Alyami Kholoud A, Alshahrany Gadah A, Al-Otaibi Kholoud M, Alam Mohammad Z, Alghamdi Badrah S, Alsufiani Hadeil M, Alshareef Nouf O, Alhoraibi Hanna M, Alkhodair Sahar A, Omar Ulfat M
Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.
Department of Chemistry, Faculty of Science, Albaha University, Albaha, Saudi Arabia.
Front Mol Neurosci. 2025 May 20;18:1567226. doi: 10.3389/fnmol.2025.1567226. eCollection 2025.
Ibudilast (IBD) is a new drug that has been released as treatment for multiple sclerosis (MS). Retinoic acid (RA), a metabolite of vitamin A, is known for its pro-regenerative and anti-inflammatory properties, therefore, it has been suggested as a supplementary treatment for MS. The objective of this study is to investigate the therapeutic effects of RA and IBD against cuprizone (CPZ) induced mouse models. Seventy-two Swiss Albino male Mice (SWR/J) were divided into two main groups control ( = 18); normal chow and CPZ ( = 54); 0.25% of CPZ mixed into chow at demyelination stage (first 5 weeks). The following 4 weeks included two stages of remyelination: early remyelination (2 weeks after CPZ discontinuation) and late remyelination (week 9). In the early stage of remyelination, the CPZ group was divided into four subgroups beside daily treatment intraperitoneal injections CPZ (+ve control- no treatment), RA (20 mg/kg), IBD (10 mg/kg), and RA + IBD, with ( = 12/group), while the control group had 12 mice. At the end of each stage 6 mice/ group were sacrificed. Mice response to different treatments was assessed using several locomotor and cognitive behavior tests including open field test, rotarod test, grip strength test, novel object recognition test (NORT) and Y-maze test. The expression levels of several genes MS associated genes Tumer Necrosis Factor- Alpha (TNF- ), Cyclooxygenase-2 (COX-2), Nerve Growth Factor (NGF), Signal transducer and activator of transcription 3 (STAT-3) and Nuclear factor kappa-light-chain-enhancer of activated b-cell (NFKB-P105) in the brain of mice were measured using quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) analysis. The results demonstrated that RA supplementation helped in alleviating the symptoms of MS induced mice with or without using IBD treatment. This was indicated as an improvement in locomotor activity, motor coordination and muscular strength as well as improving the cognition and memory functions. The mRNA expression pattern of various MS associated genes indicated that the treatments effectively mitigated the detrimental effects of CPZ in mouse brain. The findings of this study indicate that RA supplements could be effectively unitized as adjuvant therapy alongside with IBD for MS treatment.
异丁司特（IBD）是一种已获批用于治疗多发性硬化症（MS）的新药。视黄酸（RA）是维生素A的一种代谢产物，因其具有促进再生和抗炎特性而闻名，因此，它被建议作为MS的辅助治疗药物。本研究的目的是调查RA和IBD对 cuprizone（CPZ）诱导的小鼠模型的治疗效果。72只瑞士白化雄性小鼠（SWR/J）被分为两个主要组：对照组（n = 18），给予正常饲料；CPZ组（n = 54），在脱髓鞘阶段（前5周）将0.25%的CPZ混入饲料中。接下来的4周包括两个髓鞘再生阶段：早期髓鞘再生（CPZ停用后2周）和晚期髓鞘再生（第9周）。在髓鞘再生早期，CPZ组除每日腹腔注射CPZ（阳性对照 - 不进行其他处理）外，还分为四个亚组：RA（20 mg/kg）、IBD（10 mg/kg）以及RA + IBD组，每组12只，而对照组有12只小鼠。在每个阶段结束时，每组处死6只小鼠。使用包括旷场试验、转棒试验、握力试验、新物体识别试验（NORT）和Y迷宫试验等多种运动和认知行为测试来评估小鼠对不同治疗的反应。使用定量逆转录聚合酶链反应（qRT-PCR）分析测量小鼠脑中几种与MS相关基因的表达水平，这些基因包括肿瘤坏死因子 - α（TNF-α）、环氧化酶 - 2（COX-2）、神经生长因子（NGF）、信号转导和转录激活因子3（STAT-3）以及活化B细胞的核因子κ轻链增强子（NFKB-P105）。结果表明，无论是否使用IBD治疗，补充RA都有助于减轻MS诱导小鼠的症状。这表现为运动活动、运动协调性和肌肉力量的改善，以及认知和记忆功能的提高。各种与MS相关基因的mRNA表达模式表明，这些治疗有效地减轻了CPZ对小鼠脑的有害影响。本研究结果表明，RA补充剂可与IBD一起有效地用作MS治疗的辅助疗法。
