Persistent brainwave disruption and cognitive impairment induced by acute sarin surrogate sub-lethal dose exposure

Area of Science:

• Neuroscience
• Toxicology
• Pharmacology

Background:

• Warfare neurotoxicants, including organophosphorus compounds like sarin, soman, and VX, are known cholinesterase inhibitors.
• High-dose nerve agent exposure can cause seizures and brain damage, but effects of sub-lethal acute exposure are less understood.

Purpose of the Study:

• To characterize behavioral, brain activity (ECoG), and neuroinflammatory changes following acute sub-lethal exposure to 4-nitrophenyl isopropyl methylphosphonate (NIMP), a sarin surrogate.
• To determine dose-dependent effects and long-term consequences of NIMP exposure.

Main Methods:

• Mice were exposed to four different doses of NIMP (0.3, 0.5, 0.7, 0.9 LD50).
• Behavioral scoring, cholinesterase (ChE) activity measurement, and electrocorticography (ECoG) were performed.
• Long-term ECoG recordings (30 days), neuroinflammatory marker analysis (IBA-1, TNF-α, NF-κB), and a novel object recognition test were conducted.

Main Results:

• Intoxication signs and ChE inhibition were dose-dependent. The lowest dose (0.3 LD50) showed no significant effects.
• Doses of 0.5, 0.7, and 0.9 LD50 NIMP caused dose-dependent behavioral changes, ChE inhibition, and disrupted brainwave patterns.
• Long-term (30-day) ECoG recordings revealed persistent theta rhythm impairment. Hippocampal ChE activity did not recover.
• Transient increases in neuroinflammatory markers and edema were observed in the hippocampus. Short-term memory was impaired one month post-exposure.

Conclusions:

• Sub-lethal NIMP exposure induces both transient and long-lasting electrocorticographic alterations.
• Cognitive impairments, specifically short-term memory deficits, persist one month after exposure.
• These neurophysiological and cognitive changes may contribute to further morphopathological alterations in the brain.