Long-term Neuroprotective Effects of Neurosteroid Therapy Following Acute Soman Exposure-induced Status Epilepticus in Pediatric Rats
Abstract number :
2.36
Submission category :
7. Anti-seizure Medications / 7A. Animal Studies
Year :
2024
Submission ID :
493
Source :
www.aesnet.org
Presentation date :
12/8/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Xin Wu, MD – Texas A&M University School of Medicine
Tanveer Singh, PhD – Texas A&M University School of Medicine
Sreevidhya Ramakrishnan, PhD – Texas A&M Health Science Center
Doodipala Samba Reddy, PhD – Texas A&M University School of Medicine
Rationale: Children are highly vulnerable to seizures and neurotoxic effects of the nerve agent soman (GD), which can lead to developmental neuronal defects, epilepsy, and related comorbidities. New anticonvulsants are needed for nerve agent associated intoxication, especially to mitigate long-term sequelae after acute exposure in the vulnerable pediatric population. This study evaluated the efficacy of the neurosteroid ganaxolone (GX) in combating the long-term neuropathological impairments caused by acute pediatric GD intoxication and status epilepticus.
Methods: Postnatal day 21 male rats (P21) were subjected to GD and treated with GX in addition to midazolam at 40 minutes post-exposure. Quantification of MRI scans and histological analyses were performed 3 months after GD exposure in P21 rats.
Results: GD-exposed rats showed drastic hippocampal atrophy with neuronal loss and reduced hippocampal volume, indicating severe damage, but had similar T2 relaxation times to the control group, suggesting limited scarring and fluid density changes despite the volume decrease. Conversely, GD-exposed rats displayed significant increases in lateral ventricle volumes and T2 times, signifying strong cerebrospinal fluid expansion in compensation for tissue atrophy. The MRI neuronal lesions were positively correlated with histological markers of neurodegeneration and neuroinflammation 3 months after GD exposure. The group treated with midazolam alone showed marginal neuroprotection. GX, with or without midazolam treatment, reduced the chronic loss of inhibitory neurons induced by GD. Additionally, GX-treated animals showed a decreased GD-induced inflammatory response, as evidenced by reduced IBA1(+) microgliosis in the hippocampus and amygdala.
Conclusions: These results demonstrate the long-term neuroprotective effects of GX in mitigating neurologic dysfunction, neurodegeneration, and neuroinflammation in pediatric GD model.
Funding: *Correspondence: sambareddy@tamu.edu. This work was supported by NIH Grant U01- NS117209 (to D.S.R.).
Anti-seizure Medications