Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The regulation of cerebrovascular permeability is critical for normal brain homeostasis, and the "breakdown" of the blood-brain barrier (BBB) is associated with the development of vasogenic edema and intracranial hypertension in a number of neurological disorders. In this study we demonstrate that an increase in endogenous tissue-type plasminogen activator (tPA) activity in the perivascular tissue following cerebral ischemia induces opening of the BBB via a mechanism that is independent of both plasminogen (Plg) and MMP-9. We also show that injection of tPA into the cerebrospinal fluid in the absence of ischemia results in a rapid dose-dependent increase in vascular permeability. This activity is not seen with urokinase-type Plg activator (uPA) but is induced in Plg-/- mice, confirming that the effect is Plg-independent. However, the activity is blocked by antibodies to the LDL receptor-related protein (LRP) and by the LRP antagonist, receptor-associated protein (RAP), suggesting a receptor-mediated process. Together these studies demonstrate that tPA is both necessary and sufficient to directly increase vascular permeability in the early stages of BBB opening, and suggest that this occurs through a receptor-mediated cell signaling event and not through generalized degradation of the vascular basement membrane.
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PMID:Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor-related protein. 1461 49

Tissue-type plasmingen activator (tPA) is a highly specific serine proteinase that activates the zymogen plasminogen to the broad-specificity proteinase plasmin. tPA is found in the blood, where its primary function is as a thrombolytic enzyme, as well as in the central nervous system (CNS), where it promotes events associated with synaptic plasticity and cell death in a number of settings, such as cerebral ischemia and seizures. Neuroserpin is a fully inhibitory serine proteinase inhibitor (serpin) that reacts preferentially with tPA, and is located in regions of the brain where either tPA message or tPA protein are also found, suggesting that neuroserpin is the selective inhibitor of tPA in the CNS. There is a growing body of evidence demonstrating the participation of tPA in a number of physiologic and pathologic events in the CNS, and the role of neuroserpin as the natural regulator of tPA's activity in these processes.
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PMID:Tissue-type plasminogen activator and neuroserpin: a well-balanced act in the nervous system? 1526 88

Tissue-type plasminogen activator (tPA) is a highly specific serine proteinase that activates the zymogen plasminogen to the broad-specificity proteinase plasmin. Tissue-type plasminogen activator is found not only in the blood, where its primary function is as a thrombolytic enzyme, but also in the central nervous system (CNS), where it promotes events associated with synaptic plasticity and acts as a regulator of the permeability of the neurovascular unit. Tissue-type plasminogen activator has also been associated with pathological events in the CNS such as cerebral ischemia and seizures. Neuroserpin is an inhibitory serpin that reacts preferentially with tPA and is located in regions of the brain where either tPA message or tPA protein are also found, indicating that neuroserpin is the selective inhibitor of tPA in the CNS. There is a growing body of evidence demonstrating the participation of tPA in a number of physiological and pathological events in the CNS, as well as the role of neuroserpin as the natural regulator of tPA's activity in these processes. This review will focus on nonhemostatic roles of tPA in the CNS with emphasis on its newly described function as a regulator of permeability of the neurovascular unit and on the regulatory role of neuroserpin in these events.
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PMID:New functions for an old enzyme: nonhemostatic roles for tissue-type plasminogen activator in the central nervous system. 1556 35

The aim of this study was to investigate the effects of different doses of exogenous recombinant human tissue plasminogen activator (rt-PA) on the endogenous cerebral plasminogen-plasmin system in focal ischemia in rats. Ischemia was induced using the suture model. Each group of rats (n = 6) received either treatment (0.9, 9 or 18 mg rt-PA/kg body weight) or saline (control group) at the end of ischemia; a sham-operated group was added. The activity of the plasminogen activators was measured by casein-dependent plasminogen zymography. In the cortex urokinase (u-PA) rose from sham (no ischemia), 91 +/- 7% to ischemia, 176 +/- 10% (P < 0.005). Increasing rt-PA doses led to further significant (P < 0.001) cortical u-PA activation which was maximal at 18 mg: 249 +/- 13%. An extreme increase in the u-PA activity was observed in the basal ganglia to 1019 +/- 22% (P < 0.001). This increase was further aggravated by higher rt-PA doses (18 mg, 1236 +/- 15%; P < 0.001). The t-PA level did not change I3R24 during (3 h ischemia followed by reperfusion for 24 h); however, during low and moderate doses of rt-PA, endogenous t-PA was reduced. In conclusion, while ischemia leads to a significant increase in u-PA, mainly in the basal ganglia, t-PA is not altered. Increasing doses of rt-PA lead to a further elevation of u-PA. Thus, u-PA seems to play a major role in the endogenous plasminogen activator system following focal cerebral ischemia.
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PMID:Rt-PA causes a significant increase in endogenous u-PA during experimental focal cerebral ischemia. 1557 44

In this report, we provide direct demonstration that the neurotrophin nerve growth factor (NGF) is released in the extracellular space in an activity-dependent manner in its precursor form (proNGF) and that it is in this compartment that its maturation and degradation takes place because of the coordinated release and the action of proenzymes and enzyme regulators. This converting protease cascade and its endogenous regulators (including tissue plasminogen activator, plasminogen, neuroserpin, precursor matrix metalloproteinase 9, and tissue inhibitor metalloproteinase 1) are colocalized in neurons of the cerebral cortex and released upon neuronal stimulation. We also provide evidence that this mechanism operates in in vivo conditions, as the CNS application of inhibitors of converting and degrading enzymes lead to dramatic alterations in the tissue levels of either precursor NGF or mature NGF. Pathological alterations of this cascade in the CNS might cause or contribute to a lack of proper neuronal trophic support in conditions such as cerebral ischemia, seizure and Alzheimer's disease or, conversely, to excessive local production of neurotrophins as reported in inflammatory arthritis pain.
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PMID:Activity-dependent release of precursor nerve growth factor, conversion to mature nerve growth factor, and its degradation by a protease cascade. 1661 25

Tetracyclines inhibit matrix metalloproteinases (MMPs) and reduce infarction volume following cerebral ischemia. In this thesis an involvement of urokinase could be proven. Cerebral ischemia in rats was induced for 3 h followed by 24 h reperfusion (suture model). Each 6 animals received orally either doxycycline or water. Doxycycline treatment began 10 days before ischemia. MMP-2 and MMP-9 were substantially decreased. The possibility of involvement of the endogenous MMP inhibitors in the MMP inhibiting mechanisms was excluded. The plasminogen activator uPA was significantly decreased by doxycycline indicating an MMP inhibiting mechanism including the plasminogen/plasmin system. In the doxycycline group, this resulted in a decreased damage to the cerebral microvessels and less loss of the basal lamina antigen collagen type IV. Hemoglobin extravasation was also significantly reduced. Our results suggest that doxycycline may have a potential use as an anti-ischemic compound since it provides microvascular protection by inhibiting the plasminogen system.
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PMID:Doxycycline inhibits MMPs via modulation of plasminogen activators in focal cerebral ischemia. 1716 29

Tissue-type plasminogen activator (tPA) is a serine proteinase found in the intravascular space and the central nervous system. The low-density lipoprotein receptor-related protein (LRP) is a member of the low-density lipoprotein receptor gene family found in neurons and astrocytes. Cerebral ischemia induces activation of the nuclear factor (NF)-kappaB pathway. The present study investigated the role that the interaction between tPA and LRP plays on middle cerebral artery occlusion (MCAO)-induced NF-kappaB-mediated inflammatory response. We found that MCAO increased LRP expression primarily in astrocytes and that this effect was significantly decreased in the absence of tPA. The onset of the ischemic insult induced activation of the NF-kappaB pathway in wild-type and plasminogen (Plg(-/-))-deficient mice, and this effect was attenuated after inhibition of LRP or genetic deficiency of tPA. Moreover, administration of tPA to tPA(-/-) mice resulted in activation of the NF-kappaB pathway comparable with that observed in wild-type and Plg(-/-) mice. We also report that inhibition of either tPA activity or LRP or genetic deficiency of tPA resulted in a significant decrease in MCAO-induced nitric oxide production and inducible nitric-oxide synthase expression. In conclusion, our results demonstrate that after MCAO the interaction between tPA and LRP results in NF-kappaB activation in astrocytes and induction of inducible nitric-oxide synthase expression in the ischemic tissue, suggesting a cytokine-like plasminogen-independent role for tPA during cerebral ischemia.
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PMID:Tissue-type plasminogen activator and the low-density lipoprotein receptor-related protein mediate cerebral ischemia-induced nuclear factor-kappaB pathway activation. 1771 50

Clinical studies have shown that the treatment of ischemic stroke with hypothermia is promising. In this animal study, we investigated the fate of the microvasculature following focal cerebral ischemia in mice with and without hypothermia. Focal cerebral ischemia was induced by occlusion of the middle cerebral artery (MCAO) (3 h) with an intraluminal filament technique. Eight mice received normothermia (36.5 degrees C, NT) and eight received hypothermia (32-34 degrees C, HT) treatment during 24 h of reperfusion. Another six mice represented the sham group. Analysis of the hypothermic group in comparison to the normothermic group revealed a significantly reduced infarct volume (NT: 63.56+/-4.62 mm3 SEM, HT: 38.09+/-4.83 mm3 SEM; P<0.01) and showed considerably ameliorated neurological deficits (Garcia-score) after 24 h (P<0.01). In addition, the degradation of the microvascular basal lamina antigen collagen type IV after normothermia was strongly reduced (P<0.05) compared to sham. Hypothermia diminished this effect so that collagen type IV was not significantly reduced compared to sham. Moreover the hemoglobin extravasation was strongly reduced under hypothermic treatment compared to the normothermic group (P<0.01). In the hypothermia group the urokinase plasminogen-activator (uPA) activity (P=0.01) was significantly decreased compared to the normothermia group. Also MMP-9 was significantly reduced (P<0.05) during hypothermic treatment. In conclusion, for the first time we show in mice that hypothermia preserves the microvascular wall structures after ischemia. We have demonstrated that hypothermia protects the basal lamina, reduces the infarct volume and hemorrhage, and reduces proteolytic enzymes. These protective effects in an additional animal model of ischemia and reperfusion strongly recommend hypothermia as a potential beneficial treatment for stroke.
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PMID:Protection of cerebral microvasculature after moderate hypothermia following experimental focal cerebral ischemia in mice. 1858 14

Microglia are the immune cells of the central nervous system (CNS) that become activated in response to pathological situations such as cerebral ischemia. Tissue-type plasminogen activator (tPA) is a serine proteinase that is found in the intravascular space and the CNS. The low-density lipoprotein receptor-related protein 1 (LRP1) is a member of the low-density lipoprotein receptor gene family found in neurons, astrocytes, and microglia. The present study investigated whether the interaction between tPA and microglial LRP1 plays a role in cerebral ischemia-induced microglial activation. We found that middle cerebral artery occlusion (MCAO) induces microglial activation in both wild-type and plasminogen-deficient (Plg(-/-)) mice. In contrast, MCAO-induced microglial activation is significantly decreased in tPA-deficient (tPA(-/-)) mice and in mice that lack LRP1 in microglial cells (macLRP(-)). We observed a significant increase in microglial activation when tPA(-/-) mice received treatment with murine tPA after MCAO. In contrast, treatment of macLRP(-) mice with tPA did not have an effect on the extent of microglial activation. Finally, both the volume of the ischemic lesion as well as inducible nitric oxide synthase production were significantly decreased in macLRP(-) mice and macLRP(-) microglia. In summary, our results indicate that the interaction between tPA and LRP1 induces microglial activation with the generation of an inflammatory response in the ischemic brain, suggesting a cytokine-like role for tPA in the CNS.
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PMID:The low-density lipoprotein receptor-related protein 1 mediates tissue-type plasminogen activator-induced microglial activation in the ischemic brain. 1914 18

Studies in animal models of cerebral ischemia indicate that besides its thrombolytic effect, treatment with tissue-type plasminogen activator (tPA) also induces an increase in matrix metalloproteinase-9 (MMP-9) activity in the ischemic tissue associated with the development of cerebral edema. Earlier, we had shown that the low-density lipoprotein receptor-related protein 1 (LRP1) is a substrate for tPA in the brain. In this study, we investigated the effect of the interaction between tPA and microglial LRP1 on MMP-9 activity after middle cerebral artery occlusion (MCAO). We found that exposure to oxygen-glucose deprivation (OGD) conditions increases MMP-9 activity in wild-type (Wt) and plasminogen-deficient (Plg(-/-)) microglia, but not in tPA (tPA(-/-)) or LRP1-deficient (macLRP-) cells. Treatment with tPA increases MMP-9 expression in tPA(-/-) but not in macLRP- microglia. Middle cerebral artery occlusion increases MMP-9 expression and activity in Wt but not in tPA(-/-) or macLRP- mice, and treatment with tPA increases MMP-9 activity in tPA(-/-) mice but not in macLRP- animals. Finally, MCAO-induced ischemic edema and degradation of the interendothelial right junction protein claudin-5 were significantly attenuated in tPA(-/-) and macLRP- mice. The results of our study indicate that the interaction between tPA and microglial LRP1 increases MMP-9 expression and activity resulting in the degradation of claudin-5 and development of cerebral edema.
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PMID:Microglial low-density lipoprotein receptor-related protein 1 mediates the effect of tissue-type plasminogen activator on matrix metalloproteinase-9 activity in the ischemic brain. 1967 75


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