Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
Defence Research and Development Canada- Suffield Research Centre, Department of National Defence, Suffield, Alberta, Canada.
Neurotoxicology. 2018 Mar;65:28-37. doi: 10.1016/j.neuro.2018.01.007. Epub 2018 Jan 31.
Nerve agents (NAs) are potent organophosphorus (OP) compounds with applications in chemical warfare. OP compounds act by inhibiting acetylcholinesterase (AChE). Soman (O-pinacolyl methylphosphonofluoridate) is one of the most potent NAs. It is well known that small doses of NAs can be lethal, and that even non-lethal exposure leads to long-term mental debilitation/neurological damage. However, the neuropathology following exposure to sub-lethal nerve agents is not well understood. In this study, we examined changes in tissue oxygenation (pO) in the cortex and hippocampus after a sub-lethal dose of soman [80-90 μg/kg; subcutaneous]. pO changes can provide information regarding oxygen delivery and utilization and may be indicative of a disruption in cerebral blood flow and/or metabolism. Changes in oxygenation were measured with chronically implanted oxygen sensors in awake and freely moving rats. Measurements were taken before, during, and after soman-induced convulsive seizures. Soman exposure resulted in an immediate increase in pO in the cortex, followed by an even greater increase that precedes the onset of soman-induced convulsive seizures. The rise in hippocampus pO was delayed relative to the cortex, although the general pattern of brain oxygenation between these two regions was similar. After convulsive seizures began, pO levels declined but usually remained hyperoxygenated. Following the decline in pO, low frequency cycles of large amplitude changes were observed in both the cortex and hippocampus. This pattern is consistent with recurring seizures. Measuring real-time changes in brain pO provides new information on the physiological status of the brain following soman exposure. These results highlight that the measurement of brain oxygenation could provide a sensitive marker of nerve agent exposure and serve as a biomarker for treatment studies.
神经毒剂（NAs）是具有应用于化学战潜力的强效有机磷（OP）化合物。OP 化合物通过抑制乙酰胆碱酯酶（AChE）起作用。梭曼（O-频哪醇基甲基膦酸氟化物）是最有效的 NAs 之一。众所周知，小剂量的 NAs 可能是致命的，即使非致命暴露也会导致长期精神衰弱/神经损伤。然而，亚致死剂量神经毒剂暴露后的神经病理学尚不清楚。在这项研究中，我们检查了亚致死剂量梭曼[80-90μg/kg；皮下]暴露后皮质和海马中的组织氧合（pO）变化。pO 变化可提供有关氧输送和利用的信息，并且可能表明脑血流和/或代谢中断。使用慢性植入的氧传感器在清醒和自由活动的大鼠中测量氧合变化。在梭曼诱导的惊厥发作之前、期间和之后进行测量。梭曼暴露会立即增加皮质中的 pO，随后在梭曼诱导的惊厥发作之前出现更大的增加。海马体 pO 的上升相对于皮质延迟，尽管这两个区域之间的大脑氧合总体模式相似。在惊厥发作开始后，pO 水平下降但通常仍保持高氧合。pO 下降后，在皮质和海马体中观察到低频大振幅变化的循环。这种模式与反复发生的惊厥一致。测量大脑 pO 的实时变化为梭曼暴露后大脑的生理状态提供了新信息。这些结果表明，测量大脑氧合可能提供神经毒剂暴露的敏感标志物，并作为治疗研究的生物标志物。
