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