Defence Research and Development Establishment, Defence Research and Development Organization, Gwalior, India.
J Appl Toxicol. 2009 Jul;29(5):386-94. doi: 10.1002/jat.1424.
A time-course study was carried out to measure the acetylcholinesterase (AChE) gene expression in the brain of female rats exposed to different doses of sarin and physostigmine. Short-term effects were studied with an acute single subcutaneous dose (s.c.) of 80 microg kg(-1) (0.5 x LD(50)) sarin. Cortex and cerebellum showed a significant decline in AChE mRNA expression at 2.5, 24 and 72 h. Biochemical studies showed that plasma butrylcholinesterase (BChE) and brain AChE activities were significantly decreased at 2.5 h, which came back to near control values by 24 h in both cases. For long-term chronic studies, three groups of female rats received daily doses of physostigmine (0.1 mg kg(-1) day(-1)) intramuscularly (i.m.), sarin (15 microg kg(-1) day(-1)) s.c. independently and a combined dose of physostigmine (i.m.) (0.1 mg kg(-1) day(-1)) followed by sarin (s.c.) (15 microg kg(-1) day(-1)) continuously for 30 days. Differential AChE mRNA levels in cortex and cerebellum of rat brain were observed after 30 days and after a lag period of another 30 days with no further administration. Plasma (BChE) and brain (AChE) showed irregular inhibition profile in biochemical studies at 30 days and returned to control levels after 60 days. The acute single subcutaneous administration of sarin for short-term as well as chronic long-term studies showed that AChE inhibition alone does not lead to observed changes in mRNA expression of AChE gene. These observations further suggest that route of administration as well as dose exposure regimen also contributes to the regulation of AChE mRNA expression.
进行了一项时程研究，以测量暴露于不同剂量沙林和毒扁豆碱的雌性大鼠大脑中的乙酰胆碱酯酶（AChE）基因表达。通过单次急性皮下剂量（s.c.）80μg kg（-1）（0.5 x LD（50））沙林研究了短期影响。皮质和小脑在 2.5、24 和 72 h 时 AChE mRNA 表达显着下降。生化研究表明，血浆丁酰胆碱酯酶（BChE）和脑 AChE 活性在 2.5 h 显着降低，两种情况下在 24 h 均恢复到接近对照值。对于长期慢性研究，三组雌性大鼠分别接受肌内（i.m.）每日剂量的毒扁豆碱（0.1 mg kg（-1）天（-1）），皮下（s.c.）沙林（15μg kg（-1）天（-1））独立和毒扁豆碱（i.m.）（0.1 mg kg（-1）天（-1））的组合剂量随后连续 30 天皮下（s.c.）沙林（15μg kg（-1）天（-1））。在 30 天后和没有进一步给药的另外 30 天后观察到大鼠脑皮质和小脑的 AChE mRNA 水平差异。在 30 天和 60 天后的生化研究中，血浆（BChE）和脑（AChE）显示出不规则的抑制谱。急性单次皮下给予沙林进行短期和长期慢性研究表明，AChE 抑制本身不会导致 AChE 基因 mRNA 表达的观察到的变化。这些观察结果进一步表明，给药途径以及剂量暴露方案也有助于 AChE mRNA 表达的调节。
