The K+ channel activators diazoxide and cromakalim were investigated for effects on 4-aminopyridine (4AP)-induced epileptiform activity in adult rat hippocampal slices maintained in vitro. Under normal conditions of oxygenation, 4 AP (50 μM) induced two types of field potentials in extracellular recordings from the CA3 stratum radiatum (apical dendritic region): epileptiform interictal discharge-like events occurring at a frequency of 0.75 ± 0.36 Hz and long-lasting negative-going potentials mediated by GABA receptor activation that occurred at 0.03 ± 0.01 Hz (n = 36 slices). Neither diazoxide (0.65-1.3 mM, n = 21 slices) nor cromakalim (50-200 μM, n = 6 slices) altered these two types of discharge. Brief periods of anoxia (4-6 min) reduced the frequency of the 4AP-induced interictal-like events (from 0.75 ± 0.36 Hz to 0.19 ± 0.15 Hz, n = 20 slices). In 45% of the experiments, the depressant effect of anoxia was preceded by a period of hyperexcitability consisting of a transient (36.1 ± 12.9 sec) increase in the frequency of interictal-like events riding on a negative-going DC shift (n = 9 slices). Both responses to anoxia were reversible upon reoxygenation. In contrast, the rate of occurrence of the GABA-mediated potentials was unaffected by the anoxic episodes. Perfusion with cromakalim (n = 4 slices) or diazoxide (n = 5 slices) abolished the initial period of hyperexcitability produced by O2 deprivation but did not alter the subsequent depression of activity. Our experiments indicate that the K+ channel activators can prevent the initial hyperexcitability produced by anoxia, but do not influence 4AP-induced epileptiform activity in normoxic conditions. These findings suggest that K+ channel opener drugs might be useful in the treatment of seizures occurring in the setting of status epilepticus or cerebrovascular disease.
- 4-amino-pyridine (4-AP)
- Adenosine triphosphate-sensitive K channels
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience
- Drug Discovery