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

[ Vol. 19 , Issue. 4 ]

Author(s):

Udo Bonnet* and Martin Wiemann   Pages 264 - 275 ( 12 )

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- the 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, and 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 HCO3 - - driven pHi-regulation by TPM, favoring the stimulation of the passive Cl-/HCO3 - - antiporter (CBT) - an acidloader 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.

Affiliation:

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



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