Pérez-Osorio Iván Nicolás, Espinosa-Cerón José Alejandro, Álvarez-Gutiérrez Camila, Gonzalez-Flores Rodrigo, Besedovsky Hugo, Fragoso Gladis, Torres-Ramos Mónica A, Sciutto Edda
Department of Immunology, Institute of Biomedical Research Universidad Nacional Autónoma de México, UNAM, 04510 Mexico City, Mexico.
Research Group Immunophysiology, Division of Neurophysiology, Institute of Physiology and Pathophysiology, Philipps Universität, 35037 Marburg, Germany.
Front Biosci (Landmark Ed). 2024 Dec 18;29(12):420. doi: 10.31083/j.fbl2912420.
Multiple sclerosis (MS) is a demyelinating, neuroinflammatory, progressive disease that severely affects human health of young adults. Neuroinflammation (NI) and demyelination, as well as their interactions, are key therapeutic targets to halt or slow disease progression. Potent steroidal anti-inflammatory drugs such as methylprednisolone (MP) and remyelinating neurosteroids such as allopregnanolone (ALLO) could be co-administered intranasally to enhance their efficacy by providing direct access to the central nervous system (CNS).
The individual and combined effects of MP and ALLO to control the clinical score of murine experimental autoimmune encephalitis (EAE), to preserve spinal cord tissue integrity, modulate cellular infiltration and gliosis, promote remyelination, and modify the expression of Aryl hydrocarbon receptor (AhR) were evaluated. studies, to deep insight into the mechanisms involved for the treatments, were also conducted.
MP was the only treatment that significantly reduced the EAE severity, infiltration of inflammatory cells and ionized calcium-binding adapter molecule 1 () expression respect to those EAE non-treated mice but with no-significant differences between the three treatments. MP, ALLO and MP+ALLO significantly reduced tissue damage, AhR expression, and promoted remyelination. Overall, these results suggest that MP, with or without the co-administration with ALLO is an effective and safe strategy to reduce the inflammatory status and the progression of EAE. Despite the expectations of the use of ALLO to reduce the inflammation in EAE, its effect in the dose-scheme used herein is limited only to improve myelination, an effect that supports its usefulness in demyelinating diseases. These results indicate the interest in exploring different doses of ALLO to recommend its use.
ALLO treatment mainly maintain the integrity of the spinal cord tissue and the presence of myelin without affecting NI and the clinical outcome. AhR could be involved in the effect observed in both, MP and ALLO treatments. These results will help in the development of a more efficient therapy for MS patients.
多发性硬化症（MS）是一种脱髓鞘、神经炎症性进展性疾病，严重影响年轻人的健康。神经炎症（NI）和脱髓鞘及其相互作用是阻止或减缓疾病进展的关键治疗靶点。强效甾体抗炎药如甲泼尼龙（MP）和促髓鞘再生神经甾体如别孕烯醇酮（ALLO）可经鼻联合给药，通过直接进入中枢神经系统（CNS）来提高其疗效。
评估了MP和ALLO单独及联合使用对控制小鼠实验性自身免疫性脑脊髓炎（EAE）临床评分、维持脊髓组织完整性、调节细胞浸润和胶质增生、促进髓鞘再生以及改变芳烃受体（AhR）表达的作用。还进行了研究以深入了解治疗所涉及的机制。
与未治疗的EAE小鼠相比，MP是唯一能显著降低EAE严重程度、炎症细胞浸润和离子钙结合衔接分子1（）表达的治疗方法，但三种治疗之间无显著差异。MP、ALLO和MP + ALLO均能显著减少组织损伤、AhR表达并促进髓鞘再生。总体而言，这些结果表明，无论是否联合使用ALLO，MP都是减轻EAE炎症状态和疾病进展的有效且安全的策略。尽管期望使用ALLO来减轻EAE中的炎症，但在此处使用的剂量方案中，其作用仅限于改善髓鞘形成，这一作用支持了其在脱髓鞘疾病中的应用价值。这些结果表明探索不同剂量的ALLO以推荐其使用具有重要意义。
ALLO治疗主要维持脊髓组织的完整性和髓鞘的存在，而不影响NI和临床结果。AhR可能参与了MP和ALLO治疗中观察到的效应。这些结果将有助于为MS患者开发更有效的治疗方法。
