Combined Use of Intranasal Methylprednisolone and Allopregnanolone: Revisiting Anti-inflammatory and Remyelinating Treatment in a Murine Model of Multiple Sclerosis.

Abstract

Background: 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).

Methods: 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. In silico studies, to deep insight into the mechanisms involved for the treatments, were also conducted.

Results: MP was the only treatment that significantly reduced the EAE severity, infiltration of inflammatory cells and ionized calcium-binding adapter molecule 1 (Iba-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.

Conclusions: 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.