Tissue Inhibitor of Metalloproteinases Protect Blood—Brain Barrier Disruption in Focal Cerebral Ischemia

Fujimoto, Motoaki; Takagi, Yasushi; Aoki, Tomohiro; Hayase, Makoto; Marumo, Takeshi; Gomi, Masanori; Nakagawa, Masaki; Kataoka, Hiroharu; Hashimoto, Nobuo; Nozaki, Kazuhiko

doi:10.1038/jcbfm.2008.59

Cited by 138 publications

(105 citation statements)

References 43 publications

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“…Increased MMP-9 expression and gelatinolytic activity that was accompanied by increased blood-brain barrier (BBB) disruption, neuronal apoptosis, and ischemic injury was reported in 30-minute focal cerebral ischemia-induced TIMP-1 knockout mice [24]. In agreement with these studies, our recent studies in a rat model of transient focal cerebral ischemia and reperfusion reported the post-ischemic induction of MMP-9 activity through gelatin zymography analysis [4,5].…”

Section: Discussionsupporting

confidence: 70%

“…Our recent studies demonstrated the predominant upregulation of MMP-12 and its pathological role in acute brain damage after ischemic stroke [4,5]. The temporal expression profile of various MMPs in ischemic rat brains after focal cerebral ischemia and reperfusion revealed that MMP-9 and MMP-12 were upregulated (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) fold in case of MMP-9 and 47-265 fold in case of MMP-12 through days 1 to 7 after reperfusion) several fold higher than any other MMPs tested [4]. Evidence also suggests the detrimental role of MMP-9 and MMP-12 on post-stroke brain damage [4][5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

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Mesenchymal Stem Cell Treatment Prevents Post-Stroke Dysregulation of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases

Chelluboina

Nalamolu

Mendez

et al. 2017

Cell Physiol Biochem

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Background/Aims: Stem cell treatment is one of the potential treatment options for ischemic stroke. We recently demonstrated a protective effect of human umbilical cord blood-derived mesenchymal stem cells (HUCB-MSCs) in a rat model of ischemic stroke. The treatment attenuated apoptosis and prevented DNA damage. A collection of published studies, including several from our laboratory, indicated the induction and detrimental role for several matrix metalloproteinases (MMPs) in post-stroke brain injury. We hypothesized that the HUCB-MSCs treatment after focal cerebral ischemia prevents the dysregulation of MMPs and induces the expression of endogenous tissue inhibitors of metalloproteinases (TIMPs) to neutralize the elevated activity of MMPs. Methods: To test our hypothesis, we administered HUCBMSCs (0.25 million cells/animal and 1 million cells/animal) intravenously via tail vein to male Sprague-Dawley rats that were subjected to a transient (two-hour) right middle cerebral artery occlusion (MCAO) and one-day reperfusion. Ischemic brain tissues obtained from various groups of rats seven days after reperfusion were subjected to real-time PCR, immunoblot, and immunofluorescence analysis. Results: HUCB-MSCs treatment prevented the induction of MMPs, which were upregulated in ischemia-induced rats that received no treatment. HUCBMSCs treatment also prevented the induction of TIMPs expression. The extent of prevention of MMPs and TIMPs induction by HUCB-MSCs treatment is similar at both the doses tested. Conclusion: Prevention of stroke-induced MMPs upregulation after HUCB-MSCs treatment is not mediated through TIMPs upregulation.

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Section: Discussionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Mesenchymal Stem Cell Treatment Prevents Post-Stroke Dysregulation of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases

Chelluboina

Nalamolu

Mendez

et al. 2017

Cell Physiol Biochem

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“…During the subsequent synapse stabilization phase, MMP attenuation would support the re-emergence of substrate proteins which anchor new synaptic junctions. Early elevation of secreted MMPs is well documented during neuroplasticity in models of neurotrauma, including controlled cortical impact, and lateral fluid percussion injury, as well as after olfactory bulb lesion, and cerebral ischemia (Costanzo and Perrino, 2008;Costanzo et al, 2006;Fujimoto et al, 2008;Romanic et al, 1998;Truettner et al, 2005;Wang et al, 2000). For example, diffuse percussive TBI elevates MMP-9 within 4 h post-injury, with peak expression at 1-3 days for MMPs 2 and 9 (Truettner et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

MT5-MMP, ADAM-10, and N-Cadherin Act in Concert To Facilitate Synapse Reorganization after Traumatic Brain Injury

Warren

Reeves²,

Phillips³

2012

Journal of Neurotrauma

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Matrix metalloproteinases (MMPs) influence synaptic recovery following traumatic brain injury (TBI). Membrane type 5-matrix metalloproteinase (MT5-MMP) and a distintegrin and metalloproteinase-10 (ADAM-10) are membrane-bound MMPs that cleave N-cadherin, a protein critical to synapse stabilization. This study examined protein and mRNA expression of MT5-MMP, ADAM-10, and N-cadherin after TBI, contrasting adaptive and maladaptive synaptogenesis. The effect of MMP inhibition on MT5-MMP, ADAM-10, and N-cadherin was assessed during maladaptive plasticity and correlated with synaptic function. Rats were subjected to adaptive unilateral entorhinal cortical lesion (UEC) or maladaptive fluid percussion TBI + bilateral entorhinal cortical lesion (TBI + BEC). Hippocampal MT5-MMP and ADAM-10 protein was significantly elevated 2 and 7 days postinjury. At 15 days after UEC, each MMP returned to control level, while TBI + BEC ADAM-10 remained elevated. At 2 and 7 days, N-cadherin protein was below control. By the 15-day synapse stabilization phase, UEC Ncadherin rose above control, a shift not seen for TBI + BEC. At 7 days, increased TBI + BEC ADAM-10 transcript correlated with protein elevation. UEC ADAM-10 mRNA did not change, and no differences in MT5-MMP or Ncadherin mRNA were detected. Confocal imaging showed MT5-MMP, ADAM-10, and N-cadherin localization within reactive astrocytes. MMP inhibition attenuated ADAM-10 protein 15 days after TBI + BEC and increased N-cadherin. This inhibition partially restored long-term potentiation induction, but did not affect pairedpulse facilitation. Our results confirm time-and injury-dependent expression of MT5-MMP, ADAM-10, and N-cadherin during reactive synaptogenesis. Persistent ADAM-10 expression was correlated with attenuated N-cadherin level and reduced functional recovery. MMP inhibition shifted ADAM-10 and N-cadherin toward adaptive expression and improved synaptic function.

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“…Mice without TIMP-2 gene showed increased BBB leakage and apoptosis without any change in the ischemic damage. TIMP-1 could be a potential target of neuroprotective therapy [144]. Also, the increase of the MMP9/TIMP1 ratio is significantly associated with symptomatic HT [145].…”

Section: Delayed Htmentioning

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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Tissue Inhibitor of Metalloproteinases Protect Blood—Brain Barrier Disruption in Focal Cerebral Ischemia

Cited by 138 publications

References 43 publications

Mesenchymal Stem Cell Treatment Prevents Post-Stroke Dysregulation of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases

Mesenchymal Stem Cell Treatment Prevents Post-Stroke Dysregulation of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases

MT5-MMP, ADAM-10, and N-Cadherin Act in Concert To Facilitate Synapse Reorganization after Traumatic Brain Injury

Hemorrhagic transformation of ischemic stroke

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