Implications of MMP9 for Blood Brain Barrier Disruption and Hemorrhagic Transformation Following Ischemic Stroke

Turner, Renée J.; Sharp, Frank R.

doi:10.3389/fncel.2016.00056

Cited by 381 publications

(310 citation statements)

References 132 publications

(244 reference statements)

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“…MMP-9 and neutrophil levels are elevated in the cerebrospinal fluid as well. Since rtPA itself promotes neutrophil degranulation, a peak of MMP-9 elevation can be detected 30 minutes after rtPA administration as well [105][106][107].…”

Section: Mmp-9 Levelmentioning

confidence: 99%

Hemorrhagic transformation of ischemic stroke

J¹,

Hortobágyi²

2017

Vascul Dis Ther

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The better understanding of the diverse mechanisms leading to the hemorrhagic transformation of an ischemic stroke is the crucial point in the prevention of this altogether common phenomenon. The different individual risk factors include the anatomical variability of collateral blood supply, age, genetics, body weight, etiology of the occlusion, side of the occluded vessel, renal status, stroke severity, history of high serum glucose or hypertension and hypertension or hyperglycemia at the onset of the stroke, ferritin level, INR, antiplatelet usage or the platelet count etc. All these might contribute to the process of hemorrhagic transformation. These risk factors have been identified by retrospective epidemiological studies and are useful to identify patients who are at high risk for hemorrhagic conversion and help the decision between conservative, thrombolytic or more advanced treatments such as thrombectomy. The modulations of potential molecular targets participating in the process seem to be promising in animal models, but human trials are lacking the breakthrough success so far, both in extending the time frame of the thrombolysis and in replacing the recombinant tissue plasminogen activator (rtPA) as thrombolytic agent.So far, the careful preselection of patients eligible for thrombolytic therapy is the best way to prevent hemorrhagic transformation. The intensive research in the field revealing small but important molecular details are continuously contributing to the better understanding of hemorrhagic transformation with the intention of finding new agents that co-administrated to the rtPA or completely replacing that could decrease the risk of secondary bleeding.The aim of this review is to give comprehensive insight into the process of hemorrhagic transformation of ischemic stroke, starting with basic overview of the penumbra concept and the collateral supply followed by discussion of the recanalisation-reperfusion-hemorrhagic transformation process after vessel occlusion also highlighting the importance of timing and ratio of recanalisation spontaneously and in case of thrombolytic agent administration. We overview the risk factors of hemorrhagic transformation, which may be helpful to physicians to identify high risk patients before rtPA administration. The last part of the work is dealing with future therapeutic possibilities based on the so far revealed molecular mechanisms of hemorrhagic transformation. With the aim to assess the rate and influencing factors on the recanalisation and reperfusion rate 381 patients with large-vessel occlusion was investigated. The patient group involved ones treated with rtPA or treated conservatively. Partial or complete recanalisation was achieved in 121 out of 210 (58%) patients after intravenous rtPA administration. The recanalisation success was more likely if the patient had atrial fibrillation [4] -maybe because cardioembolic clots consists more fibrin and are more likely to reopen by plasmin proteolysis than thrombosis of an atherosclerotic plaq...

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Section: Mmp-9 Levelmentioning

confidence: 99%

Hemorrhagic transformation of ischemic stroke

J¹,

Hortobágyi²

2017

Vascul Dis Ther

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“…20) As a deleterious effect of tissue-type plasminogen activator (t-PA) which is a therapeutic drug for thrombus, hemorrhagic transformation by BBB disruption has been shown. 3,21) Abu Fanne et al 22) suggested that inhibiting t-PA improved brain tissue damage, edema, and mortality caused by increased BBB permeability in thromboembolic stroke rats. MMPs and VEGFs are involved in BBB disruption by t-PA.…”

Section: Hemorrhagementioning

confidence: 99%

“…3,13) Cerebral hemorrhage is a lethal condition, which results in sudden death, paralysis of the extremities, and cognitive dysfunctions. Hemorrhage results from a fracture of microvessels by cerebral contusions.…”

Section: Hemorrhagementioning

confidence: 99%

“…[1][2][3] Some pathophysiological conditions are different dependent on the type of brain damage, while blood-brain barrier (BBB) disruption is a common pathogenic feature in many types of brain damage. 4,5) The BBB is a structural and cellular barrier that forms a barrier between the peripheral blood system and the brain tissue.…”

Section: Introductionmentioning

confidence: 99%

“…Brain damage caused by traumatic brain injury (TBI), cerebral ischemia and hemorrhage cause various fatal conditions including sudden death, coma, and motor and cognitive dysfunctions. [1][2][3] To prevent these conditions, early treatments and appropriate strategies to prevent further damage should be performed. However, the beneficial effects of current therapeutic drugs used in the clinic are limited.…”

Section: Introductionmentioning

confidence: 99%

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Protection of the Blood–Brain Barrier as a Therapeutic Strategy for Brain Damage

Michinaga

Kōyama

2017

Biological & Pharmaceutical Bulletin

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Severe brain damage by trauma, ischemia, and hemorrhage lead to fatal conditions including sudden death, subsequent complications of the extremities and cognitive dysfunctions. Despite the urgent need for treatments for these complications, currently available therapeutic drugs are limited. Blood-brain barrier (BBB) disruption is a common pathogenic feature in many types of brain damage. The characteristic pathophysiological conditions caused by BBB disruption are brain edema resulting from an excessive increase of brain water content, inflammatory damage caused by infiltrating immune cells, and hemorrhage caused by the breakdown of microvessel structures. Because these pathogenic features induced by BBB disruption cause fatal conditions, their improvement is a desirable strategy. Many studies using experimental animal models have focused on molecules involved in BBB disruption, including vascular endothelial growth factors (VEGFs), matrix metalloproteinases (MMPs) and endothelins (ETs). The inhibition of these factors in several experimental animals was protective against BBB disruption caused by several types of brain damage, and ameliorated brain edema, inflammatory damage, and hemorrhagic transformation. In patients with brain damage, the up-regulation of these factors was observed and was related to brain damage severity. Thus, BBB protection by targeting VEGFs, MMPs, and ETs might be a novel strategy for the treatment of brain damage.

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Derivation and Validation of a Serum Biomarker Panel to Identify Infants With Acute Intracranial Hemorrhage

et al. 2017

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IMPORTANCE Abusive head trauma is the leading cause of death from physical abuse. Missing the diagnosis of abusive head trauma, particularly in its mild form, is common and contributes to increased morbidity and mortality. Serum biomarkers may have potential as quantitative point-of-care screening tools to alert physicians to the possibility of intracranial hemorrhage. OBJECTIVE To identify and validate a set of biomarkers that could be the basis of a multivariable model to identify intracranial hemorrhage in well-appearing infants using the Ziplex System. DESIGN, SETTING, AND PARTICIPANTS Binary logistic regression was used to develop a multivariable model incorporating 3 serum biomarkers (matrix metallopeptidase-9, neuron-specific enolase, and vascular cellular adhesion molecule-1) and 1 clinical variable (total hemoglobin). The model was then prospectively validated. Multiplex biomarker measurements were performed using Flow-Thru microarray technology on the Ziplex System, which has potential as a point-of-care system. The model was tested at 3 pediatric emergency departments in level I pediatric trauma centers (Children'

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Implications of MMP9 for Blood Brain Barrier Disruption and Hemorrhagic Transformation Following Ischemic Stroke

Cited by 381 publications

References 132 publications

Hemorrhagic transformation of ischemic stroke

Hemorrhagic transformation of ischemic stroke

Protection of the Blood–Brain Barrier as a Therapeutic Strategy for Brain Damage

Derivation and Validation of a Serum Biomarker Panel to Identify Infants With Acute Intracranial Hemorrhage

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