Santucci A C, Haroutunian V, Davis K L
Psychiatry Service, Bronx Veterans Administration Medical Center, New York.
Clin Neuropharmacol. 1991;14 Suppl 1:S1-8. doi: 10.1097/00002826-199114001-00002.
Data derived from a number of preclinical studies examining the effects of combined cholinergic and noradrenergic lesions in a rat model of Alzheimer's disease are reviewed. Results from these studies indicated that a nucleus basalis of Meynert (nbM) lesion combined with a lesion of the ascending noradrenergic bundle (ANB) did not exacerbate 72-h passive avoidance retention deficits beyond the degree of impairment produced by nbM lesions alone. However, the addition of an ANB lesion did block the efficacy of two choiinomimetics (physostigmine and oxotremorine) to reverse the lesion-induced memory impairment. Memory in combined lesioned rats was restored when cholinomimetic therapy was administered in combination with low doses of clonidine. Studies investigating a number of Hoechst-Roussel Pharmaceuticals compounds have produced memory-enhancing effects in animals prepared with combined nbM/ANB lesions without the need for clonidine supplementation. These compounds include P128, P86-7493, and P87-8184. Moreover, these compounds have also been shown to be effective in reversing passive avoidance memory deficits in animals with nbM lesions and treated with the noradrenergic toxin DSP-4. Implications for pharmacotherapeutic approaches for the treatment of Alzheimer's disease are discussed.
本文综述了多项临床前研究的数据，这些研究考察了在阿尔茨海默病大鼠模型中联合胆碱能和去甲肾上腺素能损伤的影响。这些研究结果表明，Meynert基底核（nbM）损伤与去甲肾上腺素能上行束（ANB）损伤相结合，并不会使72小时被动回避记忆保持缺陷比单独的nbM损伤所产生的损害程度更严重。然而，添加ANB损伤确实会阻断两种拟胆碱药（毒扁豆碱和氧化震颤素）逆转损伤诱导的记忆障碍的效果。当拟胆碱药疗法与低剂量可乐定联合使用时，联合损伤大鼠的记忆得以恢复。对Hoechst-Roussel制药公司的多种化合物进行的研究在制备了联合nbM/ANB损伤的动物中产生了记忆增强作用，而无需补充可乐定。这些化合物包括P128、P86 - 7493和P87 - 8184。此外，这些化合物还被证明能有效逆转患有nbM损伤并用去甲肾上腺素能毒素DSP - 4治疗的动物的被动回避记忆缺陷。本文还讨论了对阿尔茨海默病药物治疗方法的启示。
