Blood Glutamate Grabbing Does Not Reduce the Hematoma in an Intracerebral Hemorrhage Model but it is a Safe Excitotoxic Treatment Modality

Silva‐Candal, Andrés da; Vieites‐Prado, Alba; Gutiérrez-Fernández, María; Rey, R. I.; Argibay, Bárbara; Mirelman, David; Sobrino, Tomás; Rodríguez-Frutos, Berta; Castillo, José; Campos, Francisco

doi:10.1038/jcbfm.2015.28

Cited by 25 publications

(22 citation statements)

References 37 publications

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“…The same experimental design and setting were used to assess the effect of late (3 hours) CM352 treatment. Required sample size was calculated from previous studies using the same model21 in order to be able to detect a 25% effect size on hematoma growth versus controls (2‐tailed t test). Six animals per group are required to detect this difference with a power (1−β) of 0.8 and α=0.05.…”

Section: Methodsmentioning

confidence: 99%

CM352 Reduces Brain Damage and Improves Functional Recovery in a Rat Model of Intracerebral Hemorrhage

Rodríguez

Sobrino

López-Arias

et al. 2017

JAHA

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BackgroundIntracerebral hemorrhage (ICH) is an acute neurological disorder with high mortality and no effective treatment. In addition to the initial bleeding event, rebleeding and hematoma expansion are associated with poor outcome in these patients. We studied the effectiveness of the new antifibrinolytic agent CM352, a short‐half‐life matrix metalloproteinase inhibitor, for achieving early hemostasis and improving functional recovery in a rat model of collagenase‐induced ICH.Methods and Results ICH was induced by striatal injection of collagenase, and 1 hour later, rats received an intravenous injection of saline (n=6) or CM352 (1 mg/kg, n=6). Hematoma (basal and after 3 and 24 hours) and lesion (14 days) volumes were quantified on T2‐weighted (T2) magnetic resonance images. Neurological and functional recovery was evaluated by using Bederson score and a cylinder test (basal, 24 hours, and 14 days). Early treatment (1 hour) with CM352 was efficient reducing hematoma expansion at 3 hours (P<0.01) and, more markedly, at 24 hours (P<0.01). Decreased bleeding after antifibrinolytic treatment was accompanied by reduced interleukin‐6 levels at 3 hours (P<0.05) and smaller lesion volume at 14 days (P<0.01). CM352 drastically reduced sensorimotor impairment (cylinder test) after ICH in rats at 24 hours (P<0.01) and 14 days (P<0.01). Similarly, it also attenuated neurological deficit (Bederson scale) at 24 hours (P<0.01) and 14 days (P<0.01). Interestingly, late (3 hours) CM352 administration also resulted in reduced lesion size and better functional outcome.Conclusions CM352, a new antifibrinolytic agent and matrix metalloproteinase inhibitor, effectively prevented hematoma growth and reduced lesion size in ICH in association with improved functional and neurological recovery.

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Section: Methodsmentioning

confidence: 99%

CM352 Reduces Brain Damage and Improves Functional Recovery in a Rat Model of Intracerebral Hemorrhage

Rodríguez

Sobrino

López-Arias

et al. 2017

JAHA

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“…These amino acids may play an important role in the pathology of ICH, but the intricacies of the mechanism are not very clear [53] . A recent study shows that blood glutamate grabbing cannot reduce the hematoma nor improve the neurologic deficit in ICH but is a safe excitotoxic treatment modality [54] . Animal experiments demonstrated that ET-1 expression increased significantly at 6, 12, 18, and 24 h after ICH, and they observed a positive correlation between the number of ET-1-positive endothelial cells and BBB permeability [55] .…”

Section: Rbc Lysis Productionmentioning

confidence: 99%

Mechanism and Therapy of Brain Edema after Intracerebral Hemorrhage

et al. 2016

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Background: Intracerebral hemorrhage (ICH) is a subtype of stroke with a severe high mortality and disability rate and accounts for about 10-15% of all strokes. The oppression and destruction by hematoma to brain tissue cause the primary brain injury. The inflammation and coagulation response after ICH would accelerate the formation of brain edema around hematoma, resulting in a more severe and durable injury. Currently, treatments for ICH are focusing on the primary injury including reducing intracranial hypertension, blood pressure control, and rehabilitation. There is a short-of-effective medical treatment for secondary inflammation and reducing brain edema in ICH patients. So, it is very important to study on the relationship between brain edema and ICH. Summary: Many molecular and cellular mechanisms contribute to the formation and progress of brain edema after ICH; inhibition of brain edema provides favorable outcome of ICH. Key Messages: This review mainly discusses the pathology and mechanism of brain edema, the effects of brain edema on ICH, and the methods of treating brain edema after ICH.

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“…OxAc or GOT showed a therapeutic window of no longer than 3 to 4 h after insult 55 ; therefore, the efficacy of this protective mechanism depends on the time-point of drug administration. However, in a recently published model of brain hemorrhage, glutamate grabbers were shown to decrease the blood glutamate levels but did not affect the hemorrhagic hematoma, 64 suggesting that this treatment can be given as early as possible, without neuroimaging, in case of suspected stroke, which may potentially increase the number of patients treated within the therapeutic window.…”

Section: Limitations Of Glutamate Grabbersmentioning

confidence: 98%

A novel mechanism of neuroprotection: Blood glutamate grabber

Castillo

Loza

Mirelman

et al. 2015

J Cereb Blood Flow Metab

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Glutamate excitotoxicity is a primary contributor of ischemic neuronal death and other cellular components of the neurovascular unit. Several strategies have been developed against glutamate excitotoxicity, however none of them have not shown positive results in the clinical practice so far. Nowadays, the concept of blood/brain glutamate grabbing or scavenging is well recognized as a novel and attractive protective strategy to reduce the excitotoxic effect of excess extracellular glutamate that accumulates in the brain following an ischemic stroke. The main advantage of this novel therapeutic strategy is that it occurs in the blood circulation and therefore does not affect the normal brain neurophysiology, as it has been described for other drug treatments used against glutamate excitotoxicity. In this work we report all experimental data from the beginning of our studies, focused on stroke pathology, and we describe new findings about the potential application of this therapy. Future clinical trials will allow to know the real efficacy of this novel therapeutic strategy in stroke patients.

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Blood Glutamate Grabbing Does Not Reduce the Hematoma in an Intracerebral Hemorrhage Model but it is a Safe Excitotoxic Treatment Modality

Cited by 25 publications

References 37 publications

CM352 Reduces Brain Damage and Improves Functional Recovery in a Rat Model of Intracerebral Hemorrhage

CM352 Reduces Brain Damage and Improves Functional Recovery in a Rat Model of Intracerebral Hemorrhage

Mechanism and Therapy of Brain Edema after Intracerebral Hemorrhage

A novel mechanism of neuroprotection: Blood glutamate grabber

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