Authors :
Steve Reddy, BS – Texas A&M University Health Science Center
Sreevidhya Ramakrishnan, PhD – Texas A&M University College of Medicine
Xin Wu, MD – Texas A&M University College of Medicine
Presenting Author: Samba Reddy, PhD, RPh – Texas A&M University Health Science Center
Rationale:
Children are highly sensitive to the neurotoxic effects of nerve agents, which can lead to seizures, status epilepticus (SE) and long-term developmental neuronal dysfunction. Benzodiazepines often fail to prevent the chronic neuropathological effects of nerve agents. This study evaluated the efficacy of the synthetic neurosteroid ganaxolone (GX) in combating the persistent behavioral deficits, epileptogenic markers, and neuropathological damage induced by the nerve agent soman (GD) in pediatric rats.Methods:
Postnatal day 21 rats were exposed to GD and were treated with GX at 40-minutes post-exposure. MRI scanning and behavior deficits were systematically monitored up to 3 months post-exposure. video-EEG assessed spontaneous recurrent seizures (SRS), epileptiform discharges, high-frequency oscillations (HFOs), and interictal spike activity.Results:
GX treatment significantly mitigated anxiety, memory deficits, and depression-like phenotypes in GD-exposed pediatric animals. They exhibited reduced SRS and electrographic biomarkers of discharges, interictal spikes, and HFOs, which demonstrates disease-modifying effects. The MRI analysis showed a marked improvement in neuropathological changes. Histological studies showed that GX decreased the loss of PV (+) inhibitory neurons and NeuN (+) principal neurons, and increased DCX(+) neurogenesis in the hippocampus.
Conclusions:
These findings demonstrate the protective efficacy of GX in reducing epileptogenesis and mitigating comorbidities, and neurodegeneration associated with GD exposure, which confirms the potential of neurosteroid treatment for pediatric SE. Funding:
This work was supported by NIH Grant U01-NS117209 (to D.S.R.).