Fingolimod alters inflammatory mediators and vascular permeability in intracerebral hemorrhage

Li, Yujing; Chang, Guoqiang; Liu, Yuanchu; Gong, Yi; Yang, Chun-Sheng; Wood, Kristofer; Shi, Fu‐Dong; Fu, Ying; Yan, Yaping

doi:10.1007/s12264-015-1532-2

Cited by 46 publications

(33 citation statements)

References 32 publications

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“…These effects suggest that fingolimod reduces the migration of these cells and inflammatory mediators to the brain after ICH. 92 The drug also suppressed the increase in PHO that normally occurs in the first week after ICH (Figure 2) and protected the vascular barrier. Collectively, the immune modulation of fingolimod seemed to improve clinical outcomes.…”

Section: Interventions In Ischaemic Strokementioning

confidence: 86%

Immune interventions in stroke

et al. 2015

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Inflammatory and immune responses in the brain can shape the clinical presentation and outcome of stroke. Approaches for effective management of acute stroke are sparse and many measures for brain protection fail, but our ability to modulate the immune system and modify the disease progression of multiple sclerosis is increasing. As a result, immune interventions are currently being explored as therapeutic interventions in acute stroke. In this Review, we compare the immunological features of acute stroke with those of multiple sclerosis, identify unique immunological features of stroke, and consider the evidence for immune interventions. In acute stroke, microglia activation and cell death products trigger an inflammatory cascade that damages vessels and the parenchyma within minutes to hours of the ischaemia or haemorrhage. Immune interventions that restrict brain inflammation, vascular permeability and tissue oedema must be administered rapidly to reduce acute immune-mediated destruction and to avoid subsequent immunosuppression. Preliminary results suggest that the use of drugs that modify disease in multiple sclerosis might accomplish these goals in ischaemic and haemorrhagic stroke. Further elucidation of the immune mechanisms involved in stroke is likely to lead to successful immune interventions.

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Section: Interventions In Ischaemic Strokementioning

confidence: 86%

Immune interventions in stroke

et al. 2015

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“…The positive effect from fingolimod is due to reduction in lymphocytes, markers of inflammation [intercellular adhesion molecule-1 (ICAM-1), interferon-γ, and interleukin-17], apoptosis, and brain atrophy (112–114). In a human study of 23 patients, fingolimod use was associated with less inflammation (reduced ICAM-1, lymphocytes, natural killer cells, and MMP-9 levels) and positive effect on BBB (115). In a phase-II study, fingolimod use within 72 h of ICH onset was associated with less PHE and improvement in clinical outcomes at 3 months without any increase in side effects (116).…”

Section: Perihemorrhagic Edemamentioning

confidence: 99%

Intracerebral Hemorrhage: Perihemorrhagic Edema and Secondary Hematoma Expansion: From Bench Work to Ongoing Controversies

Mittal

LacKamp

2016

Front. Neurol.

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Intracerebral hemorrhage (ICH) is a medical emergency, which often leads to severe disability and death. ICH-related poor outcomes are due to primary injury causing structural damage and mass effect and secondary injury in the perihemorrhagic region over several days to weeks. Secondary injury after ICH can be due to hematoma expansion (HE) or a consequence of repair pathway along the continuum of neuroinflammation, neuronal death, and perihemorrhagic edema (PHE). This review article is focused on PHE and HE and will cover the animal studies, related human studies, and clinical trials relating to these mechanisms of secondary brain injury in ICH patients.

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“…In a pilot study conducted in patients with acute ischemic stroke, fingolimod/alteplase combination therapy was well tolerated, attenuated reperfusion injury, and improved clinical outcomes (Fu et al ., 2014; Li et al ., 2015; Zhu et al ., 2015). Fingolimod is now under a phase 2 clinical trial for acute stroke (NCT02002390).…”

Section: Development Of S1p1 Receptor Modulatorsmentioning

confidence: 99%

Sphingosine 1-Phosphate Receptor Modulators and Drug Discovery

Park

2017

Biomolecules & Therapeutics

105

100

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Initial discovery on sphingosine 1-phosphate (S1P) as an intracellular second messenger was faced unexpectedly with roles of S1P as a first messenger, which subsequently resulted in cloning of its G protein-coupled receptors, S1P1–5. The molecular identification of S1P receptors opened up a new avenue for pathophysiological research on this lipid mediator. Cellular and molecular in vitro studies and in vivo studies on gene deficient mice have elucidated cellular signaling pathways and the pathophysiological meanings of S1P receptors. Another unexpected finding that fingolimod (FTY720) modulates S1P receptors accelerated drug discovery in this field. Fingolimod was approved as a first-in-class, orally active drug for relapsing multiple sclerosis in 2010, and its applications in other disease conditions are currently under clinical trials. In addition, more selective S1P receptor modulators with better pharmacokinetic profiles and fewer side effects are under development. Some of them are being clinically tested in the contexts of multiple sclerosis and other autoimmune and inflammatory disorders, such as, psoriasis, Crohn’s disease, ulcerative colitis, polymyositis, dermatomyositis, liver failure, renal failure, acute stroke, and transplant rejection. In this review, the authors discuss the state of the art regarding the status of drug discovery efforts targeting S1P receptors and place emphasis on potential clinical applications.

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Fingolimod alters inflammatory mediators and vascular permeability in intracerebral hemorrhage

Cited by 46 publications

References 32 publications

Immune interventions in stroke

Immune interventions in stroke

Intracerebral Hemorrhage: Perihemorrhagic Edema and Secondary Hematoma Expansion: From Bench Work to Ongoing Controversies

Sphingosine 1-Phosphate Receptor Modulators and Drug Discovery

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