Immunomodulation Eliminates Inflammation in the Hippocampus in Experimental Autoimmune Encephalomyelitis, but Does Not Ameliorate Anxiety-Like Behavior

Abstract

Multiple sclerosis (MS) is an autoimmune disease targeting the central nervous system, characterized by an unpredictable disease course and a wide range of symptoms. Emotional and cognitive deficits are now recognized as primary disease manifestations and not simply the consequence of living with a chronic condition, raising questions regarding the efficacy of current therapeutics for these specific symptoms. Mechanisms underlying psychiatric sequelae in MS are believed to be similar to those underlying pathogenesis, that is mediated by cytokines and other inflammatory mediators. To gain insight into the pathogenesis of MS depression, we performed behavioral assays in the murine experimental autoimmune encephalomyelitis (EAE) MS model, in the presence or absence of immunomodulation using the drug FTY720, an analogue of the lipid signaling molecule sphingosine-1-phosphate (S1P). Specifically, mice were challenged with the elevated plus maze (EPM) test, a validated experimental paradigm for rodent-specific anxiety-like behavior. FTY720 treatment failed to ameliorate anxiety-like symptoms, irrespective of dosage. On the other hand, it was effective in reducing inflammatory infiltration, microglial reactivity and levels of pro-inflammatory molecules in the hippocampus, confirming the anti-inflammatory capacity of treatment. To explore the absence of FTY720 effect on behavior, we confirmed expression of S1P receptors (S1PR) S1PR1, S1PR3 and S1PR5 in the hippocampus and mapped the dynamics of these receptors in response to drug treatment alone, or in combination with EAE induction. We identified a complex pattern of responses, differing between (1) receptors, (2) dosage and (3) hippocampal sub-field. FTY720 treatment in the absence of EAE resulted in overall downregulation of S1PR1 and S1PR3, while S1PR5 exhibited a dose-dependent upregulation. EAE induction alone resulted in overall downregulation of all three receptors. On the other hand, combined FTY720 and EAE showed generally no effect on S1PR1 and S1PR3 expression except for the fimbrium region, but strong upregulation of S1PR5 over the range of doses examined. These data illustrate a hitherto undescribed complexity of S1PR response to FTY720 in the hippocampus, independent of drug effect on effector immune cells, but simultaneously emphasize the need to explore novel treatment strategies to specifically address mood disorders in MS.

Molecular Pharmacology and Novel Potential Therapeutic Applications of Fingolimod

“…There are some conflicting data about fingolimod's ability to reduce anxiety-like behaviors in EAE models of MS. While It was previously shown that fingolimod reduces anxiety-like behavior (Bonfiglio et al, 2017), a new study fails to show anxiety-like symptoms in EAE mice models of MS (Kocovski et al, 2021). Mounting evidence suggests that fingolimod also has neuroprotective activity (Slowik et al, 2015;Sternberg et al, 2018;Yang et al, 2021) and acts as a myelin regeneration booster by affecting neural precursor cells and oligodendrocytes lineage (Coelho et al, 2007;Miron et al, 2010;Heinen et al, 2015;Qin et al, 2017).…”

Motor Behavioral Deficits in the Cuprizone Model: Validity of the Rotarod Test Paradigm

“…In even more severe cases, there is complete hind and partial front limb paralysis, a severe condition where euthanasia is strongly recommended. Although several other behavioral domains are affected in the diverse EAE models, including the sensory domain [ 14 , 15 , 16 ] and cognition [ 17 , 18 , 19 ], or there is anxiety-like behavior [ 20 , 21 ], it is the motor behavioral deficit that serves as the primary outcome measurement in most of the EAE studies.…”

Cerebellar pathology in multiple sclerosis and experimental autoimmune encephalomyelitis: current status and future directions

“…[126][127][128][129] Coupled with technological advances already mentioned, behavioral studies provide powerful insight into brain networks. In this context, we and others have identified anxiety-like behavior prior to the earliest detectable accumulation of autoreactive T cells in EAE 90,91 in evaluation of depressive-like behavioral syndrome due to MS.…”

“…Testing should be performed with the collaboration of behavioral experts because of the complexity of data analysis, especially when dealing with NHP. The timing of the tests is also of critical importance 90,91 and should not rely on clinical scoring of ambulatory difficulties which are a reflection of spinal cord rather than cerebellar damage. They must be based on prior establishment of the spatio-temporal pattern of disease development specifically in the cerebellum. 6.…”