Tian Hailin, Song Xun, Bressler Joseph, Pruett Steve, Pope Carey N
Department of Physiological Sciences, College of Veterinary Medicine, 264 McElroy Hall, Oklahoma State University, Stillwater, OK 74078, USA.
Toxicology. 2002 Jul 1;176(1-2):39-50. doi: 10.1016/s0300-483x(02)00089-6.
Stress-induced change in the distribution of the drug pyridostigmine (PYR) has been proposed as a contributing factor to unexplained illnesses in Persian Gulf War veterans. We evaluated the effects of two stress models, forced running and forced swimming, on acute PYR (30 mg/kg, p.o.) toxicity and cholinesterase (ChE) inhibition in the blood and selected brain regions of young adult male Sprague-Dawley rats (6 weeks of age). Plasma corticosterone levels were measured at 0, 1 and 3 h after termination of forced swimming or forced running to confirm the induction of stress. PYR was given either immediately before stress (15 min swimming; 20 min running) or immediately after stress (15 min swimming; 90 min running) and cholinergic toxicity and ChE inhibition were evaluated at 1, 2 or 4 h after PYR exposure. Additionally, rats were subjected to either swimming (15 min) or running (90 min) stress, anesthetized, injected with horseradish peroxidase (HRP, 100 mg/kg, transcardial) and brain-regional HRP activity measured as an indicator of altered blood-brain barrier integrity. Both forced swimming and forced running resulted in significant elevations of plasma corticosterone levels. PYR caused cholinergic toxicity at all time-points evaluated. Swimming and running stress had little influence on expression of PYR-induced toxicity, however. Blood ChE activity was generally inhibited 77-91% at 1-4 h after PYR, but rats pretreated with PYR prior to forced swimming showed lesser inhibition (64%) 1 h after dosing, possibly because of swimming-induced hypothermia and delayed absorption of the drug. Minimal changes in ChE activity were noted in frontal cortex, cerebellum and hippocampus following PYR exposure (maximal inhibition 28%), and neither swimming nor running stress affected the degree of inhibition. Neither stress model increased HRP accumulation in any brain region. The results suggest that stress associated with forced running or forced swimming has little effect on acute PYR toxicity, entry of PYR into the brain or PYR-induced brain-regional ChE inhibition.
应激诱导的药物吡啶斯的明（PYR）分布变化被认为是导致海湾战争退伍军人出现不明病因疾病的一个因素。我们评估了两种应激模型，即强迫跑步和强迫游泳，对年轻成年雄性Sprague-Dawley大鼠（6周龄）血液及选定脑区中急性PYR（30mg/kg，口服）毒性和胆碱酯酶（ChE）抑制作用的影响。在强迫游泳或强迫跑步结束后的0、1和3小时测量血浆皮质酮水平，以确认应激的诱导情况。PYR在应激前（15分钟游泳；20分钟跑步）或应激后（15分钟游泳；90分钟跑步）立即给药，并在PYR暴露后的1、2或4小时评估胆碱能毒性和ChE抑制情况。此外，将大鼠置于游泳（15分钟）或跑步（90分钟）应激状态下，麻醉后经心内注射辣根过氧化物酶（HRP，100mg/kg），并测量脑区HRP活性，作为血脑屏障完整性改变的指标。强迫游泳和强迫跑步均导致血浆皮质酮水平显著升高。在所有评估的时间点，PYR均引起胆碱能毒性。然而，游泳和跑步应激对PYR诱导的毒性表达影响很小。PYR给药后1-4小时，血液ChE活性通常被抑制77-91%，但在强迫游泳前用PYR预处理的大鼠给药后1小时显示出较小的抑制作用（64%），这可能是由于游泳诱导的体温过低和药物吸收延迟所致。PYR暴露后，额叶皮质、小脑和海马体中的ChE活性变化最小（最大抑制率为28%），游泳和跑步应激均未影响抑制程度。两种应激模型均未增加任何脑区的HRP积累。结果表明，与强迫跑步或强迫游泳相关的应激对急性PYR毒性、PYR进入大脑或PYR诱导的脑区ChE抑制作用影响很小。
