Beneficial Effect of Fingolimod in a Lafora Disease Mouse Model by Preventing Reactive Astrogliosis-Derived Neuroinflammation and Brain Infiltration of T-lymphocytes

Abstract

Lafora disease (LD; OMIM#254780) is a rare, devastating, and fatal form of progressive myoclonus epilepsy that affects young adolescents and has no treatment yet. One of the hallmarks of the disease is the accumulation of aberrant poorly branched forms of glycogen (polyglucosans, PGs) in the brain and peripheral tissues. The current hypothesis is that this accumulation is causative of the pathophysiology of the disease. Another hallmark of LD is the presence of neuroinflammation. We have recently reported the presence of reactive glia-derived neuroinflammation in LD mouse models and defined the main inflammatory pathways that operate in these mice, mainly TNF and IL-6 signaling pathways. In addition, we described the presence of infiltration of peripheral immune cells in the brain parenchyma, which could cooperate and aggravate the neuroinflammatory landscape of LD. In this work, we have checked the beneficial effect of two compounds with the capacity to ameliorate neuroinflammation and reduce leukocyte infiltration into the brain, namely fingolimod and dimethyl fumarate. Our results indicate a beneficial effect of fingolimod in reducing reactive astrogliosis-derived neuroinflammation and T-lymphocyte infiltration, which correlated with the improved behavioral performance of the treated Epm2b-/- mice. On the contrary, dimethyl fumarate, although it was able to reduce reactive astrogliosis, was less effective in preventing neuroinflammation and T-lymphocyte infiltration and in modifying behavioral tests.

Neuroinflammation and Epilepsy: From Pathophysiology to Therapies Based on Repurposing Drugs

“…In addition, it has been reported that administration of DMF following status epilepticus increased Nrf2 activity, attenuated the status of epilepticus-induced neuronal cell death, and decreased seizure frequency and the total number of seizures compared to vehicle-treated animals [96]. However, when we used DMF in the Lafora disease mouse model, we observed only a minor effect; it was less effective in preventing neuroinflammation and T-lymphocyte infiltration [87].…”

“…Recently, we have described the beneficial effects of FGD in a mouse model of Lafora disease, a particular type of progressive myoclonus epilepsy. In this model, FGD reduced reactive astrogliosisderived neuroinflammation and T-lymphocyte infiltration, which correlated with an improved behavioral performance among the treated animals [87]. However, in the case of the Rett syndrome, although the administration of fingolimod was safe in children with this disorder, it did not provide supportive evidence for an effect on clinical, laboratory, and imaging measures in these patients [88].…”