TABLE 3.
Summary of studies evaluating the effect of fingolimod in brain injuries.
| Author/Year | Model | Molecular findings | Histologic and clinical findings | Proposed mechanisms of action |
|---|---|---|---|---|
| Zhang 2007 | Traumatic brain injury (TBI) (weight drop) | ↓EMAP-II+ and MHC-II + monocytes | - | - |
| Zhang et al. (2007) | ||||
| Zhang 2008 | TBI (Weight drop) | ↓IL16(+) cells | - | - |
| Zhang et al. (2008) | ||||
| Shichita 2009 | Cerebral ischemia-reperfusion | ↓ Infiltrating T lymphocytes | ↓Infarct volume | - |
| Shichita et al. (2009) | No change in macrophage infiltration | |||
| Czech 2009 | Focal cerebral ischemia | ↓Neutrophils | ↓lesion size | - |
| Czech et al. (2009) | ↓Activated macrophage/microglia | ↑Neurologic function | ||
| ↓Circulating blood leukocytes | ↓apoptotic cell death | |||
| Hashegawa 2010 | Ischemic stroke | ↑Akt and ERK-1 phosphorylation | ↓Infarct volume | Activation of Akt and ERK via S1PR1, which prevented apoptosis |
| Hasegawa et al. (2010) | ↑Bcl2 | ↑Neurologic function | ||
| ↓Cleaved caspase 3 | ||||
| Wei 2011 | Focal cerebral ischemia | ↓Activated macrophage/microglia | ↓ Edema | Fingolimod might decrease tissue damage by limiting the levels of cytotoxic agents, rather than by a direct neuroprotective effect |
| Wei et al. (2011) | ↓Inflammation | ↓Infarct size | ||
| ↓Neutrophil infiltration | ↓Neurological deficit | |||
| ↓ICAM-1-positive blood vessels | ↓Brain water content | |||
| ↓Apoptotic cell death | ||||
| Leisz 2011 | Permanent and transient cortical ischemia | ↓Lymphocyte brain invasion | No change in infarct volume and behavioral dysfunction | - |
| Liesz et al. (2011) | ↓IL-1β and IFN-γ | |||
| ↑IL-6 and TNF-α | ||||
| Rolland 2011 | Intracerebral hemorrhage (collagenase) | - | ↓Brian edema | - |
| Rolland et al. (2011) | ↑Neurological function | |||
| Pfeilschifter 2011 | Ischemic stroke (tMCAO) | - | ↓Lesion size | Fingolimod does not aggravate immune depression after stroke despite reducing number of circulating leukocytes |
| Pfeilschifter et al. (2011) | ↓pulmonary infections | |||
| Rolland 2013 | Intracerebral hemorrhage (collagenase) | ↓Lymphocytes | ↑Neurological function | Fingolimod reduced cerebral inflammation by reducing brain infiltration of T-lymphocytes |
| Rolland et al. (2013) | ↓ (ICAM-1), (INF-γ), and(IL-17) | ↓Brain edema | ||
| ↓Brain atrophy and neuronal cell death | ||||
| Brunkhorst 2013 | Photothrombotic stroke | ↓Reactive astrogliosis | ↑Functional outcomes | - |
| Brunkhorst et al. (2013) | ↑Postsynaptic densities | |||
| ↑ VEGFα | ||||
| Campos 2013 | Thromboembolic stroke (MCAO) | ↓Hemorrhagic transformation (in combination with tissue Plasminogen Activator) | ↓Infarct volume | - |
| Campos et al. (2013) | ↓Neurological deficits | |||
| Kraft 2013 | Ischemic stroke | ↓Lymphocyte circulation | ↓Stroke size | Lymphocytopenia induction |
| Kraft et al. (2013) | ↓Microvascular thrombosis | ↑Functional outcome | ||
| ↑Cerebral perfusion | ||||
| Hashegawa 2013 | MCAO | ↓S1PR1 expression on neurons | ↑Neurological function | Fingolimod reduced neuronal injury possibly via S1PR1 activation |
| Hasegawa et al. (2013) | ↓Infarct volume | |||
| Mencl 2014 | TBI (Focal cortical cryolesion) | ↓Circulating lymphocytes | No change in lesion size, functional outcomes, and BBB disruption | - |
| Mencl et al. (2014) | ||||
| Lu 2014 | Intracerebral hemorrhage (collagenase) | No change in CD68 (a marker for macrophage and microglia) | ↓Edema, apoptosis and brain atrophy | Protective effects of fingolimod may involve mechanisms other than inflammation |
| Lu et al. (2014) | ↑Neurologic function | |||
| Moon 2015 | MCAO | ↓Microglial activation and astrogliosis | - | - |
| Moon et al. (2015) | ↓ TNF-α | |||
| Schuhmann 2016 | tMCAO | No change in astrogliosis, BDNF expression, and synaptogenesis | ↓Infarct volume | Key mode of fingolimod action in stroke is the reduction of microvascular thrombosis |
| Schuhmann et al. (2016) | ↓Motor deficits | |||
| Schlunk 2016 | Intracerebral hemorrhage | No change in MMP-9 | No change in mortality,neurological outcomes, and edema | Fingolimod has no beneficial effects in the acute phase of experimental ICH |
| Schlunk et al. (2016) | ||||
| Nazari 2016 | MCAO | ↑ LTP magnitude without any effects on presynaptic plasticity and neurotransmitter release probability | ↓ Lesion volume | Fingolimod improved the memory performance after MCAO by LTP induction via post-synaptic mechanism |
| Nazari et al. (2016) | ↑Memory | |||
| Zhang 2016 | TBI (weight drop) | ↓Cleaved caspase 3, PARP, Bax and cytochrome C | ↑Neurobehavioral function | Fingolimod reduced TBI neuronal apoptosis via Activating modulation of PI3K/Akt and autophagy |
| Zhang et al. (2016) | ↑Bcl-2 and Bcl-xL and mitochondrial cytochrome C | ↓Brain edema | ||
| ↑Phospho-Akt | ↓Apoptotic cell death | |||
| ↑LC3-II and Beclin 1 | ||||
| ↓p62 | ||||
| Gao 2017 | TBI (controlled cortical impact injury | ↓Infiltrated T lymphocytes and NK | ↑Neurological functions | Fingolimod administration extensively modulates multiple immuno-inflammatory responses |
| Gao et al. (2017) | ↑percentage of regulatory T (Treg) cells and IL-10 | ↓Brain edema | ||
| ↑M2/M1 microglia | ↓BBB damage | |||
| ↓Inflammatory cytokines | ||||
| Liu 2017 | TBI (Weight drop) | ↓Micro vesicle | ↓Apoptotic neuron death | - |
| Liu et al. (2017) | ↓ amoeboid-like cells with P2X7R-ir | ↑ Neurobehavioral outcomes | ||
| ↓ IL-1β | ||||
| ↓Phosphorylated p38 | ||||
| ↓GFAP-ir cells | ||||
| Rolland 2017 | Neonatal germinal matrix hemorrhage | ↑ ZO1, Occludin, and Claudin-3 Expression | ↑long-term neurocognitive performance and ↓brain tissue loss | Fingolimod treatment tempered acute post-hemorrhagic BBB disruption via the activation of the S1PR1/Akt/Rac1 pathway |
| Rolland et al. (2017) | ↑Akt phosphorylation | ↓Brain water content | ||
| ↑Rac activation | ||||
| Hashegawa 2017 | Subarachnoid hemorrhage | - | ↓Neurological deficits | Fingolimod reduction of injury was associated with pleiotropic actions of the drug |
| Hasegawa et al. (2017) | ↓Brain edema | |||
| Qin 2017 | White matter (WM) ischemic injury (bilateral carotid artery stenosis) | ↓Microglial activation | ↓Cognitive decline ameliorate the disruption of Ranvier’s nodes | Fingolimod modulated microglia toward M2 polarization via STAT3 pathway |
| Qin et al. (2017) | ↑ Oligogenesis and OPCs maturation | |||
| ↓IL-1β and TNF-α | ↓OPC apoptosis | |||
| ↑IL-13 and TGF-β | ↑Oligodendrocytes survival and differentiation | |||
| Li 2017 | Ischemic stroke | ↓LC3-II and Beclin1 | ↓infarct volumes ↓neuronal apoptosis | Fingolimod suppresses neuronal autophagy through the mTOR/p70S6K pathway |
| Li et al. (2017) | ↑mTOR and p70S6K | ↓Functional deficits | ||
| Herz 2018 | Hypoxic-ischemic (HI) brain injury | ↓ CD4 &CD8 Tcells | ↑Brain tissue injury | Peripheral T Cell depletion by fingolimod Exacerbates hypoxic-ischemic brain injury in neonatal mice |
| Herz et al. (2018) | ↓MAP2 and MBP | |||
| Dong 2018 | In vitro model of cerebral ischemia and reperfusion injury, oxygen-glucose deprivation (OGD) | ↓HMGB1 &TNF-α | - | Fingolimod acts on S1PR3 to regulate the inflammatory cascades via inhibiting PI3K/NFκB signaling pathway |
| Dong et al. (2018) | ↓TLR2 | |||
| ↓PI3K phosphorylation | ||||
| ↓NF-κB activation | ||||
| Salas-Perdomo 2019 | Ischemia/reperfusion | ↓lymphocyte infiltration | - | Fingolimod attenuated HT after cerebral ischemia/reperfusion in a lymphocyte-independent fashion |
| Salas-Perdomo et al. (2019) | ↓β-catenin degradation | |||
| No change in Evans blue extravasation | ||||
| Shang 2020 | Photothrombotic (PT) Ischemic stroke | ↓CD16 and iNOS | ↓Neuronal loss | Fingolimod treatment could skew microglial polarization directly to the M2 phenotype |
| Shang et al. (2020) | ↑ CD206 and Arg-1 | ↑Motor function | ||
| Li 2020 | TMCAO in diabetic mice | ↓ZO-1 | ↓Mortality rate | Due to negative impact of fingolimod on BBB integrity, it should be used with caution for ischemic stroke with diabetic comorbidity |
| Li et al. (2020b) | ↓Occludin | No change in neurological score and infarct volume | ||
| ↓S1PR1 protein levels | ↑Brain edema | |||
| ↑ Bcl-2/Bax Ratio | ||||
| ↓TNFα | ||||
| Wang 2020 | tMCAO | ↓ Iba1 | ↓Mortality | Fingolimod protected BBB integrity by preventing the redistribution of lamellipodia-located tight and adherens junctions into the cytoplasm via S1PR1 receptor signaling |
| Wang et al. (2020b) | ↓ CD68-positive macrophages | ↓Infarct Size ↑Functional Recovery | ||
| ↑ZO-1 and VE-cadherin proteins ate cells lamellipodia | ↓Apoptotic cell death | |||
| ↑ ERK1/2 | ↓Neuroinflammation | |||
| Wang 2020 | Subarachnoid Hemorrhage (SAH) | ↓IL-6 and TNFα | ↑Neurologic function | - |
| Wang et al. (2020a) | ↑IL-10 &TGF-β1 | ↓Brain water content | ||
| ↑Treg cell | ||||
| ↓NK cells | ||||
| Diaz Diaz 2021 | Intracerebral hemorrhage (collagenase) | ↓ Circulating lymphocytes (CD3+, CD4+, and CD8+) | ↑Survival | - |
| Diaz Diaz et al. (2020) | No change in lesion size and functional outcomes | |||
| Cheng 2021 | TBI (Weight drop) | ↑Occludin and claudin-5 | ↓Endothelial cell apoptosis | - |
| Cheng et al. (2021) | ↓ERK1/2 | ↑Neurologic function | ||
| ↓S1PR1 | ↑Survival rate | |||
| ↓Activated microglia and astrocytes | ↑Neurologic function | |||
| ↓BBB breakdown |