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.

Autor: Vasanthi SS; Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011, USA., Rao NS; Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011, USA., Samidurai M; Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011, USA., Massey N; Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011, USA., Meyer C; Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011, USA., Gage M; Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011, USA., Kharate M; Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011, USA., Almanza A; Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011, USA., Wachter L; Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011, USA., Mafuta C; Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011, USA., Trevino L; Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011, USA., Carlo AM; Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011, USA., Bryant E; Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011, USA., Corson BE; Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011, USA., Wohlgemuth M; Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011, USA., Ostrander M; Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011, USA., Showman L; W.M. Keck Metabolomics Research Laboratory, College of Veterinary Medicine, Iowa State University, Ames, 50011, USA., Wang C; Department of Veterinary Diagnostic and Production Animal Medicine and Statistics, College of Veterinary Medicine, Iowa State University, Ames, 50011, USA., Thippeswamy T; Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011, USA. tswamy@iastate.edu.
Jazyk: angličtina
Zdroj: Journal of neuroinflammation [J Neuroinflammation] 2023 Jul 12; Vol. 20 (1), pp. 163. Date of Electronic Publication: 2023 Jul 12.
DOI: 10.1186/s12974-023-02847-1
Abstrakt: Background: Acute exposure to seizurogenic organophosphate (OP) nerve agents (OPNA) such as diisopropylfluorophosphate (DFP) or soman (GD), at high concentrations, induce immediate status epilepticus (SE), reactive gliosis, neurodegeneration, and epileptogenesis as a consequence. Medical countermeasures (MCMs-atropine, oximes, benzodiazepines), if administered in < 20 min of OPNA exposure, can control acute symptoms and mortality. However, MCMs alone are inadequate to prevent OPNA-induced brain injury and behavioral dysfunction in survivors. We have previously shown that OPNA exposure-induced SE increases the production of inducible nitric oxide synthase (iNOS) in glial cells in both short- and long- terms. Treating with a water soluble and highly selective iNOS inhibitor, 1400W, for 3 days significantly reduced OPNA-induced brain changes in those animals that had mild-moderate SE in the rat DFP model. However, such mitigating effects and the mechanisms of 1400W are unknown in a highly volatile nerve agent GD exposure.
Methods: Mixed-sex cohort of adult Sprague Dawley rats were exposed to GD (132 μg/kg, s.c.) and immediately treated with atropine (2 mg/kg, i.m) and HI-6 (125 mg/kg, i.m.). Severity of seizures were quantified for an hour and treated with midazolam (3 mg/kg, i.m.). An hour post-midazolam, 1400W (20 mg/kg, i.m.) or vehicle was administered daily for 2 weeks. After behavioral testing and EEG acquisition, animals were euthanized at 3.5 months post-GD. Brains were processed for neuroinflammatory and neurodegeneration markers. Serum and CSF were used for nitrooxidative and proinflammatory cytokines assays.
Results: We demonstrate a significant long-term (3.5 months post-soman) disease-modifying effect of 1400W in animals that had severe SE for > 20 min of continuous convulsive seizures. 1400W significantly reduced GD-induced motor and cognitive dysfunction; nitrooxidative stress (nitrite, ROS; increased GSH: GSSG); proinflammatory cytokines in the serum and some in the cerebrospinal fluid (CSF); epileptiform spikes and spontaneously recurring seizures (SRS) in males; reactive gliosis (GFAP + C3 and IBA1 + CD68-positive glia) as a measure of neuroinflammation, and neurodegeneration (especially parvalbumin-positive neurons) in some brain regions.
Conclusion: These findings demonstrate the long-term disease-modifying effects of a glial-targeted iNOS inhibitor, 1400W, in a rat GD model by modulating reactive gliosis, neurodegeneration (parvalbumin-positive neurons), and neuronal hyperexcitability.
(© 2023. The Author(s).)
Databáze: MEDLINE
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