Sex‐based structural and functional MRI outcomes in the rat brain after soman (GD) exposure‐induced status epilepticus

Abstract

Objective: Exposure to the nerve agent, soman (GD), induces status epilepticus (SE), epileptogenesis, and even death. Although rodent models studying the pathophysiological mechanisms show females to be more reactive to soman, no tangible sex differences in brains postexposure have been reported. In this study, we used multimodal imaging using MRI in adult rats to determine potential sexbased biomarkers of soman effects.Methods: Male and female Sprague Dawley rats were challenged with 1.2 × LD 50 soman followed by medical countermeasures. Ten weeks later, the brains were analyzed via structural and functional MRI.Results: Despite no significant sex differences in the initial SE severity after soman exposure, long-term MRI-based structural and functional differences were evident in the brains of both sexes. While T2 MRI showed lesser somaninduced neurodegeneration, large areas of T1 enhancements occurred in females than in males, indicating a distinct pathophysiology unrelated to neurodegeneration. fMRI-based resting-state functional connectivity (RSFC), indicated greater reductions in soman-exposed females than in males, associating with the T1 enhancements (unrelated to neurodegeneration) rather than T2-hyperintensity or T1-hypointensity (representing neurodegeneration). The wider T1 enhancements associating with the decreased spontaneous neuronal activity in multiple resting-state networks in soman-exposed females than males suggest that neural changes unrelated to cellular atrophy impinge on brain function postexposure. Taken together with lower spontaneous neural activity in soman-exposed females, the results indicate some form of neuroprotective state that was not present in males. Significance:The results indicate that endpoints other than neurodegeneration may need to be considered to translate sex-based nerve agent effects in humans.

Disease-modifying effects of a glial-targeted inducible nitric oxide synthase inhibitor (1400W) in mixed-sex cohorts of a rat soman (GD) model of epilepsy

“…SE-induced long-term effects on the brain structure and functions in experimental models of epilepsy are well known [ 21 , 36 , 44 ]. Soman-induced long-term effects, especially the changes in the hippocampus and amygdala, have been demonstrated in rat models [ 36 , 45 – 48 ].…”

Disease-Modifying Effects of a Glial-targeted Inducible Nitric Oxide Synthase Inhibitor (1400W) in Mixed-sex Cohorts of a Rat Soman (GD) Model of Epilepsy

“…SE-induced long-term effects on the brain structure and functions in experimental models of epilepsy are well known [21,33,41]. Soman-induced long-term effects, especially the changes in the hippocampus and amygdala, have been demonstrated in rat models [33,[42][43][44][45].…”

Inhibiting Inducible Nitric Oxide Synthase with 1400W Reduces Soman (GD)-Induced Ferroptosis in Long-Term Epilepsy-Associated Neuropathology: Structural and Functional Magnetic Resonance Imaging Correlations with Neurobehavior and Brain Pathology

“…T1- or T2-weighted MRI intensities have been used to assess brain pathology in the GD model ( Bhagat et al, 2001 , 2005 ; Gullapalli et al, 2010 ; Reddy et al, 2020 ; Gage et al, 2023 ). Although no difference in T1 and T2 intensity was observed at the ROI levels between groups in this study, the voxel-wise analysis revealed significant T1 decreases and T2 increases after GD exposure, which was consistent with previous reports ( Gullapalli et al, 2010 ).…”

“…Although structural MRI changes have been well characterized in OPNA toxicity ( Bhagat et al, 2001 , 2005 ; Gullapalli et al, 2010 ; Reddy et al, 2020 ), the use of fMRI to assess functional network connectivity and disease modification has not been investigated. We recently reported the differential findings in structural and functional MRI of brains between male and female rats in the GD-induced epilepsy model ( Gage et al, 2023 ). The current study aims to examine the potential disease-modifying effects of an iNOS inhibitor, 1400W, against GD intoxication.…”