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Diapocynin, an NADPH oxidase inhibitor, counteracts diisopropylfluorophosphate-induced long-term neurotoxicity in the rat model.

ABSTRACT: Organophosphate (OP) nerve agents are a threat to both the military and civilians. OP exposure causes cholinergic crisis and status epilepticus (SE) because of irreversible inhibition of acetylcholinesterase that can be life-threatening if left untreated. OP survivors develop long-term morbidity, such as cognitive impairment and motor dysfunction, because of oxidative stress and progressive neuroinflammation and neurodegeneration, which act as disease promoters. Current medical countermeasures (MCMs) do not mitigate these pathologies. Therefore, our goal was to target these disease promoters using diapocynin (DPO), an NADPH oxidase inhibitor, in addition to MCMs, in a rat diisopropylfluorophosphate (DFP) model. The DFP-intoxicated rats were treated with DPO (300 mg/kg, oral, six doses, 12-h intervals) or vehicle 2 h following behavioral SE termination with diazepam. The DPO treatment significantly rescued DFP-induced motor impairment and attenuated epileptiform spiking during the first 72 h after DFP exposure in severely seizing rats despite no difference in epileptiform spike rate between the vehicle and DPO groups in mild SE rats. DPO significantly reduced DFP-induced reactive astrogliosis, neurodegeneration, GP91^phox , glutathiolated protein, serum nitrite, and proinflammatory cytokines and chemokines, such as interleukins (ILs) IL-1α, IL-6, IL-2, IL-17A, leptin, and IP-10, in the hippocampus. Collectively, these data support a neuroprotective role of DPO in an OP-induced neurotoxicity model.

SUBMITTER: Putra M

PROVIDER: S-EPMC7415478 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Chemical nerve agents (CNA) are increasingly becoming a threat to both civilians and military personnel. CNA-induced acute effects on the nervous system have been known for some time and the long-term consequences are beginning to emerge. In this study, we used diisopropylfluorophosphate (DFP), a seizurogenic CNA to investigate the long-term impact of its acute exposure on the brain and its mitigation by an inducible nitric oxide synthase (iNOS) inhibitor, 1400W as a neuroprotectant in the rat model. Several experimental studies have demonstrated that DFP-induced seizures and/or status epilepticus (SE) causes permanent brain injury, even after the countermeasure medication (atropine, oxime, and diazepam). In the present study, DFP-induced SE caused a significant increase in iNOS and 3-nitrotyrosine (3-NT) at 24?h, 48?h, 7d, and persisted for a long-term (12?weeks post-exposure), which led to the hypothesis that iNOS is a potential therapeutic target in DFP-induced brain injury. To test the hypothesis, we administered 1400W (20?mg/kg, i.m.) or the vehicle twice daily for the first three days of post-exposure. 1400W significantly reduced DFP-induced iNOS and 3-NT upregulation in the hippocampus and piriform cortex, and the serum nitrite levels at 24?h post-exposure. 1400W also prevented DFP-induced mortality in <24?h. The brain immunohistochemistry (IHC) at 7d post-exposure revealed a significant reduction in gliosis and neurodegeneration (NeuN+ FJB positive cells) in the 1400W-treated group. 1400W, in contrast to the vehicle, caused a significant reduction in the epileptiform spiking and spontaneous recurrent seizures (SRS) during 12?weeks of continuous video-EEG study. IHC of brain sections from the same animals revealed a significant reduction in reactive gliosis (both microgliosis and astrogliosis) and neurodegeneration across various brain regions in the 1400W-treated group when compared to the vehicle-treated group. A multiplex assay from hippocampal lysates at 6?weeks post-exposure showed a significant increase in several key pro-inflammatory cytokines/chemokines such as IL-1?, TNF?, IL-1?, IL-2, IL-6, IL-12, IL-17a, MCP-1, LIX, and Eotaxin, and a growth factor, VEGF in the vehicle-treated animals. 1400W significantly suppressed IL-1?, TNF?, IL-2, IL-12, and MCP-1 levels. It also suppressed DFP-induced serum nitrite levels at 6?weeks post-exposure. In the Morris water maze, the vehicle-treated animals spent significantly less time in the target quadrant in a probe trial at 9d post-exposure compared to their time spent in the same quadrant 11?days previously (i.e., 2?days prior to DFP exposure). Such a difference was not observed in the 1400W and control groups. However, learning and short-term memory were unaffected when tested at 10-16d and 28-34d post-exposure. Accelerated rotarod, horizontal bar test, and the forced swim test revealed no significant changes between groups. Overall, the findings from this study suggest that 1400W may be considered as a potential therapeutic agent as a follow-on therapy for CNA exposure, after controlling the acute symptoms, to prevent mortality and some of the long-term neurotoxicity parameters such as epileptiform spiking, SRS, neurodegeneration, reactive gliosis in some brain regions, and certain key proinflammatory cytokines and chemokine.

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Diapocynin, an NADPH oxidase inhibitor, counteracts diisopropylfluorophosphate-induced long-term neurotoxicity in the rat model.

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