Neuropharmacology Division, Department of Pharmacology, I. S. F. College of Pharmacy, Moga, Punjab 142001, India.
Neuropharmacology Division, Department of Pharmacology, I. S. F. College of Pharmacy, Moga, Punjab 142001, India.
Neuroscience. 2017 Aug 15;357:67-74. doi: 10.1016/j.neuroscience.2017.05.054. Epub 2017 Jun 6.
Stimulation as well as inhibition of GABA (Gamma amino butyric acid) receptors has been reported to show beneficial effects in Alzheimer's disease (AD). Experimental evidences suggest that the use of GABAergic agents could influence learning and memory. The present study was designed to investigate the possible role of GABA receptors in streptozotocin (STZ)-induced behavioral and biochemical abnormalities in rats. Herein STZ was infused (3mg/kg) bilaterally on alternate days (day 1 and day 3) to produce experimental dementia in rats. STZ-infused rats were then treated with baclofen (GABAR agonist) 5 and 10mg/kg i.p. and CGP35348 (GABAR antagonist) 25 and 50mg/kg i.p. one week following STZ infusion for 15days. Cognitive functions were assessed by using Morris water maze (MWM) and object recognition task (ORT). Levels of malondialdehyde (MDA.), reduced glutathione (GSH), andacetylcholinesterase (AChE) were determined to evaluate oxidative stress and cholinergic function. STZ-infused rats showed decreased memory retention, elevated levels of MDA, increased AChE activity, reduced GSH levels. The combination of STZ with increasing doses of Baclofen further induced a higher decrease in memory retention and increase in oxidative stress. CGP35348 restored cognitive functions and AChE activity in STZ-infused rats. The cognitive enhancement following CGP35348 may be due to its ability to restore cholinergic, serotonergic and dopaminergic function, and its antioxidant activity. Therefore, it would be safe to conclude that the pharmacological blockade of GABA receptors would be therapeutic in the management of cognitive disorders such as Alzheimer's disease.
已报道 GABA（γ-氨基丁酸）受体的刺激和抑制在阿尔茨海默病（AD）中显示出有益的效果。实验证据表明，使用 GABA 能药物可以影响学习和记忆。本研究旨在探讨 GABA 受体在链脲佐菌素（STZ）诱导的大鼠行为和生化异常中的可能作用。在此，STZ 双侧（第 1 天和第 3 天）交替输注（3mg/kg）以在大鼠中产生实验性痴呆。STZ 输注大鼠随后用巴氯芬（GABAR 激动剂）5 和 10mg/kg 腹腔内和 CGP35348（GABAR 拮抗剂）25 和 50mg/kg 腹腔内治疗，在 STZ 输注后 1 周内进行 15 天。使用 Morris 水迷宫（MWM）和物体识别任务（ORT）评估认知功能。测定丙二醛（MDA.）、还原型谷胱甘肽（GSH）和乙酰胆碱酯酶（AChE）的水平，以评估氧化应激和胆碱能功能。STZ 输注大鼠表现出记忆保留减少、MDA 水平升高、AChE 活性增加、GSH 水平降低。STZ 与巴氯芬剂量增加的组合进一步诱导记忆保留的更高降低和氧化应激的增加。CGP35348 恢复了 STZ 输注大鼠的认知功能和 AChE 活性。CGP35348 后的认知增强可能是由于其恢复胆碱能、5-羟色胺能和多巴胺能功能及其抗氧化活性的能力。因此，可以安全地得出结论，GABA 受体的药理学阻断在治疗阿尔茨海默病等认知障碍方面可能是有效的。
