Matrix metalloproteinases as therapeutic targets for stroke

Background and Purpose: The role played by post-stroke inflammation after an ischemic event in limiting functional recovery remains unclear. One component of post-stroke inflammation is disruption of the blood-brain barrier (BBB). This study examines the relationship between post-stroke BBB disruption and functional outcome. Methods: Acute stroke patients treated with thrombolysis underwent magnetic resonance imaging scanning 24 h and 5 days after their initial event. BBB permeability maps were generated from perfusion weighted imaging. Average permeability was calculated in the affected hemisphere. Good functional outcome, defined as a modified Rankin score of 0 or 1, was compared with average permeability using logistic regression. Results: Of the 131 patients enrolled, 76 patients had the necessary data to perform the analysis at 24 h, and 58 patients had data for the 5-day assessment. Higher BBB permeability measured at 24 h (OR 0.57; 95% CI 0.33–0.99, p = 0.045) and at 5 days (OR 0.24; 95% CI 0.09–0.66, p = 0.005) was associated with worse functional outcome 1–3 months after the acute ischemic stroke. For every percentage increase in BBB disruption at 5 days, there was a 76% decrease in the chance of achieving a good functional outcome after stroke. Multivariate analysis found this to be independent of age, stroke volume, or clinical stroke severity. Conclusions: Post-stroke BBB disruption appears to be predictive of functional outcome irrespective of stroke size.

show abstract

“…Thus, treatments targeting BBB stabilization may also play a role. One approach is to identify agents that inhibit MMP activity [25].…”

Section: Discussionmentioning

confidence: 99%

Post-Stroke Blood-Brain Barrier Disruption and Poor Functional Outcome in Patients Receiving Thrombolytic Therapy

et al. 2019

View full text Add to dashboard Cite

show abstract

“…An increased number of MMP-9 positive cells has been described not only in the experimental models of cerebral ischemia but also in post mortem ischemic brain tissue, in association with neutrophil infiltration and activated microglia cells (Rosell et al, 2006). These findings suggest a deleterious role of neutrophils and microglia in human brain injury (oedema following cerebral acute ischemia) and a potential therapeutic target in stroke (Yang & Rosenberg, 2015;Zhang et al, 2017). In contrast to the significance of leukocytes, the significance of lymphocytes recruited into the brain after ischemic stroke remains uncertain.…”

Section: Discussionmentioning

confidence: 93%

Inflammatory cell populations in early neuroinflammation in the core and peri-ischemic lesions of rat brain after transient focal cerebral ischemia: A morphometric study

Horváth

Orădan

Chiriac

et al. 2018

Preprint

View full text Add to dashboard Cite

Background and Objective:Clinical and experimental observations emphasize the role of inflammation as a direct risk factor for stroke. To better characterize the inflammation, we have conducted a detailed histological analysis of the inflammatory cell population after transient middle cerebral artery occlusion in a rat model. Methods:Fifteen adult Wistar male rats were divided randomly into test (n=10) and sham (n=5) groups. In the ischemic group, transient focal cerebral ischemia was induced with an intraluminal filament technique. Histologic lesions of the ischemic core and the surrounding penumbra zone were evaluated, based on a complex algorithm. Representative morphological changes in the core and the penumbra zone were compared. Immunohistochemistry was performed for leukocytes markers (CD15, CD68, CD3), leukocyte-released effectors (MMP-9 and COX-2), and FXIII (possibly involved in microglia and macrophage activation)Results: Neuronal vacuolation and degeneration were significantly more in the core lesion, whereas cellular edema and inflammatory infiltrate were increased in the penumbra. CD68, CD3, FXIII and Cox-2 expression were significantly higher in the penumbra than in the core (p=0.026; p=0.006; p=0.002; and p<0.001).Discussion: In the rat model of middle cerebral artery occlusion, inflammatory mechanisms, microglia/macrophage cells, and T-lymphocytes likely play an important role in the penumbra. The deterioration of neurons is less in the penumbra than in the core. Appreciation of the role of the inflammatory cells and mechanisms involved in stroke might lead to measures to inhibit the injury and save brain volume. ABSTRACT Background and Objective: Clinical and experimental observations emphasize the role of inflammation as a direct risk factor for stroke. To better characterize the inflammation, we have conducted a detailed histological analysis of the inflammatory cell population after transient middle cerebral artery occlusion in a rat model.

show abstract

“…Consistently, MMP-9 knockout mice showed attenuated brain infarct after cerebral ischemia [58]. More importantly, MMP-9 greatly contributes to BBB damage during cerebral ischemia [24,59]. MMP-9 knockout in mice protected from BBB disruption in a cerebral ischemia model [58].…”

Section: Mechanisms Of T-pa-induced Htmentioning

confidence: 99%

Targeting ONOO<sup>-</sup>/HMGB1/MMP-9 Signaling Cascades: Potential for Drug Development from Chinese Medicine to Attenuate Ischemic Brain Injury and Hemorrhagic Transformation Induced by Thrombolytic Treatment

Chen¹,

Guan²,

Shen³

2016

Integr Med Int

View full text Add to dashboard Cite

Stroke is the leading cause of death and disability worldwide, and ischemic stroke accounts for more than 85% of the stroke incidence. Tissue plasminogen activator (t-PA) is the only FDA-approved drug for ischemic stroke treatment with a narrow treatment time window of 4.5 h. Hemorrhagic transformation (HT) is a severe complication of delayed t-PA treatment in ischemic stroke. Thus, it is critically important to develop combination therapies to reduce HT and extend the therapeutic time window of t-PA. Current progress suggests that peroxynitrite (ONOO^-)/high-mobility group box 1 protein (HMGB1)/matrix metalloproteinase-9 (MMP-9) signaling cascades could be important for attenuating HT during thrombolytic treatment for acute ischemic stroke. Recently, important progress has been made in seeking for natural compounds from Chinese medicine for reducing ischemic stroke injury, with some of them targeting ONOO^-/HMGB1/MMP-9 signaling cascades. Herein, we analyze the roles and interactions of these three targets in mediating HT; subsequently, we summarize the potential compounds from Chinese herbal medicine for attenuating HT and analyze the related targets. Finally, we raise the potential issues to be addressed in further development of these compounds as combination therapy.

show abstract

Matrix metalloproteinases as therapeutic targets for stroke

Cited by 203 publications

References 78 publications

Post-Stroke Blood-Brain Barrier Disruption and Poor Functional Outcome in Patients Receiving Thrombolytic Therapy

Post-Stroke Blood-Brain Barrier Disruption and Poor Functional Outcome in Patients Receiving Thrombolytic Therapy

Inflammatory cell populations in early neuroinflammation in the core and peri-ischemic lesions of rat brain after transient focal cerebral ischemia: A morphometric study

Targeting ONOO<sup>-</sup>/HMGB1/MMP-9 Signaling Cascades: Potential for Drug Development from Chinese Medicine to Attenuate Ischemic Brain Injury and Hemorrhagic Transformation Induced by Thrombolytic Treatment

Contact Info

Product

Resources

About