Journal article
Inhibiting iNOS with 1400W Reduces Soman (GD)-induced Ferroptosis in Long-term Epilepsy Associated Neuropathology: Structural and Functional MRI in correlations with neurobehavior and brain pathology
The Journal of pharmacology and experimental therapeutics, Vol.388(2), pp.724-738
02/2024
DOI: 10.1124/jpet.123.001929
PMCID: PMC10801728
PMID: 38129129
Abstract
Organophosphate (OP) nerve agent (OPNA) intoxication leads to long-term brain dysfunctions. However, the ineffectiveness of current treatments prompts a quest for more effective therapeutic approach. Our previous studies on 1400W, a highly selective nitric oxide synthase (iNOS) inhibitor, showed improvement in epilepsy and seizure-induced brain pathology in rat models of kainate and OP intoxication. In this study, magnetic resonance imaging (MRI) modalities, behaviors, and biological markers were evaluated and comprehensively examined for brain abnormalities following soman (GD) intoxication in a rat model. T1 and T2 MRI robustly identified pathological microchanges in brain structures associated with GD toxicity, while 1400W suppressed those aberrant alterations. Moreover, functional network reduction was evident in the cortex, hippocampus, and thalamus after GD exposure, while 1400W rescued the losses except in the thalamus. Behavior battery showed protection by1400W against GD-induced memory dysfunction which also correlated with the extent of brain damage observed in structural and functional MRIs. While GD upregulated iron-laden glial cells and ferritin levels in the brain and serum, 1400W decreased ferritin levels in the epileptic foci with no significant effects in the serum. The levels of ferritin also correlated with MRI parameters. Further, 1400W mitigated the overproduction of nitroxidative markers after GD exposure. Overall, this study provides direct evidence for relationships of structural and functional MRI modalities with behavioral and molecular abnormalities following GD exposure and the neuroprotective effect of an iNOS inhibitor, 1400W.
Our studies demonstrate the structural and functional MRI microchanges in the brain following GD toxicity, which strongly correlate with neurobehavioral performances and iron homeostasis. The inhibition of iNOS with 1400W mitigates GD-induced cognitive decline, iron dysregulation, and aberrant brain MRI findings.
Details
- Title: Subtitle
- Inhibiting iNOS with 1400W Reduces Soman (GD)-induced Ferroptosis in Long-term Epilepsy Associated Neuropathology: Structural and Functional MRI in correlations with neurobehavior and brain pathology
- Creators
- Marson Putra - Iowa State UniversitySuraj S Vasanthi - Iowa State UniversityNikhil S Rao - Iowa State UniversityChristina Meyer - Iowa State UniversityMadison Van Otterloo - Iowa State UniversityLal Thangi - Iowa State UniversityDaniel R Thedens - University of IowaSridhar S Kannurpatti - Rutgers New Jersey Medical School, United StatesThimmasettappa Thippeswamy - Iowa State University
- Resource Type
- Journal article
- Publication Details
- The Journal of pharmacology and experimental therapeutics, Vol.388(2), pp.724-738
- DOI
- 10.1124/jpet.123.001929
- PMID
- 38129129
- PMCID
- PMC10801728
- NLM abbreviation
- J Pharmacol Exp Ther
- eISSN
- 1521-0103
- Language
- English
- Electronic publication date
- 12/21/2023
- Date published
- 02/2024
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Radiology; Electrical and Computer Engineering
- Record Identifier
- 9984533456802771
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