Pintor A, Fortuna S, Volpe M T, Michalek H
Laboratory of Pharmacology, Istituto Superiore di Sanità, Rome, Italy.
Life Sci. 1988;42(21):2113-21. doi: 10.1016/0024-3205(88)90125-7.
Potential age-related differences in the response of Fischer 344 rats to subchronic treatment with diisopropylfluorophosphate (DFP) were evaluated in terms of brain cholinesterase (ChE) inhibition and muscarinic receptor sites. Male 3- and 24-month old rats were sc injected with sublethal doses of DFP (first dose 1.6, subsequent doses 1.1 mg/kg on alternate days) for 2 weeks and killed 48 hrs after the last treatment. In the cerebral cortex, hippocampus and striatum of control rats a significant age-related reduction of ChE and of maximum number of 3H-QNB binding sites (Bmax) was observed. The administration of DFP to senescent rats resulted in more pronounced and longer lasting syndrome of cholinergic stimulation, with marked body weight loss and 60% mortality. The percentage inhibition of brain ChE induced by DFP (over 80% in all regions) did not differ between young and senescent rats. As expected, in young rats DFP caused a significant decrease of Bmax (without apparent changes in affinity), which in the cerebral cortex reached about 40%. In the surviving senescent rats, the percentage decrease of Bmax due to DFP with respect to age-matched controls was very similar to that of young animals, especially in the cerebral cortex. Thus, there is great variability in the response of aged rats to DFP treatment, from total failure of adaptive mechanisms resulting in death to considerable muscarinic receptor plasticity. The data support the view that the ability of central neurotransmitter systems to compensate for pathological or xenobiotic induced insult is an essential part of the aging process.
从脑胆碱酯酶（ChE）抑制和毒蕈碱受体位点方面，评估了Fischer 344大鼠对二异丙基氟磷酸酯（DFP）亚慢性治疗反应中潜在的年龄相关差异。给3月龄和24月龄雄性大鼠皮下注射亚致死剂量的DFP（首剂1.6mg/kg，随后隔日注射1.1mg/kg），持续2周，并在末次给药后48小时处死。在对照大鼠的大脑皮层、海马和纹状体中，观察到ChE以及3H-QNB结合位点最大数量（Bmax）存在显著的年龄相关降低。给老年大鼠施用DFP导致更明显且持续时间更长的胆碱能刺激综合征，伴有明显体重减轻和60%的死亡率。DFP诱导的脑ChE抑制百分比（所有区域均超过80%）在年轻和老年大鼠之间没有差异。正如预期的那样，在年轻大鼠中，DFP导致Bmax显著降低（亲和力无明显变化），在大脑皮层中达到约40%。在存活的老年大鼠中，DFP导致的Bmax相对于年龄匹配对照的降低百分比与年轻动物非常相似，尤其是在大脑皮层。因此，老年大鼠对DFP治疗的反应存在很大差异，从适应机制完全失效导致死亡到相当大的毒蕈碱受体可塑性。这些数据支持这样一种观点，即中枢神经递质系统补偿病理或外源性诱导损伤的能力是衰老过程的一个重要部分。
