A Three-Day Consecutive Fingolimod Administration Improves Neurological Functions and Modulates Multiple Immune Responses of CCI Mice

Abstract

Excessive inflammation after traumatic brain injury (TBI) is a major cause of secondary TBI. Though several inflammatory biomarkers have been postulated as the risk factors of TBI, there has not been any comprehensive description of them. Fingolimod, a new kind of immunomodulatory agent which can diminish various kinds of inflammatory responses, has shown additional therapeutic effects in the treatment of intracranial cerebral hematoma (ICH), ischemia, spinal cord injury (SCI), and many other CNS disorders. However, its therapeutic application has not been confirmed in TBI. Thus, we hypothesized that a 3-day consecutive fingolimod administration could broadly modulate the inflammatory reactions and improve the outcomes of TBI. The TBI models of C57/BL6 mice were established with the controlled cortical impact injury (CCI) system. A 3-day consecutive fingolimod therapy (given at 1, 24, and 48 h post injury) was performed at a dose of 1 mg/kg. The flow cytometry, immunoflourence, cytokine array, and ELISA were all applied to evaluate the immune cells and inflammatory markers in the injured brains. Immunohistochemical staining with anti-APP antibody was performed to assess the axonal damage. The neurological functions of these TBI models were assessed by mNSS/Rota-rod and Morris water maze (MWM). The brain water content and integrity of the blood-brain barrier (BBB) were also observed. On the 3rd day after TBI, the accumulation of inflammatory cytokines and chemokines reached the peak and administration of fingolimod reduced as many as 20 kinds of cytokines and chemokines. Fingolimod decreased infiltrated T lymphocytes and NK cells but increased the percentage of regulatory T (Treg) cells, and the concentration of IL-10 on the 3rd day after TBI. Fingolimod also notably attenuated the general activated microglia but augmented the M2/M1 ratio accompanied by decreased axonal damage. The neurological functions were improved after the fingolimod treatment accompanied with alleviation of the brain edema and BBB damage. This study suggests that the 3-day consecutive fingolimod administration extensively modulates multiple immuno-inflammatory responses and improves the neurological deficits after TBI, and therefore, it may be a new approach to the treatment of secondary TBI.

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

“…Anti-inflammatory Treg T cells and M2-type microglia and IL-10 were increased by more than twofold by fingolimod. 266 These results support the antiepileptogenic and disease-modifying effects of fingolimod in animal models of SE. Investigations in additional models of acute brain injury (ie, TBI/PTE, CNS infection, stroke) are needed, as are studies of the best therapeutic window for drug intervention to maximize the drug's therapeutic effects.…”

“…These effects were associated with twofold reduction in axonal damage, brain edema and microglia activation, normalization in the cortical levels of several inflammatory molecules, and prevention of T‐cell brain extravasation assessed in the injured cortex. Anti‐inflammatory Treg T cells and M2‐type microglia and IL‐10 were increased by more than twofold by fingolimod …”

Increased miR‐124‐3p in microglial exosomes following traumatic brain injury inhibits neuronal inflammation and contributes to neurite outgrowthviatheir transfer into neurons

“…Immunomodulatory agents, including fingolimod, thymosin b4, peroxisome proliferator-activated receptors agonists (such as rosiglitazone and pioglitazone), the IL-1 receptor antagonist and cell cycle inhibitor flavopiridol have been confirmed to inhibit the inflammatory response after TBI, through inhibiting overactivation of microglia or promoting M2 polarization. However, all of these drugs are in preclinical studies (15,16,18). Consequently, it is important to further explore new strategies for alleviating the inflammatory response in the brain after TBI.…”

Administration of Tauroursodeoxycholic Acid Attenuates Early Brain Injury via Akt Pathway Activation

“…Primary brain injury, which occurs immediately after trauma, can induce biochemical changes and ultimately lead to secondary neuronal cell loss (Jindal et al, 2016). The main mechanisms underlying secondary brain injury are associated with endoplasmic reticulum stress (ER stress), oxidative stress, mitochondrial dysfunction, inflammation and apoptosis (Dash et al, 2015; Gao et al, 2016; Wang et al, 2016; Yang et al, 2017). …”