Neuroprotective effects of argatroban and C5a receptor antagonist (PMX53) following intracerebral haemorrhage

Li, G.; Fan, Ruiming; Chen, J.‐L.; Wang, C.‐M.; Zeng, Y.‐C.; Han, Chong; Song, Jing; Xia, Xue; Chen, W.; Yao, Shengtao

doi:10.1111/cei.12220

Cited by 44 publications

(27 citation statements)

References 47 publications

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“…(15, 16) However, whether PHE is an independent predictor of neurologic outcome in human ICH remains controversial, since studies have produced contradictory results. (7, 8, 17) Here we have shown that the rate of PHE expansion predicts outcome after ICH.…”

Section: Discussionmentioning

confidence: 99%

Rate of Perihematomal Edema Expansion Predicts Outcome After Intracerebral Hemorrhage

Urday

Beslow

Dai

et al. 2016

Critical Care Medicine

100

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Objective Intracerebral hemorrhage (ICH) is a devastating disorder with no current treatment. Whether peri-hematomal edema (PHE) is an independent predictor of neurologic outcome is controversial. We sought to determine whether PHE expansion rate predicts outcome after ICH. Design Retrospective cohort study Setting Tertiary medical center Patients 139 consecutive supratentorial spontaneous ICH patients >18 years admitted between 2000–2013. Interventions None Measurements and Main Results ICH, intraventricular hemorrhage (IVH), and PHE volumes were measured from computed tomography (CT) scans obtained at presentation, 24 hours, and 72 hours post-ICH. PHE expansion rate was the difference between initial and follow-up PHE volumes divided by the time interval. Logistic regression was performed to evaluate the relationship between 1) PHE expansion rate at 24 hours and 90-day mortality and 2) PHE expansion rate at 24 hours and 90-day modified Rankin Scale score (mRS). PHE expansion rate between admission and 24-hours post-ICH was a significant predictor of 90-day mortality (OR 2.97, 95%CI 1.48–5.99, p=0.002). This association persisted after adjusting for all components of the ICH score (OR 2.21, 95% CI 1.05–4.64, p=0.04). Similarly, higher 24-hour PHE expansion rate was associated with poorer mRS in an ordinal shift analysis (OR 2.40, 95% CI 1.37–4.21, p=.002), even after adjustment for all ICH score components (OR 2.07, 95% CI 1.12–3.83, p=0.02). Conclusions Faster PHE expansion rate 24 hours post-ICH is associated with worse outcome. PHE may represent an attractive translational target for secondary injury after ICH.

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Section: Discussionmentioning

confidence: 99%

Rate of Perihematomal Edema Expansion Predicts Outcome After Intracerebral Hemorrhage

Urday

Beslow

Dai

et al. 2016

Critical Care Medicine

100

View full text Add to dashboard Cite

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“…It has also been tested in mouse models for the treatment efficacy of periodontitis, sepsis, intracerebral hemorrhage, and other disorders 33, 34 . PMX53 could significantly reduce C5a-mediated inflammation in these diseases.…”

Section: Discussionmentioning

confidence: 99%

Attenuation of cGVHD by C5a/C5aR blockade is associated with increased frequency of Treg

Wang

Lai

Chen

et al. 2017

Sci Rep

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C5aR signaling plays an important role in the regulation of T cell activation and alloimmune responses in chronic graft-versus-host disease (cGVHD). However, direct evidence of this modulation and the efficacy of C5aR blockade in the treatment of cGVHD have not been demonstrated. We observed higher expression of C5aR on both monocytes and T cells of patients with cGVHD compared with healthy controls and non-GVHD patients after allogeneic hematopoietic stem cell transplantation. Our data also demonstrated a significant negative correlation between C5aR expression and regulatory T cells (Treg) frequency in cGVHD patients, indicating a potential role of C5aR in the generation and regulation of Treg. In addition, an in vitro experiment revealed C5aR deficiency promoted the development of Treg whereas C5a activation abolished the differentiation of Treg. Importantly, we found C5aR blockade by PMX53 attenuated the pathology of cGVHD and improved the survival of cGVHD mice. PMX53 had a direct regulatory effect on Treg commitment and increased TGF-β1 expression. Thus, C5aR signaling may induce and intensify cGVHD by down-regulating Treg induction. The modulation of C5aR activation by PMX53 may provide a potential therapy for cGVHD.

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“…In C5a receptor knockout mice, proinflammatory cytokine levels were decreased in the acute phase after ICH 75 . Moreover, treatment with the C5a receptor antagonist PMX53 in combination with the thrombin antagonist argatroban resulted in decreased mRNA expression of the M1 markers TNF, IL-6 and iNOS in the mouse ICH brain 76 . These data indicate a prominent role for activation of complement C3a and C5a receptors in the proinflammatory response to ICH.…”

Section: Microgliamentioning

confidence: 96%

Modulators of microglial activation and polarization after intracerebral haemorrhage

et al. 2017

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Intracerebral haemorrhage (ICH) is the most lethal subtype of stroke but currently lacks effective treatment. Microglia are among the first non-neuronal cells on the scene during the innate immune response to ICH. Microglia respond to acute brain injury by becoming activated and developing classic M1-like (proinflammatory) or alternative M2-like (anti-inflammatory) phenotypes. This polarization implies as yet unrecognized actions of microglia in ICH pathology and recovery, perhaps involving microglial production of proinflammatory or anti-inflammatory cytokines and chemokines. Furthermore, alternatively activated M2-like microglia might promote phagocytosis of red blood cells and tissue debris, a major contribution to haematoma clearance. Interactions between microglia and other cells modulate microglial activation and function, and are also important in ICH pathology. This Review summarizes key studies on modulators of microglial activation and polarization after ICH, including M1-like and M2-like microglial phenotype markers, transcription factors and key signalling pathways. Microglial phagocytosis, haematoma resolution, and the potential crosstalk between microglia and T lymphocytes, neurons, astrocytes, and oligodendrocytes in the ICH brain are described. Finally, the clinical and translational implications of microglial polarization in ICH are presented, including the evidence that therapeutic approaches aimed at modulating microglial function might mitigate ICH injury and improve brain repair.

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Neuroprotective effects of argatroban and C5a receptor antagonist (PMX53) following intracerebral haemorrhage

Cited by 44 publications

References 47 publications

Rate of Perihematomal Edema Expansion Predicts Outcome After Intracerebral Hemorrhage

Rate of Perihematomal Edema Expansion Predicts Outcome After Intracerebral Hemorrhage

Attenuation of cGVHD by C5a/C5aR blockade is associated with increased frequency of Treg

Modulators of microglial activation and polarization after intracerebral haemorrhage

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