1400W, an Inos Inhibitor, Suppresses Soman-induced and Epilepsy-associated Brain Pathology: Structural and Functional Magnetic Resonance Imaging Studies
Abstract number :
3.04
Submission category :
1. Basic Mechanisms / 1D. Mechanisms of Therapeutic Interventions
Year :
2022
Submission ID :
2204180
Source :
www.aesnet.org
Presentation date :
12/5/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:23 AM
Authors :
Marson Putra, MD, PhD – Iowa State University; Meghan Gage, PhD – Biomedical Sciences – Iowa State University; Sridhar Kannurpatti, PhD – Adjunct Assistant Professor, Radiology, Rutgers New Jersey Medical School; Christina Meyer, MS – Graduate Student, Biomedical Sciences, Iowa State University; Nikhil Rao, DVM – Graduate Student, Biomedical Sciences, Iowa State University; Manikandan Samidurai, PhD – Post Doctoral Research Associate, Biomedical Sciences, Iowa State University; Thimmasettappa Thippeswamy, DVM, PhD – Professor, Biomedical Sciences, Iowa State University; Suraj Vasanthi, DVM – Graduate Student, Biomedical Sciences, Iowa State University
This abstract has been invited to present during the Basic Science Poster Highlights poster session.
Rationale: Organophosphate nerve agent (OPNA) intoxication leads to long-term brain injury and neuropsychiatric dysfunction. Current treatments inadequately mitigate OPNA-induced neuropathology, compelling a need for a more effective treatment. Previously, we discovered that 1400W, an iNOS inhibitor, significantly reduced spontaneous seizures and seizure-induced brain pathology in a rat model of organophosphate intoxication. In this soman (GD) model, we used structural and functional Magnetic Resonance Imaging (MRI) to determine anatomical and functional brain abnormalities induced by GD and the impact of 1400W treatment.
Methods: Mixed-sex Sprague Dawley rats (7-8 weeks) were intoxicated with soman (GD, 132 µg/kg, s.c. 1.2 LD50), followed by HI-6 (125 mg/kg, i.m.) and atropine sulfate (2 mg/kg, i.m.). The animals had status epilepticus (SE) for ~40 minutes before midazolam was given (3 mg/kg, i.m.). An hour later, the animals were treated with vehicle (Veh) or 1400W (20 mg/kg, i.m. daily for two weeks). Ten weeks post-GD, the animals were imaged in a horizontal bore 7 Tesla animal scanner for Spoiled gradient recalled echo (SPGR) T1-weighted, fast imaging employing steady-state acquisition (FIESTA) T2-weighted, conventional T2-weighted, and T2*-weighted functional MRI using the blood oxygen level-dependent (BOLD) contrast. Signal intensities and resting-state functional connectivity (RSFC) were determined and compared between groups.
Results: T1 intensity was significantly increased in the hippocampus, thalamus, and sensory/piriform/entorhinal cortices in GD treated groups compared to the controls. T1 decreases (atrophy) in the subventricular zones, rostral hippocampus, nucleus accumbens, and amygdala of GD+veh animals were significantly attenuated in the GD +1400W group. 1400W treatment significantly lowered the GD-induced FIESTA-T2 enhancements in the hippocampus, subventricular zones, corpus callosum, substantia nigra, amygdala, and piriform cortex. The effects of 1400W in T1 and FIESTA-T2 are mainly driven by male rats. In contrast, conventional T2 showed similar regional effects of GD with no significant effects of 1400W. The RSFC signal in the hippocampal, cortical, and thalamic network connectivity, was significantly reduced in GD+veh group, whereas GD+1400W group revealed significant improvement except in the thalamus.
Conclusions: Both T1 and T2 analyses identified unique brain abnormalities associated with soman exposure, indicating the robustness and sensitivity of these approaches. 1400W treatment rescues soman-induced T1 (SPGR) and FIESTA-T2 intensity changes, but not in the conventional T2. RSFC MRI suggests that 1400W protects the loss of connectivity in hippocampal and cortical epileptic foci. Overall, this study highlights the ability of structural and functional MRI modalities to capture the pathological features of soman-induced neurotoxicity and the neuroprotective effects of 1400W.
Funding: NIH/NINDS (U01 NS117284-01A1)
Basic Mechanisms