Schliebs R, Liebmann A, Bhattacharya S K, Kumar A, Ghosal S, Bigl V
Paul Flechsig Institute for Brain Research, Department of Neurochemistry, University of Leipzig, Germany.
Neurochem Int. 1997 Feb;30(2):181-90. doi: 10.1016/s0197-0186(96)00025-3.
Although some promising results have been achieved by acetylcholinesterase inhibitors, an effective therapeutic intervention in Alzheimer's disease still remains an important goal. Sitoindosides VII-X, and withaferin-A, isolated from aqueous methanol extract from the roots of cultivated varieties of Withania somnifera (known as Indian Ginseng), as well as Shilajit, a pale-brown to blackish brown exudation from steep rocks of the Himalaya mountain, are used in Indian medicine to attenuate cerebral functional deficits, including amnesia, in geriatric patients. The present investigation was conducted to assess whether the memory-enhancing effects of plant extracts from Withania somnifera and Shilajit are owing to neurochemical alterations of specific transmitter systems. Therefore, histochemistry to analyse acetylcholinesterase activity as well as receptor autoradiography to detect cholinergic, glutamatergic and GABAergic receptor subtypes were performed in brain slices from adult male Wistar rats, injected intraperitoneally daily with an equimolar mixture of sitoindosides VII-X and withaferin-A (prepared from Withania somnifera) or with Shilajit, at doses of 40 mg/kg of body weight for 7 days. Administration of Shilajit led to reduced acetylcholinesterase staining, restricted to the basal forebrain nuclei including medial septum and the vertical limb of the diagonal band. Systemic application of the defined extract from Withania somnifera, however, led to differential effects on AChE activity in basal forebrain nuclei: slightly enhanced AChE activity was found in the lateral septum and globus pallidus, whereas in the vertical diagonal band AChE activity was reduced following treatment with sitoindosides VII-X and withaferin-A. These changes were accompanied by enhanced M1-muscarinic cholinergic receptor binding in lateral and medial septum as well as in frontal cortices, whereas the M2-muscarinic receptor binding sites were increased in a number of cortical regions including cingulate, frontal, piriform, parietal and retrosplenial cortex. Treatment with Shilajit or the defined extract from Withania somnifera affected neither GABAA and benzodiazepine receptor binding nor NMDA and AMPA glutamate receptor subtypes in any of the cortical or subcortical regions studied. The data suggest that Shilajit and the defined extract from Withania somnifera affect preferentially events in the cortical and basal forebrain cholinergic signal transduction cascade. The drug-induced increase in cortical muscarinic acetylcholine receptor capacity might partly explain the cognition-enhancing and memory-improving effects of extracts from Withania somnifera observed in animals and humans.
尽管乙酰胆碱酯酶抑制剂已取得了一些令人鼓舞的成果，但对阿尔茨海默病进行有效的治疗干预仍是一个重要目标。从栽培的睡茄（又称印度人参）根的甲醇提取物中分离出的 sitoindosides VII-X 和睡茄素 A，以及从喜马拉雅山陡峭岩石上的浅棕色至黑褐色渗出物希拉季特，在印度医学中用于减轻老年患者的脑功能缺陷，包括失忆。本研究旨在评估睡茄和希拉季特的植物提取物增强记忆的作用是否归因于特定递质系统的神经化学改变。因此，对成年雄性 Wistar 大鼠进行了组织化学分析乙酰胆碱酯酶活性以及受体放射自显影以检测胆碱能、谷氨酸能和 GABA 能受体亚型，这些大鼠每天腹腔注射 40mg/kg 体重的 sitoindosides VII-X 和睡茄素 A（从睡茄制备）或希拉季特的等摩尔混合物，持续 7 天。给予希拉季特导致乙酰胆碱酯酶染色减少，仅限于基底前脑核，包括内侧隔和斜角带垂直支。然而，系统性应用从睡茄中提取的特定提取物对基底前脑核中的乙酰胆碱酯酶活性产生了不同的影响：在外侧隔和苍白球中发现乙酰胆碱酯酶活性略有增强，而在用 sitoindosides VII-X 和睡茄素 A 治疗后，垂直对角带中的乙酰胆碱酯酶活性降低。这些变化伴随着外侧和内侧隔以及额叶皮质中 M1-毒蕈碱胆碱能受体结合增强，而 M2-毒蕈碱受体结合位点在包括扣带回、额叶、梨状、顶叶和压后皮质在内的多个皮质区域增加。用希拉季特或从睡茄中提取的特定提取物治疗在所研究的任何皮质或皮质下区域均未影响 GABAA 和苯二氮䓬受体结合以及 NMDA 和 AMPA 谷氨酸受体亚型。数据表明，希拉季特和从睡茄中提取的特定提取物优先影响皮质和基底前脑胆碱能信号转导级联中的事件。药物诱导的皮质毒蕈碱乙酰胆碱受体容量增加可能部分解释了在动物和人类中观察到的睡茄提取物增强认知和改善记忆的作用。
