1400 W, a selective inducible nitric oxide synthase inhibitor, mitigates early neuroinflammation and nitrooxidative stress in diisopropylfluorophosphate-induced short-term neurotoxicity rat model

by Selleckchem | Jul 29 2023

Organophosphate nerve agent (OPNA) exposure induces acute and long-term neurological deficits. OPNA exposure at sub-lethal concentrations induces irreversible inhibition of acetylcholinesterase and cholinergic toxidrome and develops status epilepticus (SE). Persistent seizures have been associated with increased production of ROS/RNS, neuroinflammation, and neurodegeneration. A total of 1400W is a novel small molecule, which irreversibly inhibits inducible nitric oxide synthase (iNOS) and has been shown to effectively reduce ROS/RNS generation. In this study, we investigated the effects of 1400W treatment for a week or two weeks at 10 mg/kg or 15 mg/kg per day in the rat diisopropylfluorophosphate (DFP) model. 1400W significantly reduced the number of microglia, astroglia, and NeuN+FJB positive cells compared to the vehicle in different regions of the brain. 1400W also significantly reduced nitrooxidative stress markers and proinflammatory cytokines in the serum. However, neither of the two concentrations of 1400W for two weeks of treatment had any significant effect on epileptiform spike rate and spontaneous seizures during the treatment period in mixed sex cohorts, males, or females. No significant sex differences were found in response to DFP exposure or 1400W treatment. In conclusion, 1400W treatment at 15 mg/kg per day for two weeks was more effective in significantly reducing DFP-induced nitrooxidative stress, neuroinflammatory and neurodegenerative changes.

Comments:

The study investigated the effects of a compound called 1400W on the neurological deficits caused by exposure to an organophosphate nerve agent (OPNA) called diisopropylfluorophosphate (DFP). OPNA exposure leads to the inhibition of acetylcholinesterase and the development of neurological symptoms. The researchers focused on the role of 1400W in reducing reactive oxygen and nitrogen species (ROS/RNS) generation, neuroinflammation, and neurodegeneration.

The study involved treating rats with 1400W for either one week or two weeks at two different doses: 10 mg/kg or 15 mg/kg per day. The researchers evaluated the effects of 1400W treatment by assessing various parameters in different brain regions and in the serum.

The results showed that 1400W treatment significantly reduced the number of microglia, astroglia, and NeuN+FJB positive cells compared to the control group (treated with vehicle) in various brain regions. This indicates a reduction in neuroinflammatory and neurodegenerative changes. Additionally, 1400W treatment significantly reduced nitrooxidative stress markers and proinflammatory cytokines in the serum, further suggesting a reduction in neuroinflammation.

However, the study did not find any significant effect of 1400W treatment on epileptiform spike rate or spontaneous seizures during the treatment period. This implies that 1400W did not have a significant impact on the occurrence of seizures in response to OPNA exposure.

The study also did not observe any significant differences between male and female rats in response to either DFP exposure or 1400W treatment.

In conclusion, the findings suggest that 1400W treatment at a dose of 15 mg/kg per day for two weeks was more effective in reducing DFP-induced nitrooxidative stress, neuroinflammatory changes, and neurodegeneration. However, it did not have a significant effect on the occurrence of seizures.