Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran.
Anatomy Department, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
Psychopharmacology (Berl). 2018 May;235(5):1513-1525. doi: 10.1007/s00213-018-4862-3. Epub 2018 Apr 10.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory impairment, neuronal death, and synaptic loss in the hippocampus. Long-term potentiation (LTP), a type of synaptic plasticity, occurs during learning and memory. Serotonin receptor type 7 (5-HTR7) activation is suggested as a possible therapeutic target for AD.
The aim of the present study was to examine the effects of chronic treatment with the 5-HTR7 agonist, AS19, on cognitive function, memory, hippocampal plasticity, amyloid beta (Aβ) plaque accumulation, and apoptosis in an adult rat model of AD.
AD was induced in rats using Aβ (single 1 μg/μL intracerebroventricular (icv) injection during surgery). The following experimental groups were included: control, sham-operated, Aβ + saline (1 μL icv for 30 days), and Aβ + AS19 (1 μg/μL icv for 30 days) groups. The animals were tested for cognition and memory performance using the novel object recognition and passive avoidance tests, respectively. Next, anesthetized rats were placed in a stereotaxic apparatus for electrode implantation, and field potentials were recorded in the hippocampal dentate gyrus. Lastly, brains were removed and Aβ plaques and neuronal apoptosis were evaluated using Congo red staining and TUNEL assay, respectively.
Administration of AS19 in the Aβ rats increased the discrimination index of the novel object recognition test. Furthermore, AS19 treatment decreased time spent in the dark compartment during the passive avoidance test. AS19 also enhanced both the population spike (PS) amplitude and the field excitatory postsynaptic potential (fEPSP) slope evoked potentials of the LTP components. Aβ plaques and neuronal apoptosis were decreased in the AS19-treated Aβ rats.
These results indicate that chronic treatment with a 5-HTR7 agonist can prevent Aβ-related impairments in cognition and memory performance by alleviating Aβ plaque accumulation and neuronal apoptosis, hence improving neuronal plasticity. AS19 may be useful as a therapeutic agent for AD.
阿尔茨海默病（AD）是一种神经退行性疾病，其特征是记忆力减退、神经元死亡和海马突触丧失。长时程增强（LTP）是一种突触可塑性，发生在学习和记忆过程中。5-羟色胺受体 7 型（5-HTR7）的激活被认为是 AD 的一种潜在治疗靶点。
本研究旨在探讨 5-HTR7 激动剂 AS19 对 AD 成年大鼠模型认知功能、记忆、海马可塑性、β-淀粉样蛋白（Aβ）斑块积累和细胞凋亡的影响。
通过 Aβ（手术时单个 1μg/μL 侧脑室（icv）注射）诱导大鼠 AD。包括以下实验组：对照组、假手术组、Aβ+生理盐水（30 天内 1μL icv）和 Aβ+AS19（30 天内 1μg/μL icv）组。采用新物体识别和被动回避试验分别测试动物的认知和记忆表现。然后，将麻醉大鼠置于立体定向仪中进行电极植入，并记录海马齿状回的场电位。最后，取出大脑，用刚果红染色和 TUNEL 法评估 Aβ 斑块和神经元凋亡。
AS19 给药可增加 Aβ 大鼠新物体识别试验的辨别指数。此外，AS19 治疗可减少被动回避试验中大鼠在黑暗隔间的停留时间。AS19 还增强了 LTP 成分的群体峰（PS）幅度和场兴奋性突触后电位（fEPSP）斜率诱发的电位。AS19 治疗可减少 Aβ 大鼠的 Aβ 斑块和神经元凋亡。
这些结果表明，5-HTR7 激动剂的慢性治疗可以通过减轻 Aβ 斑块积累和神经元凋亡来预防 Aβ 相关的认知和记忆功能障碍，从而改善神经元可塑性。AS19 可能是治疗 AD 的一种有前途的药物。
