Data_Sheet_1_Tetramethylpyrazine Alleviates Behavioral and Psychological Symptoms of Dementia Through Facilitating Hippocampal Synaptic Plasticity in Rats With Chronic Cerebral Hypoperfusion.DOCX

Behavioral and psychological symptoms of dementia (BPSD) ubiquitously disturb all patients with dementia at some point in the disease course. Although a plethora of non-pharmacological and pharmacological methods targeting the relief BPSD have been developed, the therapeutic effect is still far from ideal. Here, a rat BPSD model combining the physiological changes with mental insults was successfully established. Meanwhile, our results indicated that TMP attenuated anxious behavior using an elevated plus maze (EPM) test, ameliorated recognitive ability and sociability through a novel object recognition test (NORT) and social interaction test (SIT), and improved learning and memory impairments via a Barnes maze in rats with bilateral common carotid arteries occlusion (BCCAO) plus chronic restraint stress (CRS). Given that hippocampus chronic cerebral hypoperfusion (CCH) always causes damage to the hippocampus, and the majority of cognitive impairments, behaviors, and stress responses are associated with pathology in the hippocampus including anxiety and depression, we paid attention to investigate the role of the hippocampus in BPSD. Our results indicated that Tetramethylpyrazine (TMP) attenuated anxiety and ameliorated recognitive ability, sociability, learning, and memory impairments due to alleviating dendritic and spine deficits, and upregulating the expression of synapse-related proteins (including PSD95, SYN, GAP43, SYP) in the hippocampus. We also found that the underlying mechanism was that TMP could activate the TrkB/ERK/CREB signaling pathway to promote synaptic remodeling in vivo and in vitro. Mechanically, the present study enlarges the therapeutic scope of TMP in neurodegenerative disorders and provides basic knowledge and feasible candidates for treating BPSD, particularly for vascular dementia.

痴呆症（Dementia）的行为和心理症状（BPSD）普遍干扰疾病过程中痴呆患者的各个阶段。尽管已开发出众多旨在缓解BPSD的非药物和药物方法，但治疗效果仍远未达到理想状态。在此，我们成功建立了一个结合生理变化和心理创伤的大鼠BPSD模型。同时，我们的研究结果显示，TMP通过加高迷宫（EPM）测试减轻了焦虑行为，通过新颖物体识别测试（NORT）和社会互动测试（SIT）改善了认知能力和社交能力，并通过Barnes迷宫改善了双侧颈动脉闭塞（BCCAO）加慢性束缚应激（CRS）大鼠的学习和记忆障碍。鉴于海马体慢性脑低灌注（CCH）始终会导致海马体损伤，且大多数认知障碍、行为和应激反应都与海马体的病理学有关，包括焦虑和抑郁，我们关注于研究海马体在BPSD中的作用。我们的研究结果表明，四甲基吡嗪（TMP）通过缓解树突和棘突缺陷，上调海马体中突触相关蛋白（包括PSD95、SYN、GAP43、SYP）的表达，减轻了焦虑并改善了认知能力、社交能力、学习和记忆障碍。我们还发现，其潜在机制是TMP能够激活TrkB/ERK/CREB信号通路，在体内和体外促进突触重塑。从机制上讲，本研究扩大了TMP在神经退行性疾病治疗中的应用范围，并为治疗BPSD，尤其是血管性痴呆提供了基本知识和可行的候选药物。