Novel Drug Discovery and Development, Lupin Limited (Research Park), 46A/47A, Village, Nande, Mulshi Taluka, Pune, Pin 412 115, India.
Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, Karnataka, Pin 576104, India.
Psychopharmacology (Berl). 2018 May;235(5):1557-1570. doi: 10.1007/s00213-018-4866-z. Epub 2018 Mar 3.
5-HT6 receptors are mainly expressed in brain areas associated with learning and memory. Several studies have reported procognitive effects of both 5-HT6 agonist and antagonists. However, the exact mechanism 5-HT6 receptor modulation has not been properly studied especially in the context of cholinergic functions, cerebral blood flow (CBF), brain-derived neural factor (BDNF), oxidative stress, and behavioral changes.
In the present study, memory impairment was induced in albino Wistar rats by two doses of intracerebroventricular (ICV) injection of streptozotocin (STZ, 3 mg/kg) on first and third day. These rats were evaluated in a battery of behavioral tasks after 14 days from the first day of ICV-STZ.
Significant memory impairment was seen when ICV-STZ induced rats are assessed by Morris water maze, novel object recognition, social recognition, and passive avoidance tests. There was a significant reduction in CBF, increased oxidative stress (MDA, GSH, and ROS), acetylcholinesterase (AChE) activity, and a decrease in BDNF. Treatment with selective 5-HT6 agonist EMD-386088 (5 mg/kg) and antagonist SB-399885 (10 mg/kg) prevented ICV-STZ-induced memory impairment when assessed by behavioral tests. Treatment with 5-HT6 ligands significantly prevented the change in CBF and BDNF. Further, protected from MDA and ROS and decreasing GSH in the brain compared to ICV-STZ rats. The rice in brain AChE activity was normalized by both ligands. The changes in locomotor activity by EMD-386088 and SB-399885 treatment were negligible.
The findings in this study support the therapeutic potential of 5-HT6 receptor ligands in the treatment of cognitive dysfunction.
5-羟色胺 6（5-HT6）受体主要表达于与学习和记忆相关的脑区。多项研究报道，5-HT6 激动剂和拮抗剂均具有认知改善作用。然而，5-HT6 受体调节的确切机制，特别是在胆碱能功能、脑血流（CBF）、脑源性神经营养因子（BDNF）、氧化应激和行为改变的背景下，尚未得到充分研究。
本研究采用侧脑室（ICV）注射链脲佐菌素（STZ，3mg/kg）的方法诱导 Wistar 白化大鼠产生记忆障碍，第 1 天和第 3 天各注射 1 次。首次 ICV-STZ 注射后第 14 天，对这些大鼠进行一系列行为学测试。
Morris 水迷宫、新物体识别、社交识别和被动回避测试结果显示，ICV-STZ 诱导的大鼠出现明显的记忆障碍。CBF 降低，氧化应激标志物（MDA、GSH 和 ROS）增加，乙酰胆碱酯酶（AChE）活性降低，BDNF 减少。5-HT6 选择性激动剂 EMD-386088（5mg/kg）和拮抗剂 SB-399885（10mg/kg）治疗可改善行为学测试中的记忆障碍。5-HT6 配体治疗可显著防止 CBF 和 BDNF 的变化，同时还可降低脑内 MDA 和 ROS，增加 GSH，并使脑内 AChE 活性恢复正常。与 ICV-STZ 大鼠相比，EMD-386088 和 SB-399885 治疗对大鼠的运动活性变化影响可以忽略不计。
本研究结果支持 5-HT6 受体配体在治疗认知功能障碍方面的治疗潜力。
