School of Pharmacy, Brac University, Dhaka, Bangladesh.
Department of Clinical Pathology, Dhaka Medical College Hospital, Dhaka, Bangladesh.
PLoS One. 2024 Sep 24;19(9):e0308632. doi: 10.1371/journal.pone.0308632. eCollection 2024.
Autism spectrum disorder (ASD) is one of the leading causes of distorted social communication, impaired speech, hyperactivity, anxiety, and stereotyped repetitive behaviour. The aetiology of ASD is complex; therefore, multiple drugs have been suggested to manage the symptoms. Studies with histamine H3 receptor (H3R) blockers and acetylcholinesterase (AchE) blockers are considered potential therapeutic agents for the management of various cognitive impairments. Therefore, the aim of this study was to evaluate the neuro-behavioural effects of Betahistine, an H3R antagonist, and Donepezil, an acetylcholinesterase inhibitor on Swiss albino mouse model of autism. The mice were intraperitoneally injected with valproic acid (VPA) on the embryonic 12.5th day to induce autism-like symptoms in their offspring. This induced autism-like symptoms persists throughout the life. After administration of different experimental doses, various locomotor tests: Open Field, Hole-Board, Hole Cross and behavioural tests by Y-Maze Spontaneous Alternation and histopathology of brain were performed and compared with the control and negative control (NC1) groups of mice. The behavioural Y-Maze test exhibits significant improvement (p <0.01) on the short term memory of the test subjects upon administration of lower dose of Betahistine along with MAO-B inhibitor Rasagiline once compared with the NC1 group (VPA-exposed mice). Furthermore, the tests showed significant reduction in locomotion in line crossing (p <0.05), rearing (p <0.001) of the Open Field Test, and the Hole Cross Test (p <0.01) with administration of higher dose of Betahistine. Both of these effects were observed upon administration of acetylcholinesterase inhibitor, Donepezil. Brain-histopathology showed lower neuronal loss and degeneration in the treated groups of mice in comparison with the NC1 VPA-exposed mice. Administration of Betahistine and Rasagiline ameliorates symptoms like memory deficit and hyperactivity, proving their therapeutic effects. The effects found are dose dependent. The findings suggest that H3R might be a viable target for the treatment of ASD.
自闭症谱系障碍（ASD）是导致社交沟通障碍、言语障碍、多动、焦虑和刻板重复行为的主要原因之一。ASD 的病因复杂，因此有多种药物被建议用于治疗症状。研究发现组胺 H3 受体（H3R）阻滞剂和乙酰胆碱酯酶（AchE）阻滞剂可能是治疗各种认知障碍的潜在治疗药物。因此，本研究旨在评估 H3R 拮抗剂倍他司汀和乙酰胆碱酯酶抑制剂多奈哌齐对自闭症瑞士白化小鼠模型的神经行为影响。在胚胎第 12.5 天，通过腹腔注射丙戊酸（VPA）诱导其后代出现自闭症样症状。这些自闭症样症状会持续一生。在给予不同的实验剂量后，进行了各种运动测试：旷场、洞板、洞十字和 Y 迷宫自发交替行为测试，并与对照组和阴性对照组（NC1）的小鼠进行了比较。行为 Y 迷宫测试显示，与 NC1 组（VPA 暴露的小鼠）相比，较低剂量的倍他司汀联合 MAO-B 抑制剂雷沙吉兰给药一次可显著改善测试对象的短期记忆（p <0.01）。此外，在旷场测试和洞十字测试中，较高剂量的倍他司汀给药可显著减少线交叉（p <0.05）和直立（p <0.001）次数。这些作用在乙酰胆碱酯酶抑制剂多奈哌齐给药时也观察到。与 NC1 VPA 暴露的小鼠相比，大脑组织病理学显示治疗组小鼠的神经元丢失和退化减少。倍他司汀和雷沙吉兰的给药改善了记忆缺陷和多动等症状，证明了它们的治疗效果。这些效果是剂量依赖性的。研究结果表明，H3R 可能是治疗 ASD 的一个可行靶点。
