Authors :
Presenting Author: Sreevidhya Ramakrishnan, PhD – Texas A&M Health Science Center
Tanveer Singh, PhD – Postdoctoral Research Associate, Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center; Xin Wu, MD – Research Assistant Professor, Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center; Samba Reddy, PhD, RPh, FAAAS, FAAPS, FAES – Professor, Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center
Rationale:
Nerve agents such as sarin and soman (GD) are lethal chemicals that can induce acute seizures, status epilepticus (SE), and long-term morbidity. Current antidotes are effective if administered within 30 minutes of nerve agent exposure, a timeline often impractical for first responders in the aftermath of a chemical attack. Thus, there is an urgent need for new anticonvulsants for nerve agents, especially for mitigating the long-term sequelae after acute exposure. Neurosteroids, which are positive modulators of extrasynaptic and synaptic GABA-A receptors, represent a new class of anticonvulsants for epilepsy. In this study, we investigated the long-term efficacy of two novel synthetic neurosteroid (NS) analogs in a rat model of GD-induced SE.Methods:
Adult rats were exposed to GD and treated with standard antidotes to improve survival. Novel synthetic NS analogs were administered 40 minutes post-GD exposure in combination with midazolam. They were monitored for spontaneous recurrent seizures (SRS), epileptiform discharges, and high-frequency oscillations (HFOs) for up to three months.Results:
Within 60 days of GD exposure, rats developed chronic epilepsy characterized by frequent SRS, epileptiform discharges, and HFOs. Post-exposure therapy with NS analogs significantly reduced the development of long-term SRS and electrographic ictal abnormalities, indicating potential disease-modifying activity. This response was dose-related, with higher doses eliciting greater protection in reducing seizures and electrographic ictal abnormalities.Conclusions:
These results demonstrate the disease-modifying potential of synthetic neurosteroids in the nerve agent post-SE model with implications to mitigate epileptic seizures and ictal abnormalities associated with nerve agent exposure. Funding: This work was supported by NIH Grant U01-NS117278* (to D.S.R.).