Alzheimer’s disease (AD) is one of the most common causes of neurodegenerative diseases in the elderly. Cholinergic dysfunction is one of the

pathological hallmarks of AD and leads to learning and memory impairment. Transient receptor potential vanilloid 4(TRPV4), a nonselective cation channel, is involved in learning and memory functions. HC067047, a TRPV4 specific inhibitor, has been reported to protect neurons against cerebral ischemic injury and amyloid-β -(Aβ) 40-induced hippocampal cell death. However, whether HC067047 could improve scopolamine (SCP)-induced cognitive dysfunction in mice is still unknown. The aims of this study were to verify whether HC067047 could ameliorate the SCP-induced learning and memory impairments in mice and to elucidate its underlying mechanisms of action. In this study, we examined the neuroprotective effect of the HC067047 against cognitive dysfunction induced by SCP (5 mg/kg, i.p.), a muscarinic receptor antagonist. The results showed that administration of HC067047(10 mg/kg, i.p.) significantly ameliorated SCP-induced cognitive dysfunction as assessed by the novel place recognition test (NPRT) and novel object recognition test (NORT). In the Y-maze test, HC067047 significantly enhanced the time spent in the novel arm in SCP mice. To further investigate the molecular mechanisms underlying the neuroprotective effect of HC067047, expression of several proteins involved in apoptosis was examined. The results demonstrated that HC067047 treatment decreased the protein levels of proapoptotic proteins such as Bax and caspase-3 in the hippocampus of SCP mice. In addition, HC067047 enhanced expression of the neurogenesis marker DCX and improved levels of the mature neuronal marker NeuN in SCP mice. These findings suggest the neuroprotective potential of the TRPV4 inhibitor HC067047 for the management of dementia with learning and memory loss.

阿尔茨海默病 (AD) 是老年人神经退行性疾病的最常见原因之一。胆碱能功能障碍是其中之一

AD 的病理特征并导致学习和记忆障碍。瞬时受体电位香草醛 4(TRPV4) 是一种非选择性阳离子通道，参与学习和记忆功能。HC067047 是一种 TRPV4 特异性抑制剂，据报道可保护神经元免受脑缺血性损伤和淀粉样蛋白-β -(Aβ) 40 诱导的海马细胞死亡。然而，HC067047是否能改善东莨菪碱（SCP）引起的小鼠认知功能障碍仍不清楚。本研究的目的是验证 HC067047 是否可以改善 SCP 引起的小鼠学习和记忆障碍，并阐明其潜在的作用机制。在这项研究中，我们检查了 HC067047 对毒蕈碱受体拮抗剂 SCP (5 mg/kg, ip) 诱导的认知功能障碍的神经保护作用。结果表明，通过新地点识别测试 (NPRT) 和新物体识别测试 (NORT) 评估，HC067047 (10 mg/kg, ip) 显着改善了 SCP 诱导的认知功能障碍。在 Y 迷宫测试中，HC067047 显着增加了 SCP 小鼠在新手臂上花费的时间。为了进一步研究 HC067047 的神经保护作用的分子机制，检测了几种参与细胞凋亡的蛋白质的表达。结果表明，HC067047 处理降低了 SCP 小鼠海马中促凋亡蛋白如 Bax 和 caspase-3 的蛋白水平。此外，HC067047 增强了 SCP 小鼠中神经发生标志物 DCX 的表达并提高了成熟神经元标志物 NeuN 的水平。