Abstracts

Topiramate (TPM) effectively inhibits focal and generalized epilepsies by multiple anticonvulsant actions on ion channels. As TPM also decreases carbonic anhydrase (CA) activity, the aim of this study was to evaluate inasmuch inhibition of neuronal CA and concomitant changes of neuronal intracellular pH (pHi) add to TPM[acute]s anticonvulsant properties.
Effects of TPM (25 [micro]M-1mM) on spontaneous and epileptiform activity (induced by 50 [micro]M 4-aminopyridine) were analyzed by extended intracellular recordings of CA3 neurons (hippocampus slice) superfused with bicarbonate buffered artificial cerebral fluid. Neural pHi was mearsured in parallel in 2[acute],7-bis(2-carboxyethyl)-5(6)-carboxyfluorescein-acetoxymethylester loaded neurons.
In the majority of the neurons (17/25) TPM reversibly decreased steady-state pHi by 0.16 [plusmn] 0.05 (SD) pH-units within 10 min. This effect became obvious with 25-50 [micro]M TPM which also elicited typical effects of CA inhibition on pHi: Slope of intracellular acidification upon CO[sub]2[/sub]/HCO[sub]3[/sub]^- withdrawal was reduced (50 [micro]M, n= 5) and onset times of acidic pHi shifts due to an elevation of PCO[sub]2[/sub] (100 mm Hg) were significantly prolonged (n= 9), as was observed with acetazolamide (1 mM). In the 4-AP epileptic model system frequency of epileptiform bursts and intermittent action potentials was inhibited in 12/16 neurons. Shape of epileptiform bursts and action potentials remained unchanged unless high concentrations (0.5-1 mM) of TPM were used. However, GABAergic hyperpolarizations elicited by 4-AP were prolonged, pointing to reduced efflux of bicarbonate.
The effects of TPM on steady state pHi and, consequently, on bioelectric activity are in line with an inhibitory effect of TPM on neuronal CA. The results suggest that CA inhibition contributes to TPM[acute]s anticonvulsive property.
[Supported by: R.W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania, U.S.A.]