Neurosteroid Protection of Nerve Agent-induced Long-term Seizures and Neurological Dysfunction in a Pediatric Rat Model
Abstract number :
3.39
Submission category :
7. Anti-seizure Medications / 7A. Animal Studies
Year :
2024
Submission ID :
348
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Sreevidhya Ramakrishnan, PhD – Texas A&M Health Science Center
Tanveer Singh, PhD – Texas A&M University School of Medicine
Xin Wu, MD – Texas A&M University School of Medicine
D Samba Reddy, PhD, RPh – Texas A&M University School of Medicine
Rationale: Nerve agents such as sarin and soman (GD) are lethal chemicals that can cause seizures, status epilepticus (SE), and long-term morbidity. Children are highly susceptible and vulnerable to seizures and developmental neurotoxic effects of these compounds. Multiple reports have indicated that GD has high systemic toxicity in neonates and disrupts neuronal development at the cellular and network levels. Thus, there is a need for new pediatric anticonvulsants that are age-specific in children. 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 protective effects of the synthetic neurosteroid ganaxolone (GX) in a pediatric rat model of GD exposure and status epilepticus.
Methods: Postnatal day 21 (P21) rats were exposed to GD and treated with standard antidotes to improve survival. Ganaxolone was administered 40 minutes post-GD exposure, standalone, or with standard anticonvulsant midazolam. Behavior changes were observed at 1, 2, and 3 months post-exposure. After three months, video-EEG was monitored to record spontaneous recurrent seizures (SRS) and epileptiform discharges for up to 60 days.
Results: Within three months of GD exposure, rats developed chronic epilepsy characterized by frequent SRS and epileptiform discharges. In GX-treated animals, there was a significant reduction in the incidence of epilepsy development and occurrence of SRS and epileptiform discharges, indicating potential disease-modifying activity. GX-treated animals showed significantly reduced aggression, anxiety, and depressive-like behavior. They also exhibited improved spatial learning and memory, confirming significant neuroprotection against behavioral and cognitive deficits.
Conclusions: These results demonstrate the neuroprotective effect of the neurosteroid GX in the GD exposure model, which has implications for mitigating epileptic seizures and long-term neuropsychiatric dysfunction associated with nerve agent exposure.
Funding: This work was supported by NIH Grant U01-NS117209* (to D.S.R.).
Anti-seizure Medications