Multiple roles for MMPs and TIMPs in cerebral ischemia

Cunningham, Lee Anna; Wetzel, Monica; Rosenberg, Gary A.

doi:10.1002/glia.20169

Cited by 385 publications

(337 citation statements)

References 115 publications

(51 reference statements)

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“…It has been shown that TIMPs play essential roles with MMPs on central nervous system plasticity (Cunningham et al, 2005;Gasche et al, 2006). The present study is the first to show the effects of TIMP-1 and TIMP-2 on BBB dysfunction and ischemic injury, using TIMP-1 À/À and TIMP-2 À/À mice.…”

Section: Discussionmentioning

confidence: 57%

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

Fujimoto

Takagi

Aoki

et al. 2008

J Cereb Blood Flow Metab

138

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Enhanced matrix metalloproteinases (MMPs) can cause vasogenic edema and hemorrhagic transformation after cerebral ischemia, and affect the extent of ischemic injury. We hypothesized that the endogenous MMP inhibitors, tissue inhibitor of MMPs (TIMPs), were essential to protect against blood-brain barrier (BBB) disruption after ischemia by regulating the activities of MMPs. We confirmed the transition of MMP-2 and MMP-9, and the TIMPs family after 30 mins of middle cerebral artery occlusion, and elucidated the function of TIMP-1 and TIMP-2 in focal ischemia, using TIMP-1 À/À and TIMP-2 À/À mice. TIMP-1 mRNA expression was gradually increased until 24 h after reperfusion. In TIMP-1 À/À mice, MMP-9 protein expression and gelatinolytic activity were significantly more augmented after cerebral ischemia than those in WT mice, and were accompanied by exacerbated BBB disruption, neuronal apoptosis, and ischemic injury. In contrast, TIMP-2 gene deletion mice exhibited no significant difference in MMP expressions and the degree of ischemic injury despite an increased Evans blue leakage. These results suggest that TIMP-1 inhibits MMP-9 activity and can play a neuroprotective role in cerebral ischemia.

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Section: Discussionmentioning

confidence: 57%

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

Fujimoto

Takagi

Aoki

et al. 2008

J Cereb Blood Flow Metab

138

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“…Src seems to play a greater role than MMP-2 in HEK293/A 1 R cells, because inhibition of MMP-2 with BiPs only inhibited ERK1/2 phosphorylation and not Akt phosphorylation. However, the inhibition of Src The literature of cerebral ischemia indicates that MMPs play multiple roles [34] . MMP-9 exhibits high levels of activity during ischemia, especially in the acute phase, while MMP-2 has been found to be elevated in the delayed phase and showed contrary performance which remains to disclosure [35] .…”

Section: Discussionmentioning

confidence: 99%

Paeoniflorin ameliorates ischemic neuronal damage in vitro via adenosine A1 receptor-mediated transactivation of epidermal growth factor receptor

Zhong

Song

et al. 2015

Acta Pharmacol Sin

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Aim: Paeoniflorin from Chinese herb Paeoniae Radix has been shown to ameliorate middle cerebral artery occlusion-induced ischemia in rats. The aim of this study was to investigate the mechanisms underlying the neuroprotective action of PF in cultured rat cortical neurons. Methods: Primary cultured cortical neurons of rats were subjected to oxygen-glucose deprivation and reoxygenation (OGD/R) insult. Cell survival was determined using MTT assay. HEK293 cells stably transfected with A 1 R (HEK293/A 1 R) were used for detailed analysis. Phosphorylation of the signaling proteins was evaluated by Western blot or immunoprecipitation. Receptor interactions were identified using co-immunoprecipitation and immunofluorescence staining. Results: Paeoniflorin (10 nmol/L to 1 μmol/L) increased the survival of neurons subjected to OGD/R. Furthermore, paeoniflorin increased the phosphorylation of Akt and ERK1/2 in these neurons. These effects were blocked by PI3K inhibitor wortmannin or MEK inhibitor U0126. Paeoniflorin also increased the phosphorylation of Akt and ERK1/2 in HEK293/A 1 R cells. Both A 1 R antagonist DPCPX and EGFR inhibitor AG1478 not only blocked paeoniflorin-induced phosphorylation of ERK1/2 and Akt in HEK293/A 1 R cells, but also paeoniflorin-increased survival of neurons subjected to OGD/R. In addition, paeoniflorin increased the phosphorylation of Src kinase and activation of MMP-2 in HEK293/A 1 R cells. Both Src inhibitor PP2 and MMP-2/MMP-9 inhibitor BiPs not only blocked paeoniflorininduced phosphorylation of ERK1/2 (and Akt) in HEK293/A 1 R cells, but also paeoniflorin-increased survival of neurons subjected to OGD/R. Conclusion: Paeoniflorin promotes the survival of cultured cortical neurons by increasing Akt and ERK1/2 phosphorylation via A 1 Rmediated transactivation of EGFR.

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“…1C). 113,114 For example, MMP-9 knockout mice have less severe strokes and inhibitors of the MMP-9 reduce stroke volume. 115 In contrast, at several days after ischemia, MMP-9 serves a neuroprotective role by cleaving and activating VEGF (FIG.…”

Section: Figmentioning

confidence: 99%

Targeting Astrocytes for Stroke Therapy

2010

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Summary: Stroke remains a major health problem and is a leading cause of death and disability. Past research and neurotherapeutic clinical trials have targeted the molecular mechanisms of neuronal cell death during stroke, but this approach has uniformly failed to reduce stroke-induced damage or to improve functional recovery. Beyond the intrinsic molecular mechanisms inducing neuronal death during ischemia, survival and function of astrocytes is absolutely required for neuronal survival and for functional recovery after stroke. Many functions of astrocytes likely improve neuronal viability during stroke. For example, uptake of glutamate and release of neurotrophins enhances neuronal viability during ischemia. Under certain conditions, however, astrocyte function may compromise neuronal viability. For example, astrocytes may produce inflammatory cytokines or toxic mediators, or may release glutamate. The only clinical neurotherapeutic trial for stroke that specifically targeted astrocyte function focused on reducing release of S-100␤ from astrocytes, which becomes a neurotoxin when present at high levels. Recent work also suggests that astrocytes, beyond their influence on cell survival, also contribute to angiogenesis, neuronal plasticity, and functional recovery in the several days to weeks after stroke. If these delayed functions of astrocytes could be targeted for enhancing stroke recovery, it could contribute importantly to improving stroke recovery. This review focuses on both the positive and the negative influences of astrocytes during stroke, especially as they may be targeted for translation to human trials.

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Multiple roles for MMPs and TIMPs in cerebral ischemia

Cited by 385 publications

References 115 publications

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

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

Paeoniflorin ameliorates ischemic neuronal damage in vitro via adenosine A1 receptor-mediated transactivation of epidermal growth factor receptor

Targeting Astrocytes for Stroke Therapy

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