Department of Pharmacology, Faculty of Medicine, University of Latvia, 1 Jelgavas St., LV 1004, Riga, Latvia.
Department of Pharmacology, Faculty of Medicine, University of Latvia, 1 Jelgavas St., LV 1004, Riga, Latvia.
Neuropharmacology. 2019 Jan;144:319-326. doi: 10.1016/j.neuropharm.2018.11.003. Epub 2018 Nov 5.
Early manifestations of Alzheimer's disease (AD) include neuroinflammation, disrupted neurotransmission and cognitive deficits. Impairment of the GABAergic system is essentially involved in the pathogenesis of AD. Traditionally, agonists of GABA receptors at doses above 1 mg/kg are known to possess memory impairing effects. However, we have previously found that GABA receptor GABA site ligand muscimol at very low doses acted contrary - enhanced spatial learning/memory, as well as prevented neuroinflammation and augmented neurotransmission in AD model rats. Therefore, in the present study we focused on the assessment of the effects of non-sedative - very low (0.05 mg/kg) and moderate (1 mg/kg) - doses of diazepam, a positive allosteric modulator of benzodiazepine site of GABA receptors. Its effects on spatial learning/memory and brain proteins related to neuroinflammation (GFAP and Iba-1), synaptic plasticity (SYP1), as well as acetylcholine breakdown and GABA biosynthesis were studied. Non-transgenic AD model rats (intracerebroventricular streptozocin injection) were used with the aim to mimic the pre-dementia stage of AD in humans. The obtained data showed that diazepam at both doses protected against streptozocin induced detrimental effects by enhancing spatial learning/memory, preventing neuroinflammation, preserving synaptic plasticity, as well as normalizing the hippocampal and cortical protein expression related to acetylcholine breakdown and GABA biosynthesis. One may suggest that at low and moderate doses diazepam is targeting non-specific, probably allosteric GABA receptor sites, thus leading to stimulatory effects that can be beneficial for diazepam use in early pre-dementia stages of AD.
阿尔茨海默病（AD）的早期表现包括神经炎症、神经传递中断和认知障碍。GABA 能系统的损伤本质上涉及 AD 的发病机制。传统上，GABA 受体激动剂在 1mg/kg 以上的剂量已知具有记忆损害作用。然而，我们之前发现，GABA 受体 GABA 位点配体毒蕈碱在非常低的剂量下作用相反——增强空间学习/记忆，以及预防 AD 模型大鼠的神经炎症和增加神经传递。因此，在本研究中，我们专注于评估非镇静剂 - 非常低（0.05mg/kg）和中等（1mg/kg）- 剂量地西泮的作用，地西泮是 GABA 受体苯二氮䓬位点的正变构调节剂。其对空间学习/记忆以及与神经炎症（GFAP 和 Iba-1）、突触可塑性（SYP1）相关的脑蛋白的影响，以及乙酰胆碱分解和 GABA 生物合成进行了研究。使用非转基因 AD 模型大鼠（侧脑室链脲佐菌素注射），旨在模拟人类 AD 的痴呆前阶段。获得的数据表明，地西泮在这两种剂量下都通过增强空间学习/记忆、预防神经炎症、保持突触可塑性以及使与乙酰胆碱分解和 GABA 生物合成相关的海马和皮质蛋白表达正常化，来对抗链脲佐菌素引起的有害作用。人们可以推测，在低剂量和中等剂量下，地西泮靶向非特异性的，可能是变构的 GABA 受体位点，从而导致刺激作用，这对地西泮在 AD 的早期痴呆前阶段的使用可能是有益的。
