Early low-anticoagulant desulfated heparin after traumatic brain injury: Reduced brain edema and leukocyte mobilization is associated with improved watermaze learning ability weeks after injury

Nagata, Katsuhiro; Suto, Yujin; Cognetti, John S.; Browne, Kevin D.; Kumasaka, Kenichiro; Johnson, Victoria E.; Kaplan, Lewis J.; Marks, Joshua A.; Smith, Douglas H.; Pascual, José L.

doi:10.1097/ta.0000000000001819

Cited by 13 publications

(8 citation statements)

References 41 publications

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“…This postulated CX-01-HMGB1 binding is not only a phenomenon that would affect the HMGB1 measurement, but also even more importantly would block HMGB1 from activating its proinflammatory PRRs (RAGE, TLR2, TLR4, etc.) on macrophages/monocytes [ 36 , 37 , 38 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

“…Although both unfractionated heparin and low-molecular-weight heparin have anti-HMGB1 and anti-inflammatory properties, their anticoagulant activity limits their use in TH. CX-01 (2- O , 3 -O -desulfated heparin) is a novel HMGB1 inhibitor with <5% anticoagulant activity [ 39 , 40 , 41 ]. We hypothesized that treatment with CX-01 would alleviate tissue damage and improve survival in a rat model of TH that recapitulates the immunological responses seen in injured patients [ 42 ].…”

Section: Introductionmentioning

confidence: 99%

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HMGB1 Inhibition to Ameliorate Organ Failure and Increase Survival in Trauma

et al. 2022

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Several preclinical and clinical reports have demonstrated that levels of circulating high mobility group box 1 protein (HMGB1) are increased early after trauma and are associated with systemic inflammation and clinical outcomes. However, the mechanisms of the interaction between HMGB1 and inflammatory mediators that lead to the development of remote organ damage after trauma remain obscure. HMGB1 and inflammatory mediators were analyzed in plasma from 54 combat casualties, collected on admission to a military hospital in Iraq, and at 8 and 24 h after admission. In total, 45 (83%) of these patients had traumatic brain injury (TBI). Nine healthy volunteers were enrolled as controls. HMGB1 plasma levels were significantly increased in the first 8 h after admission, and were found to be associated with systemic inflammatory responses, injury severity score, and presence of TBI. These data provided the rationale for designing experiments in rats subjected to blast injury and hemorrhage, to explore the effect of HMGB1 inhibition by CX-01 (2-O, 3-O desulfated heparin). Animals were cannulated, then recovered for 5–7 days before blast injury in a shock tube and volume-controlled hemorrhage. Blast injury and hemorrhage induced an early increase in HMGB1 plasma levels that coincided with severity of tissue damage and mortality. CX-01 inhibited systemic HMGB1 activity, decreased local and systemic inflammatory responses, significantly reduced tissue and organ damage, and tended to increase survival. These data suggest that CX-01 has potential as an adjuvant treatment for traumatic hemorrhage.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

HMGB1 Inhibition to Ameliorate Organ Failure and Increase Survival in Trauma

et al. 2022

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“…It is well-characterised, commercially available, and is currently involved in a clinical trial for acute myeloid leukemia [32]. It was also used as an early therapeutic intervention after traumatic brain injury and showed beneficial functional outcomes [33]. We were, therefore, interested to determine if such beneficial effects could be observed in our in vitro CNS injury models.…”

Section: Introductionmentioning

confidence: 99%

The Use of Myelinating Cultures as a Screen of Glycomolecules for CNS Repair

McCanney

Lindsay

McGrath

et al. 2019

Biology

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In vitro cell-based assays have been fundamental in modern drug discovery and have led to the identification of novel therapeutics. We have developed complex mixed central nervous system (CNS) cultures, which recapitulate the normal process of myelination over time and allow the study of several parameters associated with CNS damage, both during development and after injury or disease. In particular, they have been used as a reliable screen to identify drug candidates that may promote (re)myelination and/or neurite outgrowth. Previously, using these cultures, we demonstrated that a panel of low sulphated heparin mimetics, with structures similar to heparan sulphates (HSs), can reduce astrogliosis, and promote myelination and neurite outgrowth. HSs reside in either the extracellular matrix or on the surface of cells and are thought to modulate cell signaling by both sequestering ligands, and acting as co-factors in the formation of ligand-receptor complexes. In this study, we have used these cultures as a screen to address the repair potential of numerous other commercially available sulphated glycomolecules, namely heparosans, ulvans, and fucoidans. These compounds are all known to have certain characteristics that mimic cellular glycosaminoglycans, similar to heparin mimetics. We show that the N-sulphated heparosans promoted myelination. However, O-sulphated heparosans did not affect myelination but promoted neurite outgrowth, indicating the importance of structure in HS function. Moreover, neither highly sulphated ulvans nor fucoidans had any effect on remyelination but CX-01, a low sulphated porcine intestinal heparin, promoted remyelination in vitro. These data illustrate the use of myelinating cultures as a screen and demonstrate the potential of heparin mimetics as CNS therapeutics.

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“…ODSH is another heparanase inhibitor (108) which blocks multiple steps of inflammation. As described for heparin, ODSH reduces leukocyte rolling, adhesion, and accumulation (109, 110). ODSH has also been shown to inhibit neutrophil elastase and inflammation in a mouse model of neutrophil elastase-induced airway inflammation (111) and in the sputum of cystic fibrosis patients (112).…”

Section: Heparanase Inhibitors and Leukocyte Functionmentioning

confidence: 82%

Leukocyte Heparanase: A Double-Edged Sword in Tumor Progression

2019

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Heparanase is a β-D-endoglucuronidase that cleaves heparan sulfate, a complex glycosaminoglycan found ubiquitously throughout mammalian cells and tissues. Heparanase has been strongly associated with important pathological processes including inflammatory disease and tumor metastasis, through its ability to promote various cellular functions such as cell migration, invasion, adhesion, and cytokine release. A number of cell types express heparanase including leukocytes, cells of the vasculature as well as tumor cells. However, the relative contribution of heparanase from these different cell sources to these processes is poorly defined. It is now well-established that the immune system plays a critical role in shaping tumor progression. Intriguingly, leukocyte-derived heparanase has been shown to either assist or impede tumor progression, depending on the setting. This review covers our current knowledge of heparanase in immune regulation of tumor progression, as well as the potential applications and implications of exploiting or inhibiting heparanase in cancer therapy.

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Early low-anticoagulant desulfated heparin after traumatic brain injury: Reduced brain edema and leukocyte mobilization is associated with improved watermaze learning ability weeks after injury

Abstract: 2,3-O desulfated heparin after TBI reduces cerebral LEU recruitment, microvascular permeability and edema. 2,3-O desulfated heparin may also improve acute neurologic recovery leading to improved learning/memory ability weeks after injury.

Cited by 13 publications

References 41 publications

HMGB1 Inhibition to Ameliorate Organ Failure and Increase Survival in Trauma

HMGB1 Inhibition to Ameliorate Organ Failure and Increase Survival in Trauma

The Use of Myelinating Cultures as a Screen of Glycomolecules for CNS Repair

Leukocyte Heparanase: A Double-Edged Sword in Tumor Progression

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