Modulation of the epileptic seizure threshold: Implications of biphasic dose responses

Considerable evidence has emerged that hormetic-like biphasic dose-response relationships are common in the biomedical sciences. Consequently, this article assesses dose-response relationships of agents known to modulate epileptic-like seizure thresholds in screening tests with animal models. Biphasic dose responses have been commonly reported as measured by changes in seizure threshold concentrations across a broad dose-response continuum of chemically diverse agents that act via different receptor-based mechanisms. Despite such differences in chemical structure and modes of actions, the quantitative features of these dose responses are quite similar, being consistent with the hormetic dose-response model with respect to the magnitude and width of the stimulatory responses. The hormetic responses were also independent of the animal model employed as well as type of seizure-related endpoint measured. These findings support the generalizability of the hormetic dose-response concept and may have important implications for the discovery of antiseizure drugs and their clinical evaluation.