Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran.
Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran.
Behav Brain Res. 2019 May 17;364:205-212. doi: 10.1016/j.bbr.2019.02.004. Epub 2019 Feb 5.
Alzheimer's disease (AD) is the most common cause of dementia, characterized by memory impairment and synaptic loss. Long-term potentiation (LTP), a type of synaptic plasticity, is impaired during AD. Serotonin type 6 receptor (5-HT6R) inactivation is proposed as a therapeutic target for AD. This study examined the effects of chronic administration of the 5-HT6R antagonist, SB-258585, on cognitive, memory, and hippocampal plasticity in a rat model of AD. Abeta neurotoxicity was induced in rats using Aβ (1.35 pmol intracerebroventricular [ICV] injection). The following groups were formed: control sustained surgery and saline-treated, Aβ+saline (1 μL ICV for 30 days), and Aβ+SB-258585 (0.024 mg/kg, ICV for 30 days). The learning and memory were tested using the novel object recognition and passive avoidance tests. Next, anesthetized rats were placed in a stereotaxic apparatus. The population spike (PS) amplitude and the slope of the excitatory postsynaptic potentials (fEPSPs) of the LTP were measured following high-frequency stimulation in the dentate gyrus. The Aβ injection reduced step-through latency in the passive avoidance test and decreased the discrimination index in the novel object test. Aβ diminished both the amplitude of hippocampal neuron population spikes and the slope of excitatory postsynaptic potentials, compared to the control group. The administration of SB-258585 in rats receiving Aβ attenuated the Aβ-induced deficits in cognition, memory, and LTP in comparison with the Aβ group. It can be concluded that chronic treatment with SB-258585 antagonist can prevent Aβ-related deficiencies in learning and memory performance by improving neuronal plasticity. SB-258585 can prevent the progression of AD.
阿尔茨海默病（AD）是痴呆症最常见的病因，其特征是记忆障碍和突触丧失。AD 期间长时程增强（LTP），一种突触可塑性，受损。5-羟色胺 6 受体（5-HT6R）失活被提议作为 AD 的治疗靶点。本研究检查了慢性给予 5-HT6R 拮抗剂 SB-258585 对 AD 大鼠模型认知、记忆和海马可塑性的影响。使用 Aβ（脑室内 1.35 pmol 注射）在大鼠中诱导 Abeta 神经毒性。形成以下组：对照持续手术和盐水处理、Aβ+盐水（30 天 1 μL 脑室内）和 Aβ+SB-258585（0.024 mg/kg，30 天脑室内）。使用新物体识别和被动回避测试测试学习和记忆。接下来，将麻醉大鼠置于立体定向仪器中。在齿状回中进行高频刺激后，测量群体峰（PS）幅度和兴奋性突触后电位（fEPSP）的斜率。Aβ 注射降低了被动回避测试中的跨步潜伏期，并降低了新物体测试中的辨别指数。与对照组相比，Aβ 降低了海马神经元群体峰的幅度和兴奋性突触后电位的斜率。与 Aβ 组相比，在接受 Aβ 的大鼠中给予 SB-258585 可减轻认知、记忆和 LTP 中 Aβ 诱导的缺陷。可以得出结论，慢性给予 SB-258585 拮抗剂可通过改善神经元可塑性来预防与 Aβ 相关的学习和记忆表现缺陷。SB-258585 可以预防 AD 的进展。
