Progress in translational research on intracerebral hemorrhage: Is there an end in sight?

Xi, Guohua; Strahle, Jennifer; Hua, Ya; Keep, Richard F.

doi:10.1016/j.pneurobio.2013.09.007

Cited by 133 publications

(109 citation statements)

References 257 publications

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“…18 We analyzed the gene expression profiles of several chemokines in the hemorrhagic brains 24 hours after ICH. The results revealed that ICH strongly elevated the levels of chemokine (C-X-C motif) ligand 1 (CXCL1), CX3CL1, and the chemokine (C-C motif) receptor 1 (CCR1) when compared with the sham-operated group ( Figure 1A).…”

Section: Recombinant Adamts 13 Attenuated Ich-associated Cerebral Infmentioning

confidence: 99%

Recombinant ADAMTS 13 Attenuates Brain Injury After Intracerebral Hemorrhage

Cai

Luo

et al. 2015

Stroke

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S pontaneous intracerebral hemorrhage (ICH) results from rupture of blood vessels in the brain. It represents ≈10% to 20% of all strokes and is a devastating clinical condition with a 30-day mortality rate of 30% to 55%.1 Currently, there is no proven treatment available for improving ICH outcome. Evidence suggest that ICH is associated with activation of local immune cells and release of inflammatory mediators, which result in enhanced disruption of the blood-brain barrier (BBB), causing an increase in peri-hematomal edema formation and consequent neuronal injury. [2][3][4] Cerebral edema is present in most patients with ICH and is an independent predictor of neurological deterioration.1,2 Therefore, strategies aimed at limiting inflammatory response and BBB dysfunction could be potential therapeutic targets for ICH.von Willebrand factor (VWF) is a multimeric adhesive protein that is released from endothelial Weibel-Palade bodies during injury or inflammation. 5 The multimeric size of VWF is modulated by ADAMTS 13 (a disintegrin and metalloprotease with thrombospondin type I motif, member 13), which processed proteolytically VWF into smaller lessreactive forms. 6 Accumulating data indicate that ADAMTS 13 and VWF play an opposite role in thrombus formation and Background and Purpose-Inflammatory responses and blood-brain barrier (BBB) dysfunction play important roles in brain injury after intracerebral hemorrhage (ICH). The metalloprotease ADAMTS 13 (a disintegrin and metalloprotease with thrombospondin type I motif, member 13) was shown to limit inflammatory responses through its proteolytic effects on von Willebrand factor. In the present study, we addressed the role of ADAMTS 13 after experimental ICH. Methods-ICH was induced in mice by intracerebral infusion of autologous blood. The peri-hematomal inflammatory responses, levels of matrix metalloproteinase-9 and intercellular adhesion molecule-1, pericyte coverage on brain capillaries, and BBB permeability were quantified at 24 hours. Functional outcomes, cerebral edema, and hemorrhagic lesion volume were quantified at day 3. Results-Treatment with recombinant ADAMTS 13 (rADAMTS 13) reduced the levels of chemokines and cytokines, myeloperoxidase activity, and microglia activation and neutrophil recruitment after ICH. rADAMTS 13 also decreased interleukin-6 expression in brain endothelial cells stimulated by lipopolysaccharide, whereas recombinant von Willebrand factor reversed this effect. The anti-inflammatory effect of rADAMTS 13 was accompanied by reduced expression of intercellular adhesion molecule-1 and less activation of matrix metalloproteinase, enhanced pericyte coverage of brain microvessels, and attenuated BBB disruption. Furthermore, neutrophil depletion protected against BBB damage, and rADAMTS 13 treatment had no further beneficial effect. Finally, treatment of mice with rADAMTS 13 reduced cerebral edema and hemorrhagic lesion volume and improved neurological functions. Conclusions-Our findings reveal the importance of rADAMTS 13 in regulating...

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Section: Recombinant Adamts 13 Attenuated Ich-associated Cerebral Infmentioning

confidence: 99%

Recombinant ADAMTS 13 Attenuates Brain Injury After Intracerebral Hemorrhage

Cai

Luo

et al. 2015

Stroke

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“…Intracerebral hemorrhage (ICH) is an intractable neurological malady with high morbidity and mortality 1. Despite stable incidence rates and declining mortality rates over the past 2 decades, motor dysfunction remains an intractable problem with no clinically available interventions except rehabilitation 2.…”

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confidence: 99%

Epothilone B Benefits Nigrostriatal Pathway Recovery by Promoting Microtubule Stabilization After Intracerebral Hemorrhage

Yang

Zhang

et al. 2018

JAHA

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BackgroundMany previous clinical studies have demonstrated that the nigrostriatal pathway, which plays a vital role in movement adjustment, is significantly impaired after stroke, according to medical imaging and autopsies. However, the basic pathomorphological changes have been poorly investigated to date. This study was designed to explore the pathomorphological changes, mechanism, and therapeutic method of nigrostriatal impairment after intracerebral hemorrhage (ICH).Methods and ResultsIntrastriatal injection of autologous blood or microtubule depolymerization reagent nocodazole was performed to mimic the pathology of ICH in C57/BL6 mice. Immunofluorescence, Western blotting, electron microscopy, functional behavioral tests, and anterograde and retrograde neural circuit tracking techniques were used in these mice. The data showed that the number of dopamine neurons and the dopamine concentration were severely decreased and that fine motor function was impaired after ICH. Microtubule depolymerization was the main contributor to the loss of dopamine neurons and to motor function deficits after ICH, as was also proven by intrastriatal injection of nocodazole. Moreover, administration of the microtubule stabilizer epothilone B (1.5 mg/kg) improved the integrity of the nigrostriatal pathway neural circuit, increased the number of dopamine neurons (4598±896 versus 3125±355; P=0.034) and the dopamine concentration (4.28±0.99 versus 3.08±0.75 ng/mg; P=0.041), and enhanced fine motor functional recovery associated with increased acetylated α‐tubulin expression to maintain microtubule stabilization after ICH.ConclusionsOur results clarified the pathomorphological changes of the nigrostriatal pathway after ICH and found that epothilone B helped alleviate nigrostriatal pathway injury after ICH, associated with promoting α‐tubulin acetylation to maintain microtubule stabilization, thus facilitating motor recovery.

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“…These results suggest that compounds that interrupt the free radical cascade might improve ICH outcome. Although there are a number of ongoing clinical trials (Xi et al, 2014), currently there is no FDA-approved treatment for ICH and the use of alternative means such as green tea, which could be part of people's diet, could be an interesting, inexpensive and easy way to avoid some ICH sequelae without side effects. In this study, we did not show any difference on GSH levels and GPx activity.…”

Section: Discussionmentioning

confidence: 99%

Green Tea Treatment Attenuates Oxidative Damage and Neuromotor Deficit Induced by an Experimental Model of Intracerebral Hemorrhage in Rats

Souza

Altermann

Martins

et al. 2016

Neuroscience International

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The present study shows the neuroprotective effect of green tea supplementation (GT; Camellia sinensis) in a model of Intracerebral Hemorrhage (ICH) in rats. ICH was induced by intra-striatum collagenase infusion in male Wistar rats. GT (400 mg Kg ) was administered via gavage for 10 days after ICH. We assessed the effect of GT on neuromotor recovery and oxidative damage. Our results show that ICH causes neuromotor deficits observed by Neurological Deficit Scale (NDS), Open Field (OF) and Rotarod (RR). GT treatment attenuates this deficit on day 3 for NDS and OF and on day 7 for RR. Also, ICH increases Reactive Oxygen Species (ROS) production and lipid peroxidation, what is not observed in ICH + GT group. Currently, there are no effective pharmacologic or non-pharmacologic neuroprotective treatments for ICH. Nutritional interventions that help on its outcome are important, since they are generally accessible and have few side effects.

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Progress in translational research on intracerebral hemorrhage: Is there an end in sight?

Cited by 133 publications

References 257 publications

Recombinant ADAMTS 13 Attenuates Brain Injury After Intracerebral Hemorrhage

Recombinant ADAMTS 13 Attenuates Brain Injury After Intracerebral Hemorrhage

Epothilone B Benefits Nigrostriatal Pathway Recovery by Promoting Microtubule Stabilization After Intracerebral Hemorrhage

Green Tea Treatment Attenuates Oxidative Damage and Neuromotor Deficit Induced by an Experimental Model of Intracerebral Hemorrhage in Rats

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