW, Hassinen P, et al. Five percent CO₂ is a potent, fast-acting inhalation anticonvulsant. Epilepsia, 2011, 52(1): 104-114.
36. Lv RJ, He JS, Fu YH, et al. ASIC1a polymorphism is associated with temporal lobe epilepsy. Epilepsy Research, 2011, 96(1-2): 74-80.
37. Guo W, Chen X, He JJ, et al. Down-regulated expression of acid-sensing ion channel 1a in cortical lesions of patients with focal cortical dysplasia. Journal of Molecular Neuroscience : MN, 2014, 53(2): 176-182.
38. Liu X, Xie L, Fang Z, et al. Case Report: Novel SLC9A6 Splicing Variant in a Chinese Boy With Christianson Syndrome With Electrical Status Epilepticus During Sleep. Frontiers in Neurology, 2021, 12: 796283.

Journal of Epilepsy

Effects of acid-base balance in the brain in epileptogenesis

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