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

Author:

Bonnet Udo1ORCID,Wiemann Martin2

Affiliation:

1. Department of Psychiatry, Psychotherapy, and Psychosomatic Medicine, Evangelisches Krankenhaus Castrop-Rauxel, Academic Teaching Hospital of the University Duisburg-Essen, Castrop-Rauxel, Germany

2. Institute of Physiology, University of Duisburg-Essen, Essen, Germany

Abstract

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 fluometrically. 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 APP-acidification 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 HCO3(-)-driven pHi-regulation by TPM, favoring the 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. Study Limitations: Although these results are the only available pHi-measurements of human brain neurons to this issue, to the best of our knowledge, the study is limited by the small number of cells analyzed due to limited human material. Thus, the results presented here are preliminary data. Greater sample size is required to reach more reliable conclusions.”

Publisher

Bentham Science Publishers Ltd.

Subject

Pharmacology,General Neuroscience

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3