Authors :
Presenting Author: Robert Blair, PhD – Virginia Commonwealth University
Elisa Hawkins, BS – Virginia Commonwealth University; Robert DeLorenzo, PhD – Virginia Commonwealth University; Laxmikant Deshpande, PhD – Virginia CommonWealth University
Rationale:
Organophosphate (OP) compounds are chemical threat agents and include commonly used pesticides and chemical warfare nerve agents. OP exposure could lead to rapid onset of lethal status epilepticus (SE) that is known to injure the heart and the brain. We recently showed that treatment with atenolol and levetiracetam (AT+LV) administered after the onset of paraoxon (POX)-induced SE significantly reduced SE mortality. AT is a beta-adrenergic blocker while LV is a neuronal calcium-induced calcium release inhibitor. Here, we investigated whether combination therapy of AT+LV would exert cardioprotective and neuroprotective effects to lower mortality and neurobehavioral morbidities following POX-induced SE.
Methods:
Male Sprague-Dawley rats were injected with POX (2 mg/kg, s.c). One minute later, atropine sulfate (0.5 mg/kg, i.m.) and 2-PAM (25 mg/kg, i.m) were injected. At 1-h post SE onset, midazolam (1.78 mg/kg, i.m.) was used to terminate SE.
Following POX-SE, rats were treated for seven days with AT+LV (AT, 5 mg/kg, LV 50 mg/kg, i.m., b.i.d for 7 days) or saline control (CON). Separate groups of rats were used for each experimental endpoint. In the first group, cardiac irritability was measured by the QTc and QTd intervals from electrocardiogram (ECG) analysis out to seven days post POX-SE. A second group of rats were sacrificed thirty-days post SE, and hearts were processed for the assessment of cardiac pathology. A cardiac damage index (CDI) was calculated that included multiple histopathological features like contraction bands, fibrosis. A third group of rats was sacrificed six months post SE and brain sections stained for NeuN to evaluate hippocampal cell counts.
Results:
QT parameters (QTc and QTd) were significantly increased immediately following and for five days following POX-SE. QT values were normalized to baseline levels with AT+LV treatment. Analyses of the CDI results showed that AT+LV lowered the CDI from 2.65 ± 0.19 in POX SE rats to 0.76 ± 0.18 (n= 6 rats/ condition, p< 0.001, Tukey-test). AT+LV treatment resulted in significant neuronal cell protection in the dentate gyrus hilus when compared to CON, represented by an increase to 135.6±8.4 from 103.7±11.2 cells/mm2 respectively (n=13, AT+LV; n=11, CON, p