Garrone B, Luparini M R, Tolu L, Magnani M, Landolfi C, Milanese C
Laboratory of Neuropharmacology, Angelini Research, Roma, Italy.
Neurosci Lett. 1998 Mar 27;245(1):53-7. doi: 10.1016/s0304-3940(98)00133-5.
The effect of subchronic administration of the acetylcholinesterase (AChE) inhibitor heptastigmine (HEP 0.6 mg/kg s.c. daily for 15 days) was investigated on cortical extracellular acetylcholine (ACh) levels and on memory function in aged male rats (26 months old at the beginning of the experiments) using microdialysis and behavioural techniques. Twenty-four hours after the last treatment, cortical ACh levels were significantly higher in rats subchronically treated with HEP than in rats treated with saline and AChE activity was still inhibited in cortex, hippocampus and striatum. The injection of a challenge dose of HEP (0.6 mg/kg s.c.) 24 h after the last treatment produced a faster and a more sustained increase of ACh in the cortex of subchronically treated rats compared to those repeatedly injected with saline. However, the maximum increase of ACh levels after injection of the challenge was comparable in both groups. In an object recognition test in which the pretest and test phase were spaced by 45 days, HEP prevented the deterioration of spatial memory occurring during this period, but had no effect on non-spatial memory. The present results suggest that moderate inhibition of brain AChE is able to maintain high levels of cortical extracellular ACh in aged rats and that this increase matches facilitatory effect of HEP on spatial memory.
采用微透析和行为学技术，研究了亚慢性给予乙酰胆碱酯酶（AChE）抑制剂海他司明（HEP，每日皮下注射0.6mg/kg，共15天）对老年雄性大鼠（实验开始时26月龄）皮质细胞外乙酰胆碱（ACh）水平及记忆功能的影响。末次给药24小时后，亚慢性给予HEP的大鼠皮质ACh水平显著高于给予生理盐水的大鼠，且皮质、海马和纹状体中的AChE活性仍受到抑制。末次给药24小时后注射一次激发剂量的HEP（0.6mg/kg皮下注射），与反复注射生理盐水的大鼠相比，亚慢性给予HEP的大鼠皮质中ACh的升高更快且更持久。然而，注射激发剂后两组ACh水平的最大升高幅度相当。在一项物体识别试验中，预试验和试验阶段间隔45天，HEP可防止在此期间发生的空间记忆衰退，但对非空间记忆无影响。目前的结果表明，适度抑制脑AChE能够维持老年大鼠皮质细胞外ACh的高水平，且这种升高与HEP对空间记忆的促进作用相匹配。
