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

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.”