Evaluation of acetylcholine, seizure activity and neuropathology following high-dose nerve agent exposure and delayed neuroprotective treatment drugs in freely moving rats

Abstract

Organophosphorus nerve agents such as soman (GD) inhibit acetylcholinesterase, producing an excess of acetylcholine (ACh), which results in respiratory distress, convulsions and status epilepticus that leads to neuropathology. Several drugs (topiramate, clobazam, pregnanolone, allopregnanolone, UBP 302, cyclopentyladenosine [CPA], ketamine, midazolam and scopolamine) have been identified as potential neuroprotectants that may terminate seizures and reduce brain damage. To systematically evaluate their efficacy, this study employed in vivo striatal microdialysis and liquid chromatography to respectively collect and analyze extracellular ACh in freely moving rats treated with these drugs 20 min after seizure onset induced by a high dose of GD. Along with microdialysis, EEG activity was recorded and neuropathology assessed at 24 h. GD induced a marked increase of ACh, which peaked at 30 min post-exposure to 800% of control levels and then steadily decreased toward baseline levels. Approximately 40 min after treatment, only midazolam (10 mg/kg) and CPA (60 mg/kg) caused a significant reduction of ACh levels, with CPA reducing ACh levels more rapidly than midazolam. Both drugs facilitated a return to baseline levels at least 55 min after treatment. At 24 h, only animals treated with CPA (67%), midazolam (18%) and scopolamine (27%) exhibited seizure termination. While all treatments except for topiramate reduced neuropathology, CPA, midazolam and scopolamine showed the greatest reduction in pathology. Our results suggest that delayed treatment with CPA, midazolam, or scopolamine is effective at reducing GD-induced seizure activity and neuropathology, with CPA and midazolam capable of facilitating a reduction in GD-induced ACh elevation.

Antiseizure and neuroprotective effects of delayed treatment with midazolam in a rodent model of organophosphate exposure

“…These data are consistent with those of other reports that have shown little or no effect of MDZ on neuronal death in delayed treatment (≥40 minutes) of NA‐induced SE . In contrast, treatment with MDZ at 10 to 20 minutes appears to be effective at reducing neuronal death . Our analysis of the change in power in the gamma band for up to 20 hours from the time of treatment suggests that the observed neuronal damage may be affected by the reemergence of epileptiform activity hours after treatment, which is similar to what has been previously shown by Wu et al …”

“…13,39,40 In contrast, treatment with MDZ at 10 to 20 minutes appears to be effective at reducing neuronal death. 40,46 Our analysis of the change in power in the gamma band for up to 20 hours from the time of treatment suggests that the observed neuronal damage may be affected by the reemergence of epileptiform activity hours after treatment, which is similar to what has been previously shown by Wu et al 40 The primary goal of the CNS Program is to provide a screening assay available to any participant who is interested in generating data toward application for grant funding from the CounterACT program. As such, the scope of the work here is limited to the development of a medium-throughput assay that somewhat models a real-life exposure scenario, and not open to traditional academic scientific endeavor.…”

Altered Fecal Microbiota and Urine Metabolome as Signatures of Soman Poisoning

“…Similarly, Beta Diversity were calculated using QIIME and visualized using Principal Coordinate Analysis (PCoA) to visualize distances between samples on an x-y-z plot. The ranked abundance profile was created using BiodiversityR R Bioconductor package (2 7-2…”

“…Soman, pinacolyl methylphosphonofluoridate or GD (German agent D), is one of the G class nerve agents (volatile agents associated with inhalation toxicity) that inhibits AChE much more rapidly but less specifically than V class nerve agents (viscous agents associated with transdermal toxicity) (2, 6, 8). Whole body autoradiography studies in mice revealed that intravenously administered tritiated-soman ( 3 H-soman) spreads within the entire body in less than 5 min (9).…”

The Use of Intracerebral Microdialysis to Elucidate Environmentally Induced Neurotoxic Mechanisms

“…Acon‐Chen et al. () also studied the acute effects of soman and tested several drugs for their post‐exposure neuroprotectant properties versus seizures and neuropathology in rats. Striatal microdialysis was employed to monitor the changes in extracellular acetylcholine induced by soman: The neurotransmitter peaked 30 min post‐exposure at 8‐fold levels over baseline.…”