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

After brain injury, neuroblast cells from the subventricular zone (SVZ) expand and migrate toward damaged tissue. The mechanisms that mediate these neurogenic and migratory responses remain to be fully dissected. Here, we show that bromodeoxyuridine-labeled and doublecortin-positive cells from the SVZ colocalize with the extracellular protease matrix metalloproteinase-9 (MMP-9) during the 2 week recovery period after transient focal cerebral ischemia in mice. Treatment with the broad spectrum MMP inhibitor GM6001 significantly decreases the migration of doublecortin-positive cells that extend from the SVZ into the striatum. These data suggest that MMPs are involved in endogenous mechanisms of neurogenic migration as the brain seeks to heal itself after injury.
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PMID:Involvement of matrix metalloproteinase in neuroblast cell migration from the subventricular zone after stroke. 1657 56

Thrombolysis with tissue plasminogen activator (tPA) is the only pharmacotherapy available for cerebral ischemia. However, the use of tPA can increase the risk of hemorrhage due to blood-brain barrier (BBB) breakdown. Recent evidence suggests that increased activation of matrix metalloproteinases (MMPs) may be involved in this breakdown. This study examines the temporal profile of MMP-2 and -9 following tPA administration to ischemic rats. Male Sprague-Dawley rats were randomly assigned to one of four groups (Sham-tPA; Sham-Saline; Ischemia-tPA; Ischemia-Saline; group n = 6, total N = 120). Focal embolic ischemia was induced by middle cerebral artery occlusion through injection of an autologous clot. One hour post-surgery, tPA (10 mg/kg) or saline was delivered intravenously and animals were euthanized at 3, 6, 12, or 24 h after onset of ischemia. Infarct volume was measured by TTC staining; BBB components examined immunohistochemically; and MMP activation measured by gelatin zymography. Our results show that tPA significantly reduced infarct volumes (overall infarct volume-Sham-tPA: 5.80 +/- 4.55 [mean +/- SE]; Sham-Saline: 5.00 +/- 4.23; Ischemia-tPA: 186.1 +/- 73.45; Ischemia-Saline: 284.8 +/- 88.74; all P < 0.05). Treatment with tPA was also associated with the activation of MMP-9 at 6, 12, and 24 h following ischemia. No temporal changes were observed in MMP-2 activation, although tPA administration increased its activity compared to saline treatment. Analyses of immunohistochemistry showed that destruction of components of the BBB followed MMP-9 activation. Thus, increased MMP-9 activation may, in part, be responsible for the increases in hemorrhagic transformation reported with use of tPA. Our study is the first to demonstrate the temporal profile of MMP activation following thrombolysis with tPA in a model of thrombotic focal cerebral ischemia.
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PMID:Matrix metalloproteinase activation and blood-brain barrier breakdown following thrombolysis. 1662 94

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily. TWEAK acts via binding to a cell surface receptor named Fn14. To study the role of this cytokine in the regulation of the permeability of the neurovascular unit (NVU) during cerebral ischemia, TWEAK activity was inhibited in wild-type mice with a soluble Fn14-Fc decoy receptor administered either immediately or 1 h after middle cerebral artery occlusion (MCAO). Administration of Fn14-Fc decoy resulted in faster recovery of motor function and a 66.4%+/-10% decrease in Evans blue dye extravasation when treatment was administered immediately after MCAO and a 46.1%+/-13.1% decrease when animals were treated 1 h later (n=4, P<0.05). Genetic deficiency of Fn14 resulted in a 60%+/-12.8% decrease in the volume of the ischemic lesion (n=6, P<0.05), and a 87%+/-22% inhibition in Evans blue dye extravasation 48 h after the onset of the ischemic insult (n=6, P<0.005). Compared with control animals, treatment with Fn14-Fc decoy or genetic deficiency of Fn14 also resulted in a significant inhibition of nuclear factor-kappaB pathway activation, matrix metalloproteinase-9 activation and basement membrane laminin degradation after MCAO. These findings show that the cytokine TWEAK plays a role in the disruption of the structure of the NVU during cerebral ischemia and that TWEAK antagonism is a potential therapeutic strategy for acute cerebral ischemia.
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PMID:TWEAK-Fn14 pathway inhibition protects the integrity of the neurovascular unit during cerebral ischemia. 1683 30

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

Local environmental conditions contribute to the activation state of cells. Extracellular matrix glycoproteins participate in cell-cell boundaries within the microvascular and extravascular tissues of the central nervous system and provide a scaffold for the local environment. These conditions are altered during focal cerebral ischemia (and other central nervous system disorders) when extracellular matrix boundaries are degraded or when matrix proteins in the vascular circulation enter the neuropil as the microvascular permeability barrier is degraded. Microglia in the resting state become activated after the onset of ischemia. During activation these cells can express a number of factors and proteases, including latent matrix metalloproteinase-9 (pro-MMP-9). Whereas MMP-9 and MMP-2 are generated early during focal ischemia in select models, their cellular sources in vivo are still under study. In vitro microglia cells activate and respond to exposure to specific matrix proteins (eg, vitronectin, fibronectin) that circulate. Certain MMP inhibitors, specifically tetracycline derivatives, can modulate microglial activation and reduce injury volume in limited studies. But, the injury reduction relies on preinjury exposure to the tetracycline. Other studies underway suggest the hypothesis that microglial cell activation and pro-MMP-9 generation during focal cerebral ischemia is promoted in part by matrix proteins in the circulation that extravasate into the neuropil when the blood-brain barrier is compromised. These matrix proteins are known to activate microglia through their specific cell surface matrix receptors.
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PMID:Microglial activation and matrix protease generation during focal cerebral ischemia. 1726 8

This paper studied the effects of crocin, a pharmacologically active component of Crocus sativus L., on ischemia/reperfusion (I/R) injury in mice cerebral microvessels. Transient global cerebral ischemia (20 min), followed by 24 h of reperfusion, significantly promoted the generation of nitric oxide (NO) and malondialdehyde (MDA) in cortical microvascular homogenates, as well as markedly reduced the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) and promoted the activity of nitric oxide synthase (NOs). Reperfusion for 24 h led to serous edema with substantial microvilli loss, vacuolation, membrane damage and mitochondrial injuries in cortical microvascular endothelial cells (CMEC). Furthermore, enhanced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and decreased expression of matrix metalloproteinase-9 (MMP-9) were detected in cortical microvessels after I (20 min)/R (24 h). Reperfusion for 24 h also induced membrane (functional) G protein-coupled receptor kinase 2 (GRK2) expression, while it reduced cytosol GRK2 expression. Pretreatment with crocin markedly inhibited oxidizing reactions and modulated the ultrastructure of CMEC in mice with 20 min of bilateral common carotid artery occlusion (BCCAO) followed by 24 h of reperfusion in vivo. Furthermore, crocin inhibited GRK2 translocation from the cytosol to the membrane and reduced ERK1/2 phosphorylation and MMP-9 expression in cortical microvessels. We propose that crocin protects the brain against excessive oxidative stress and constitutes a potential therapeutic candidate in transient global cerebral ischemia.
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PMID:Effects of crocin on reperfusion-induced oxidative/nitrative injury to cerebral microvessels after global cerebral ischemia. 1727 61

Inhibition of matrix metalloproteinase-9 (MMP-9) protects the adult brain after cerebral ischemia. However, the role of MMP-9 in the immature brain after hypoxia-ischemia (HI) is unknown. We exposed MMP-9(-/-) [MMP-9 knock-out (KO)] and wild-type (WT) mice to HI on postnatal day 9. HI was induced by unilateral ligation of the left carotid artery followed by hypoxia (10% O2; 36 degrees C). Gelatin zymography showed that MMP-9 activity was transiently increased at 24 h after HI in the ipsilateral hemisphere and MMP-9-positive cells were colocalized with activated microglia. Seven days after 50 min of HI, cerebral tissue volume loss was reduced in MMP-9 KO (21.8 +/- 1.7 mm3; n = 22) compared with WT (32.3 +/- 2.1 mm3; n = 22; p < 0.001) pups, and loss of white-matter components was reduced in MMP-9 KO compared with WT pups (neurofilament: WT, 50.9 +/- 5.4%; KO, 18.4 +/- 3.1%; p < 0.0001; myelin basic protein: WT, 57.5 +/- 5.8%; KO, 23.2 +/- 3.5%; p = 0.0001). The neuropathological changes were associated with a delayed and diminished leakage of the blood-brain barrier (BBB) and a decrease in inflammation in MMP-9-deficient animals. In contrast, the neuroprotective effects after HI in MMP-9-deficient animals were not linked to either caspase-dependent (caspase-3 and cytochrome c) or caspase-independent (apoptosis-inducing factor) processes. This study demonstrates that excessive activation of MMP-9 is deleterious to the immature brain, which is associated with the degree of BBB leakage and inflammation. In contrast, apoptosis does not appear to be a major contributing factor.
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PMID:Matrix metalloproteinase-9 gene knock-out protects the immature brain after cerebral hypoxia-ischemia. 1730 Nov 59

Despite advances in imaging, understanding the underlying pathways, and clinical translation of animal models of disease there remains an urgent need for therapies that reduce brain damage after stroke and promote functional recovery in patients. Blocking oxidant radicals, reducing matrix metalloproteinase-induced neuronal damage, and use of stem cell therapy have been proposed and tested individually in prior studies. Here we provide a comprehensive integrative management approach to reducing damage and promoting recovery by combining biological therapies targeting these areas. In a rat model of transient cerebral ischemia (middle cerebral artery occlusion) gene delivery vectors were used to overexpress tissue inhibitor of matrix metalloproteinase 1 and 2 (TIMP1 and TIMP2) 3 days before ischemia. After occlusion, autologous bone marrow cells alone or in combination with agents to improve NO bioavailability were administered intraarterially. When infarct size, BrdU incorporation, and motor function recovery were determined in the treatment groups the largest beneficial effect was seen in rats receiving the triple combined therapy, surpassing effects of single or double therapies. Our study highlights the utility of combined drug, gene, and cell therapy in the treatment of stroke.
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PMID:Brain protection using autologous bone marrow cell, metalloproteinase inhibitors, and metabolic treatment in cerebral ischemia. 1736 Jun 88

The c-Jun N-terminal kinase (JNK) is induced by cerebral ischemia and injurious blood components acutely after subarachnoid hemorrhage (SAH). We hypothesized that inhibition of JNK will prevent damage to the neurovascular unit in the early brain injury period after SAH. Ninety-nine male SD rats (300-350 g) were randomly assigned to sham, SAH, and SAH treated with JNK inhibitor groups. SAH was induced by endovascular perforation. The JNK inhibitor SP600125 was administered intraperitoneally at 1 hr before and 6 hr after SAH. At 24 hr after SAH, we observed increased phosphorylation of JNK and c-Jun. Signs of neurovascular damage were observed in the hemorrhagic brains; these included the increases of aquaporin (AQP)-1 expression and brain water content as well as enhanced matrix metalloproteinase (MMP)-9 activity, vascular collagen IV loss, increased VEGF tissue level, and Evans blue extravasation. The appearances of cleaved caspase-3 expression, TUNEL-positive cells, and apoptotic morphology in cerebral tissues were associated with neurological deficit after SAH. JNK inhibition prevented c-Jun phosphorylation and suppressed AQP1, MMP-9, VEGF, and caspase-3 activation, with concomitant diminution of neuronal injury, blood-brain barrier preservation, reduced brain swelling, and improved neurological deficit in rats after SAH. This study demonstrates a multitude of beneficial effects of JNK inhibition, including protection of the neurovascular unit in early brain injury after SAH.
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PMID:Role of c-Jun N-terminal kinase in early brain injury after subarachnoid hemorrhage. 1741 Jun

We investigated whether an angiotensin-converting enzyme (ACE) inhibitor could inhibit matrix metalloproteinase (MMP) activities in cerebral infarct lesions after middle cerebral artery occlusion (MCAO) in rats. After placebo or trandolapril (5 mg/kg per day) was administered orally for 7 days, we permanently occluded the right middle cerebral artery. ACE activity in extracts from the infarct side of placebo-treated rats was significantly higher than that in extracts from the non-infarct side from 5 days after MCAO, though they did not differ at 1 day. ACE activities in extracts from both hemispheric segments in the trandolapril-treated group were significantly decreased compared with those in the placebo-treated group before MCAO, and this significant reduction persisted even at 7 days after MCAO. In the placebo-treated group, MMP-9 and MMP-2 activities in the infarct side were significantly increased at 12 h and at 1 day after MCAO, respectively. Trandolapril treatment significantly reduced MMP-9 and MMP-2 activities to 68.5% and 53.2%, respectively. Seven days after MCAO, the ratios of infarct areas to the hemispheric sectional areas in placebo- and trandolapril-treated rats were 55.4+/-2.1% and 30.9+/-2.9%, respectively, and this difference was significant. Neurological severity scores were significantly improved from 1 to 7 days after MCAO in trandolapril-treated rats. Cumulative survival in trandolapril-treated rats was significantly increased compared with that in placebo-treated rats. Thus, the inhibition of MMP-9 by trandolapril might be part of the mechanism that prevents cerebral damage after cerebral ischemia.
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PMID:Inhibition of matrix metalloproteinase-9 activity by trandolapril after middle cerebral artery occlusion in rats. 1758 59


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