Pham Hang Thi Nguyet, Tran Hong Nguyen, Le Xoan Thi, Do Ha Thi, Nguyen Tue Trong, Le Nguyen Chien, Yoshida Hideki, Yamaguchi Masamistu, William Folk R, Matsumoto Kinzo
National Institute of Medicinal Materials, Hoan Kiem District, Hanoi, 110100, Vietnam.
Hanoi Medical University, Dong Da District, Hanoi, 116001, Vietnam.
Neurochem Res. 2021 Aug;46(8):1995-2007. doi: 10.1007/s11064-021-03337-7. Epub 2021 May 5.
Autism spectrum disorders (ASD) have heterogeneous etiologies involving dysfunction of central nervous systems, for which no effective pan-specific treatments are available. Ilex kudingcha (IK) C.J. Tseng is a nootropic botanical used in Asia for neuroprotection and improvement of cognition. This study establishes that a chemically characterized extract from IK (IKE) mitigates behavioral traits in the Drosophila melanogaster rugose mutant, whose traits resemble human ASD, and examines possible mechanisms. IKE treatment significantly ameliorated deficits in social interaction, short-term memory, and locomotor activity in Drosophila rugose, and significantly increased synaptic bouton number of size more than 2 μm in the neuromuscular junctions (NMJs) of Drosophila rugose. To clarify mechanism(s) of IKE action, methylphenidate (MPH), a dopamine transporter inhibitor, was included as a reference drug in the behavioral assays: MPH significantly improved social interaction and short-term memory deficit in Drosophila rugose; administration of the dopamine D1 receptor antagonist SCH23390 and dopamine D2 receptor antagonist sulpiride reversed the ameliorative effects of both MPH and IKE on the social interaction deficits of Drosophila rugose. To extend analysis of IKE treatment to the vertebrate central nervous system, ASD-associated gene expression in mouse hippocampus was studied by RNA-seq: IKE treatment altered the expression of genes coding phosphoinositide 3-kinases/protein kinase B (PI3K-Akt), proteins in glutamatergic, dopaminergic, serotonergic, and GABAergic synapses, cAMP response element-binding protein (CREB), and RNA transporter proteins. These results provide a foundation for further analysis of IKE as a candidate for treatment of some forms of ASD.
自闭症谱系障碍（ASD）病因多样，涉及中枢神经系统功能障碍，目前尚无有效的通用治疗方法。苦丁茶（IK）C.J. Tseng是一种益智植物，在亚洲用于神经保护和改善认知。本研究证实，苦丁茶的一种化学特征提取物（IKE）可减轻黑腹果蝇粗糙突变体的行为特征，该突变体的特征类似于人类ASD，并研究了可能的机制。IKE处理显著改善了粗糙果蝇的社交互动、短期记忆和运动活动缺陷，并显著增加了粗糙果蝇神经肌肉接头（NMJ）中大小超过2μm的突触小体数量。为了阐明IKE作用的机制，在行为测定中加入了多巴胺转运体抑制剂哌甲酯（MPH）作为参考药物：MPH显著改善了粗糙果蝇的社交互动和短期记忆缺陷；给予多巴胺D1受体拮抗剂SCH23390和多巴胺D2受体拮抗剂舒必利可逆转MPH和IKE对粗糙果蝇社交互动缺陷的改善作用。为了将IKE治疗的分析扩展到脊椎动物中枢神经系统，通过RNA测序研究了小鼠海马体中与ASD相关的基因表达：IKE处理改变了编码磷酸肌醇-3激酶/蛋白激酶B（PI3K-Akt）、谷氨酸能、多巴胺能、5-羟色胺能和γ-氨基丁酸能突触中的蛋白质、环磷酸腺苷反应元件结合蛋白（CREB）以及RNA转运蛋白的基因表达。这些结果为进一步分析IKE作为治疗某些形式ASD的候选药物奠定了基础。
