Rasha Mohammed Alderbi ^1,2* Mohammad Zubair Alam ^3,4 Badrah Saeed Alghamdi ^3,5 Hadeil Muhanna Alsufiani ² Gamal Said Abd El-Aziz ⁶ Ulfat Omar ^2,7 Maryam Abdo Al-Ghamdi ^2,8,9

• ¹ Research Centre, King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia
• ² Biochemistry Department, King Abdulaziz University, Jeddah, Saudi Arabia
• ³ Neuroscience and Geroscience Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
• ⁴ Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
• ⁵ Department of Physiology, Neuroscience Unit, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
• ⁶ Department of Clinical Anatomy, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
• ⁷ Princess Dr. Najlaa Bint Saud Al-Saud Center of Excellence Research in Biotechnology, King Abdulaziz University, Jeddah, Saudi Arabia
• ⁸ Vitamin D Pharmacogenomics Research Group, King Abdulaziz University, Jeddah, Saudi Arabia
• ⁹ Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia

Multiple sclerosis (MS) affects 2.8 million people worldwide. Although the cause is unknown, various risk factors might be involved. MS involves the immune system attacking the central nervous system's myelin sheath, leading to neuron damage. This study used a cuprizone (CPZ)-intoxicated mouse model to simulate MS's demyelination/remyelination process. It evaluated the molecular, histological, and behavioral effects of vanillic acid (VA), a natural phenolic acid, alone and with Ibudilast (IBD), a clinically tested MS medication. Mice were divided into a control group (regular chow) and a CPZ group (0.3% cuprizone chow for 5 consecutive weeks). During remyelination, the CPZ group was split into four groups: no therapy, 10 mg/kg of IBD, 30 mg/kg of VA, and combined, each treated for 4 weeks. Behavioral, biochemical, molecular, and histopathological tests occurred in the 5 th week (demyelination), 7 th (early remyelination), and 9 th (late remyelination). Cognitive assessments were at weeks 5 and 9. VA enhanced motor, coordination, and cognitive impairments in CPZ-intoxicated mice and improved histopathological, molecular, and biochemical features during early remyelination. IBD improved behavioral abnormalities across all tests, but combined therapy showed no significant difference from single therapies. Further investigations are necessary to understand VA's mechanisms and potential as an MS treatment.