Ashwini Sri Hari, University of Colorado
Conference: Society of Toxicology 2018, San Antonio, TX
Abstract Title: Thiol-containing compounds attenuate oxidative stress and neuronal hyperexcitability in vitro
Abstract: Chemical agents such as industrial chemicals, pesticides, and chemical warfare agents can induce uncontrolled seizure activity (neuronal hyperexcitability). Oxidative stress has been implicated as a pathogenic factor in the etiology of seizures and epilepsy. However, whether and how cellular redox status modulates neuronal hyperexcitability is unclear. We hypothesized that the modulation of cellular redox status with thiol containing compounds would decrease oxidative stress, and attenuate neuronal hyperexcitability in vitro. TC1, a thiol-containing compound significantly (p<0.001 vs vehicle control) increased intracellular glutathione levels in mixed rat primary cortical cultures at 4 and 24h. Next, we determined if TC1 could dampen “seizure-like” activity in vitro induced by 4-Aminopyridine (4AP), a toxicant that inhibits potassium channels. In mixed rat primary neuronal-glial cultures, incubation with 100μM TC1 for 4h significantly (p<0.0001 vs 1mM 4AP) decreased 4AP-induced neuronal hyperexcitability. We tested the ability of another thiol compound, TC2 which is FDA approved as a systemic protective agent against chemotherapy, for its ability to alter oxidative stress and neuronal hyperexcitability in vitro. To visualize and quantify the oxidative stress response in primary cortical cultures, we utilized a highly sensitive fluorescent probe, HKSOX-1r, that could detect endogenous superoxide levels. Co-treatment with TC2 decreased Antimycin A-induced superoxide levels to control values. In addition, 500μM TC2 significantly (p<0.0001 vs 1mM 4AP) attenuated 4AP induced neuronal hyperexcitability in mixed rat primary cortical cultures. Taken together, the data suggest that thiol-containing compounds decrease oxidative stress and attenuate neuronal hyperexcitability.