Giovannini M G, Scali C, Bartolini L, Schmidt B, Pepeu G
Department of Preclinical and Clinical Pharmacology, University of Florence, Italy.
Eur J Pharmacol. 1998 Jul 31;354(1):17-24. doi: 10.1016/s0014-2999(98)00429-4.
The effects of 21-day treatment with the acetylcholinesterase inhibitors metrifonate (80 mg kg(-1) per os (p.o.)) and tacrine (3 mg kg(-1) p.o.), twice daily, on cortical and hippocampal cholinergic systems were investigated in aged rats (24-26 months). Extracellular acetylcholine levels were measured by transversal microdialysis in vivo; choline acetyltransferase and acetylcholinesterase activities were measured ex vivo by means of radiometric methods. Basal cortical and hippocampal extracellular acetylcholine levels, measured 18 h after the last metrifonate treatment, were about 15 and two folds higher, respectively, than in control and tacrine-treated rats. A challenge with metrifonate further increased cortical and hippocampal acetylcholine levels by about three and four times, respectively. Basal extracellular acetylcholine levels, measured 18 h after the last treatment with tacrine were not statistically different from those of the control rats. A challenge with tacrine increased cortical and hippocampal extracellular acetylcholine levels by about four and two times. A 75% inhibition of cholinesterase activity was found 18 h after the last metrifonate administration, while only a 15% inhibition was detectable 18 h after the last tacrine administration. The challenge with metrifonate or tacrine resulted in 90 and 80% cholinesterase inhibition, respectively. These results demonstrate that in aging rats a subchronic treatment with metrifonate results in a long-lasting, cholinesterase inhibition, and a persistent increase in acetylcholine extracellular levels which compensate for the age-associated cholinergic hypofunction. Metrifonate is therefore a potentially useful agent for the cholinergic deficit accompanying Alzheimer's disease.
研究了在老年大鼠（24 - 26个月）中，每日两次口服给予乙酰胆碱酯酶抑制剂美曲膦酯（80毫克/千克）和他克林（3毫克/千克），连续治疗21天对皮质和海马胆碱能系统的影响。通过体内横向微透析测量细胞外乙酰胆碱水平；通过放射测量法离体测量胆碱乙酰转移酶和乙酰胆碱酯酶活性。在最后一次美曲膦酯治疗18小时后测量的基础皮质和海马细胞外乙酰胆碱水平，分别比对照组和他克林治疗组大鼠高约15倍和两倍。用美曲膦酯激发可使皮质和海马乙酰胆碱水平分别进一步增加约三倍和四倍。在最后一次他克林治疗18小时后测量的基础细胞外乙酰胆碱水平与对照大鼠无统计学差异。用他克林激发可使皮质和海马细胞外乙酰胆碱水平分别增加约四倍和两倍。在最后一次美曲膦酯给药18小时后发现胆碱酯酶活性受到75%的抑制，而在最后一次他克林给药18小时后仅可检测到15%的抑制。用美曲膦酯或他克林激发分别导致胆碱酯酶抑制90%和80%。这些结果表明，在老年大鼠中，亚慢性给予美曲膦酯可导致持久的胆碱酯酶抑制以及乙酰胆碱细胞外水平持续升高，这补偿了与年龄相关的胆碱能功能减退。因此，美曲膦酯是治疗阿尔茨海默病伴发的胆碱能缺陷的潜在有用药物。
