Impact of fingolimod treatment on motor neuron survival and neuroinflammation in the spinal cord of a mouse model of ALS
Embargo Date
2028-02-13
OA Version
Citation
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder primarily impacting motor neurons (MNs) of the central nervous system (CNS). Neurodegeneration of these MNs, especially the lower MNs located in the spinal cord, is accompanied by an increase in neuroinflammation, often mediated through the action of glial cells throughout the CNS. Fingolimod is a sphingosine analog that is used as a treatment for multiple sclerosis (MS), mainly through activating sphingosine-1-phosphate receptor 1 (S1PR1), and 1) prevents release of peripheral lymphocytes from the lymph nodes that become cytotoxic upon infiltrating the CNS and 2) has direct actions on glia and neurons to reduce neuroinflammation. Previously, our lab observed in an Alzheimer’s disease (AD) mouse model that a high dose of fingolimod (1.0 mg/kg/day) which prevents lymphocytes from circulating, resulted in reduced amyloid deposition in the brain, while a fingolimod low dose of (0.03 mg/kg/day) did not have affect lymphocytes but strongly reduced neuroinflammation as well as improved memory performance in the Morris water maze test. As in MS and AD, ALS is characterized by neuroinflammation and neurodegeneration, and thus, we wanted to test fingolimod’s potential applicability as a therapy for ALS.To test the hypothesis that fingolimod treatment is beneficial to ALS, we treated transgenic SOD1G93A, a mouse model of ALS, with fingolimod at a high dose (1.0 mg/kg/day) or low dose (0.03 mg/kg/day). We started treating transgenic SOD1G93A mice and non-transgenic mice as controls from 30 days of age (pre-symptomatic stage) to 120 days of age (advanced disease stage) when we euthanized the mice to obtain the spinal cord to measure MN degeneration and neuroinflammation. The tissue analysis was performed in the lumbar section of the spinal cord, the most key region of ALS pathophysiology that is responsible for motor function. We also evaluated fingolimod’s effects on its main receptor by measuring the protein expression of S1PR1 in lumbar spinal tissue.
We found that both female and male SOD1G93A mice that were administered the low dosage of fingolimod displayed increased density of MN in the ventral horn of the lumbar spinal cord compared to transgenic untreated mice, indicating a reduction in neurodegeneration. These fingolimod-treated mice also displayed decreased density of activated microglia, indicating decreased neuroinflammation. Treatment with the high dosage of fingolimod (1.0mg/kg/day) had minimal impact on MN survival and microglia activation. We also demonstrated that SOD1G93A mice display lower S1PR1 expression compared to wildtype mice, which appeared to be elevated after fingolimod treatment. Moreover, we found that S1PR1 expression correlated with measures of neurodegeneration and neuroinflammation, suggesting that fingolimod has direct actions on CNS cells to improve ALS pathophysiology. Overall, these findings provide support for fingolimod as a putative treatment for ALS and indicate that a lower dose of fingolimod that does not affect peripheral lymphocytes may be the most beneficial.
Description
2025