Baireddy Praveena, Mirajkar Nikita, Nallapaneni Anuradha, Singleton Nicole, Pope Carey N
Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University, 264 McElroy Hall, Stillwater, OK 74078, USA.
Arch Toxicol. 2007 Apr;81(4):283-9. doi: 10.1007/s00204-006-0144-7. Epub 2006 Aug 30.
A number of studies have evaluated the possibility that stress-induced changes in blood-brain barrier permeability enhanced the central effects of the carbamate acetylcholinesterase inhibitor, pyridostigmine. We previously found relatively little evidence of stress-induced changes in the acute toxicity of pyridostigmine in rats using a variety of restraint, forced running and forced swimming stress conditions. In this study, we evaluated the effects of sequential pre-exposure to multiple stressors on the acute toxicity of pyridostigmine. Rats (n = 8 per treatment group) were either un-stressed or stressed by restraint (60 min), forced running (60 min, 15 m/min, 6 degrees incline) and forced swimming (15 min), and then given either vehicle (saline, 1 ml/kg, po) or pyridostigmine (30 mg/kg, po) immediately after the final stressor. Functional signs of cholinergic toxicity (involuntary movements, autonomic dysfunction) were recorded at 0.5, 1 and 2 h after dosing. Body temperature was measured both before stress and 2 h after dosing. Rats were sacrificed immediately after 2-h functional observations to collect tissues (whole blood, diaphragm, frontal cortex, hippocampus and cerebellum) for measurement of cholinesterase activity. Stressed rats treated with pyridostigmine exhibited higher lethality (2/8) compared to unstressed rats given pyridostigmine (0/8). Pyridostigmine elicited classical signs of cholinergic toxicity, but the rats that died did not show increased cholinergic signs and no significant differences in cholinergic signs were noted between treatment groups. Cholinesterase activity was significantly inhibited in blood (47-50%) and diaphragm (80%) following pyridostigmine exposure regardless of stress conditions. Slight but significant inhibition (11-15%) of cerebellar cholinesterase activity was observed following pyridostigmine exposure, but inhibition was not influenced by stress. We conclude that while acute lethality from pyridostigmine may be increased by combined, multiple stressors, increased lethality does not appear due to enhanced cholinergic toxicity or via increased cholinesterase inhibition in either central or peripheral tissues.
多项研究评估了应激诱导的血脑屏障通透性变化增强氨基甲酸酯类乙酰胆碱酯酶抑制剂吡啶斯的明中枢效应的可能性。我们之前发现，在使用多种束缚、强迫跑步和强迫游泳应激条件下，应激诱导的吡啶斯的明对大鼠急性毒性变化的证据相对较少。在本研究中，我们评估了序贯预先暴露于多种应激源对吡啶斯的明急性毒性的影响。大鼠（每个治疗组n = 8）要么不施加应激，要么通过束缚（60分钟）、强迫跑步（60分钟，15米/分钟，6度坡度）和强迫游泳（15分钟）施加应激，然后在最后一个应激源后立即给予载体（生理盐水，1毫升/千克，口服）或吡啶斯的明（30毫克/千克，口服）。在给药后0.5、1和2小时记录胆碱能毒性的功能体征（不自主运动、自主神经功能障碍）。在应激前和给药后2小时测量体温。在2小时功能观察后立即处死大鼠，收集组织（全血、膈肌、额叶皮质、海马和小脑）用于测量胆碱酯酶活性。与给予吡啶斯的明的未应激大鼠（0/8）相比，给予吡啶斯的明的应激大鼠表现出更高的致死率（2/8）。吡啶斯的明引发了胆碱能毒性的典型体征，但死亡的大鼠未表现出胆碱能体征增加，且各治疗组之间胆碱能体征无显著差异。无论应激条件如何，吡啶斯的明暴露后血液（47 - 50%）和膈肌（80%）中的胆碱酯酶活性均受到显著抑制。吡啶斯的明暴露后观察到小脑胆碱酯酶活性有轻微但显著的抑制（11 - 15%），但抑制不受应激影响。我们得出结论，虽然联合多种应激源可能会增加吡啶斯的明的急性致死率，但致死率增加似乎不是由于胆碱能毒性增强或中枢或外周组织中胆碱酯酶抑制增加所致。
