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Biomedical subjects

Eng H Lo

Publications and source records attributed to Eng H Lo.

At least 19 recordsLinked to original sources
PubMed2006

Baicalein and 12/15-lipoxygenase in the ischemic brain.

BACKGROUND AND PURPOSE: The natural product baicalein is a specific inhibitor of 12/15-lipoxygenase, but it also has antioxidant properties. The current study was designed to test if the neuroprotective properties of baicalein are related to its lipoxygenase inhibition. METHODS: The presence of 12/15-lipoxygenase in the ischemic mouse brain was demonstrated by immunohistochemistry. A mouse model of transient middle cerebral artery occlusion was used to study lipoxygenase-dependent protection of the ischemic brain by baicalein. Rat primary neurons were subjected to oxidative stress in the presence or absence of baicalein. RESULTS: In a mouse model of transient middle cerebral artery occlusion, 12/15-lipoxygenase is increased in the peri-infarct area surrounding the primary infarction, predominantly in neurons. Oxidative toxicity in primary rat neurons is reduced by baicalein. C57Bl6J mice are protected against transient focal ischemia by intraperitoneal injection of baicalein, and a similar degree of protection is seen in 12/15-lipoxygenase knockout mice compared with wild-type mice. In contrast, the 12/15-LOX knockout mice are not further protected by baicalein. CONCLUSIONS: Baicalein protects against ischemia/reperfusion injury by inhibiting the 12/15-lipoxygenase pathway to neuronal cell death.

Animals↗
PubMed2006

Effects of apoE isoforms on beta-amyloid-induced matrix metalloproteinase-9 in rat astrocytes.

Matrix metalloproteinase-9 (MMP-9) may play a role in the inflammatory glial response during Alzheimer's disease (AD). Astrocytes can degrade beta-amyloid (Abeta) and extracellular proteolysis via MMP-9 may be involved. Because Apolipoprotein E (APOE) genotype is an important factor for AD, we ask whether various apoE isoforms can influence Abeta-induced MMP-9 responses in primary rat astrocytes. Our data show that apoE4 significantly dampens Abeta-induced MMP-9 levels, possibly by downregulating the Rho-Rho kinase (ROCK) pathway. Reduction of astrocytic MMP-9 by apoE4 may affect Abeta clearance and promote Abeta deposition in AD.

Alzheimer Disease↗
PubMed2006

Astrocytic induction of matrix metalloproteinase-9 and edema in brain hemorrhage.

We tested the hypothesis that astrocytic matrix metalloproteinase-9 (MMP-9) mediates hemorrhagic brain edema. In a clinical case of hemorrhagic stroke, MMP-9 co-localized with astrocytes and neurons in peri-hematoma areas. In a mouse model where blood was injected into striatum, MMP-9 was colocalized with astrocytes surrounding the hemorrhagic lesion. Because MMP-9 is present in blood as well as brain, we compared four groups of wild type (WT) and MMP-9 knockout (KO) mice: WT blood injected into WT brain, KO blood into KO brain, WT blood into KO brain, and KO blood into WT brain. Gel zymography showed that MMP-9 was elevated in WT hemorrhagic brain tissue but absent from KO hemorrhagic brain tissue. Edematous water content was elevated when WT blood was injected into WT brain. However, edema was ameliorated when MMP-9 was absent in either blood or brain or both. To further assess the mechanisms involved in astrocytic induction of MMP-9, we next examined primary mouse astrocyte cultures. Exposure to hemoglobin rapidly upregulated MMP-9 in conditioned media within 1 to 24 h. Hemoglobin-induced MMP-9 was reduced by the free radical scavenger U83836E. Taken together, these data suggest that although there are large amounts of MMP-9 in blood, hemoglobin-induced oxidative stress can trigger MMP-9 in astrocytes and these parenchymal sources of matrix degradation may also be an important factor in the pathogenesis of hemorrhagic brain edema.

Animals↗
PubMed2006

Reduction of tissue plasminogen activator-induced matrix metalloproteinase-9 by simvastatin in astrocytes.

BACKGROUND AND PURPOSE: Hemorrhagic conversion after tissue plasminogen activator (tPA) stroke therapy has been linked with elevations in matrix metalloproteinase-9 (MMP-9) at the neurovascular interface. Here, we test the idea that statins may directly ameliorate tPA-induced MMP-9 dysregulation. METHODS: Recombinant human tPA (5 microg/mL) was added to primary rat cortical astrocytes. Zymography was used to quantify MMP-9 levels in conditioned media. Effects of simvastatin or the Rho kinase inhibitor Y-27632 were assessed by pretreating cells before tPA exposure. RESULTS: Simvastatin (1 to 10 micromol/L) significantly reduced tPA-induced MMP-9 in cortical astrocytes. This effect may be mediated via the Rho kinase pathway because tPA-induced activation of Rho signaling was suppressed by simvastatin, and tPA-induced MMP-9 levels were similarly reduced by the Rho kinase inhibitor Y-27632 (1 to 10 micromol/L). CONCLUSIONS: Statins reduce tPA-induced MMP-9 dysregulation by inhibiting the Rho signaling pathway. Statins may ameliorate tPA-associated MMP imbalances in stroke.

Amides↗
PubMed2006

fMRI of delayed albumin treatment during stroke recovery in rats: implication for fast neuronal habituation in recovering brains.

Accumulating experimental and clinical data suggest that albumin may be neuroprotective for stroke. Here, we use functional magnetic resonance imaging (fMRI) to evaluate the therapeutic efficacy of albumin and its effects on the recovery of stimuli-induced cerebral hemodynamics. For this purpose, fMRI activity in the ipsilesional somatosensory (SS) cortex was assessed using a well established rat model of transient 90 min focal ischemia and electrical forelimb stimulation. Rats were treated with either saline or albumin via intracerebroventricular injections at 12 h post-stroke onset. Despite this delayed treatment time, when compared to the saline-treated rats (n=7), there were significant enhancements of the fMRI activation in the albumin-treated rats (n=6) for both blood oxygenation level dependence (BOLD) and functional cerebral blood volume (fCBV) responses. Interestingly, the temporal characteristics of the ipsilesional SS BOLD responses in the albumin-treated rats appeared considerably altered compared to those of contralesional responses while such temporal alterations were not pronounced for the fCBV responses. These characteristic fMRI temporal profiles of the albumin-treated brains may be due to altered neuronal responses rather than altered integrity of neurovascular coupling, which implies an unusually fast habituation of neuronal responses in the lesional SS cortex. The correlation between various MRI-derived structural parameters and the fMRI response magnitude was also characteristic for albumin and control groups. Taken together, these data suggest that restoration of fMRI response magnitudes, temporal profiles, and correlations with structure may reveal the extent and specific traits of albumin treatment associated stroke recovery.

Albumins↗
PubMed2006

Increased brain expression of matrix metalloproteinase-9 after ischemic and hemorrhagic human stroke.

BACKGROUND AND PURPOSE: Abnormal expression of some matrix metalloproteinases (MMP) has shown to play a deleterious role in brain injury in experimental models of cerebral ischemia. We aimed to investigate MMP-2 (gelatinase A) and MMP-9 (gelatinase B) in brain parenchyma in both ischemic and hemorrhagic strokes. METHODS: Postmortem fresh brain tissue from 6 ischemic and 8 hemorrhagic stroke patients was obtained within the first 6 hours after death. Finally, 78 brain tissue samples from different areas (infarct, peri-infarct, perihematoma and contralateral hemisphere) were studied. To quantify gelatinase content we performed gelatin zymograms that were confirmed by Western Blot Analysis, immunohistochemistry to localize MMP source, and in situ zymography to detect gelatinase activity. RESULTS: Among ischemic cases, gelatin zymography showed increased MMP-9 content in infarct core although peri-infarct tissue presented also higher levels than contralateral hemisphere (P<0.0001 and P=0.042, respectively). Within infarct core, MMP-9 was mainly located around blood vessels, associated to neutrophil infiltration and activated microglial cells. In peri-infarct areas the major source of MMP-9 were microglial cells. Tissue around intracranial hemorrhage also displayed higher MMP-9 levels than contralateral hemisphere (P=0.008) in close relationship with glial cells. MMP-2 was constitutively expressed and remained invariable in different brain areas. CONCLUSIONS: Our results demonstrate in situ higher levels of MMP-9 in human brain tissue after ischemic and hemorrhagic stroke, suggesting a contribution of MMP-9 to ischemic brain injury and perihematoma edema.

Aged↗
PubMed2006

Infarct prediction and treatment assessment with MRI-based algorithms in experimental stroke models.

There is increasing interest in using algorithms combining multiple magnetic resonance imaging (MRI) modalities to predict tissue infarction in acute human stroke. We developed and tested a voxel-based generalized linear model (GLM) algorithm to predict tissue infarction in an animal stroke model in order to directly compare predicted outcome with the tissue's histologic outcome, and to evaluate the potential for assessing therapeutic efficacy using these multiparametric algorithms. With acute MRI acquired after unilateral embolic stroke in rats (n=8), a GLM was developed and used to predict infarction on a voxel-wise basis for saline (n=6) and recombinant tissue plasminogen activator (rt-PA) treatment (n=7) arms of a trial of delayed thrombolytic therapy in rats. Pretreatment predicted outcome compared with post-treatment histology was highly accurate in saline-treated rats (0.92+/-0.05). Accuracy was significantly reduced (P=0.04) in rt-PA-treated animals (0.86+/-0.08), although no significant difference was detected when comparing histologic lesion volumes. Animals that reperfused had significantly lower (P<0.01) GLM-predicted infarction risk (0.73+/-0.03) than nonreperfused animals (0.81+/-0.05), possibly reflecting less severe initial ischemic injury and therefore tissue likely more amenable to therapy. Our results show that acute MRI-based algorithms can predict tissue infarction with high accuracy in animals not receiving thrombolytic therapy. Furthermore, alterations in disease progression due to treatment were more sensitively monitored with our voxel-based analysis techniques than with volumetric approaches. Our study shows that predictive algorithms are promising metrics for diagnosis, prognosis and therapeutic evaluation after acute stroke that can translate readily from preclinical to clinical settings.

Algorithms↗
PubMed2006

Involvement of matrix metalloproteinase in neuroblast cell migration from the subventricular zone after stroke.

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.

Animals↗
PubMed2006

Role of matrix metalloproteinases in delayed cortical responses after stroke.

Matrix metalloproteinases (MMPs) are zinc-endopeptidases with multifactorial actions in central nervous system (CNS) physiology and pathology. Accumulating data suggest that MMPs have a deleterious role in stroke. By degrading neurovascular matrix, MMPs promote injury of the blood-brain barrier, edema and hemorrhage. By disrupting cell-matrix signaling and homeostasis, MMPs trigger brain cell death. Hence, there is a movement toward the development of MMP inhibitors for acute stroke therapy. But MMPs may have a different role during delayed phases after stroke. Because MMPs modulate brain matrix, they may mediate beneficial plasticity and remodeling during stroke recovery. Here, we show that MMPs participate in delayed cortical responses after focal cerebral ischemia in rats. MMP-9 is upregulated in peri-infarct cortex at 7-14 days after stroke and is colocalized with markers of neurovascular remodeling. Treatment with MMP inhibitors at 7 days after stroke suppresses neurovascular remodeling, increases ischemic brain injury and impairs functional recovery at 14 days. MMP processing of bioavailable VEGF may be involved because inhibition of MMPs reduces endogenous VEGF signals, whereas additional treatment with exogenous VEGF prevents MMP inhibitor-induced worsening of infarction. These data suggest that, contrary to MMP inhibitor therapies for acute stroke, strategies that modulate MMPs may be needed for promoting stroke recovery.

Animals↗
PubMed2006

Neural stem cell transplant survival in brains of mice: assessing the effect of immunity and ischemia by using real-time bioluminescent imaging.

PURPOSE: To use bioluminescent imaging in a murine transplant model to monitor the in vivo responses of transplanted luciferase-gene-positive neural progenitor cells (NPCs) to host immunity and ischemia. MATERIALS AND METHODS: All animal studies were conducted according to institutional guidelines, with approval of the Subcommittee on Research Animal Care. Cranial windows were created in all animals, and all animals underwent NPC (C17.2-Luc-GFP-gal) transplantation into the right basal ganglia. An observational study was performed on C57 BL/6 (n = 5), nude (n = 4), and CD-1 (n = 4) mice, with bioluminescent imaging performed at days 7, 11, and 14 after transplantation. A study on the effects of ischemia was performed in a similar manner, but with the following differences: On day 9 after transplantation, the C57 BL/6 mice underwent 18 minutes of transient forebrain ischemia by means of temporary bilateral carotid occlusions (n = 6). A control group of C57 BL/6 mice underwent sham surgery (n = 6). Bioluminescent imaging was performed on the ischemic animals and control animals at days 7, 9, 11, and 14. Repeated-measures analysis of variance or Student t test was used to compare the means of the luciferase activities. RESULTS: In vivo cell tracking demonstrated that (a) C17.2-Luc-GFP-gal NPCs survived and proliferated better in the T-cell deficient nude mice than in the immunocompetent C57 BL/6 or CD-1 mice, in which progressive immune mediated cell loss was shown, and (b) transient forebrain ischemia appeared, unexpectedly, to act as a short-term stimulus to transplanted NPC growth and survival in immunocompetent mice. CONCLUSION: Immune status and host immunity can have an influence on NPC graft survival, and these changes can be noninvasively assessed with bioluminescent imaging in this experimental model.

Animals↗
PubMed2005

Granulocyte colony-stimulating factor enhances angiogenesis after focal cerebral ischemia.

Granulocyte colony-stimulating factor (G-CSF) is a neuroprotective agent and activates endothelial proliferation and bone marrow stem cell mobilization. We studied the effect of G-CSF on angiogenesis and neurological recovery after focal cerebral ischemia. After the induction of transient focal ischemia in rats, G-CSF (50 micro/day, i.p.) or PBS was administered for 3 days. We evaluated the functional recovery, infarct volume, inflammatory infiltration, blood-brain barrier (BBB) disruption, hemispheric atrophy, protein expressions of endothelial nitric oxide synthase (eNOS) and angiopoietins, and the therapeutic time window of G-CSF administration. We then analyzed endothelial cell proliferation, the vascular surface area, the number of branch points, and the vascular length. G-CSF treatment improved behavioral recovery and reduced the infarct volume, the inflammatory infiltration, the BBB disruption, and the hemispheric atrophy. G-CSF injection, starting at 2 h, 1 day, or 4 days after ischemia, resulted in a better functional recovery and a greater reduction in hemispheric atrophy than injection starting at day 7. The vascular surface area, the vascular branch points, the vascular length, the number of BrdU(+) endothelial cells, and eNOS/angiopoietin-2 expression were significantly increased in the G-CSF group compared with the ischemia-only group. G-CSF injection starting at 1 day induced larger endothelial proliferation compared with injection starting at 7 days. In this study, we provide evidences that G-CSF enhances the angiogenesis and reduces the ischemic damage, which promotes the long-term functional recovery.

Angiopoietin-1↗
PubMed2005

Tissue plasminogen activator promotes matrix metalloproteinase-9 upregulation after focal cerebral ischemia.

BACKGROUND AND PURPOSE: Thrombolytic therapy with tissue plasminogen activator (tPA) in ischemic stroke is limited by increased risks of cerebral hemorrhage and brain injury. In part, these phenomena may be related to neurovascular proteolysis mediated by matrix metalloproteinases (MMPs). Here, we used a combination of pharmacological and genetic approaches to show that tPA promotes MMP-9 levels in stroke in vivo. METHODS: In the first experiment, spontaneously hypertensive rats were subjected to 3 hours of transient focal cerebral ischemia. The effects of tPA (10 mg/kg IV) on ischemic brain MMP-9 levels were assessed by zymography. In the second experiment, wild-type (WT) and tPA knockout mice were subjected to 2 hours of transient focal cerebral ischemia, and MMP-9 levels and brain edema during reperfusion were assessed. Phenotype rescue was performed by administering tPA to the tPA knockout mice. RESULTS: In the first experiment, exogenous tPA did not change infarct size but amplified MMP-9 levels in ischemic rat brain at 24 hours. Coinfusion of the plasmin inhibitor tranexamic acid (300 mg/kg) did not ameliorate this effect, suggesting that it was independent of plasmin. In the second experiment, ischemic MMP-9 levels, infarct size, and brain edema in tPA knockouts were significantly lower than WT mice. Administration of exogenous tPA (10 mg/kg IV) did not alter infarction but reinstated the ischemic MMP-9 response back up to WT levels and correspondingly worsened edema. CONCLUSIONS: These data demonstrate that tPA upregulates brain MMP-9 levels in stroke in vivo, and suggest that combination therapies targeting MMPs may improve tPA therapy.

Animals↗
PubMed2005

Crossing the blood-brain barrier: a potential application of myristoylated polyarginine for in vivo neuroimaging.

As basic neurological research continues to reveal novel targets for therapy, the need to deliver therapeutic agents across the blood-brain barrier (BBB) becomes increasingly important. If developed, delivery modules would bring targeting molecules across the BBB to their respective active sites. In addition, it would be highly advantageous if the bioavailability of these delivered agents could be monitored over time using non-invasive imaging techniques. Here, we describe a versatile delivery module based on a myristoylated polyarginine backbone, which crosses the BBB. Incorporation of the fatty acid group was achieved using a Schotten-Bauman reaction with quantitative yield, and the peptide was further synthesized by conventional solid phase peptide synthesis (SPPS). We report for the first time the in vivo distribution of the delivery module over time into mouse brain using near-infrared (NIR) fluorescence imaging. The fluorescent cargo was detected in vivo from 24-48 h post IV injection and was further characterized in perfused brains. Immunohistochemical staining of excised brain showed that the delivery module primarily accumulated in neurons with occasional localization in astrocytes and endothelial cells. We conclude that this approach can be used for the delivery of imaging probes and potentially targeted therapeutics across the BBB.

Animals↗
PubMed2005

A pilot study of normobaric oxygen therapy in acute ischemic stroke.

BACKGROUND AND PURPOSE: Therapies that transiently prevent ischemic neuronal death can potentially extend therapeutic time windows for stroke thrombolysis. We conducted a pilot study to investigate the effects of high-flow oxygen in acute ischemic stroke. METHODS: We randomized patients with acute stroke (<12 hours) and perfusion-diffusion "mismatch" on magnetic resonance imaging (MRI) to high-flow oxygen therapy via facemask for 8 hours (n=9) or room air (controls, n=7). Stroke scale scores and MRI scans were obtained at baseline, 4 hours, 24 hours, 1 week, and 3 months. Clinical deficits and MR abnormalities were compared between groups. RESULTS: Stroke scale scores were similar at baseline, tended to improve at 4 hours (during therapy) and 1 week, and significantly improved at 24 hours in hyperoxia-treated patients. There was no significant difference at 3 months. Mean (+/-SD) relative diffusion MRI lesion volumes were significantly reduced in hyperoxia-treated patients at 4 hours (87.8+/-22% versus 149.1+/-41%; P=0.004) but not subsequent time points. The percentage of MRI voxels improving from baseline "ischemic" to 4-hour "non-ischemic" values tended to be higher in hyperoxia-treated patients. Cerebral blood volume and blood flow within ischemic regions improved with hyperoxia. These "during-therapy" benefits occurred without arterial recanalization. By 24 hours, MRI showed reperfusion and asymptomatic petechial hemorrhages in 50% of hyperoxia-treated patients versus 17% of controls (P=0.6). CONCLUSIONS: High-flow oxygen therapy is associated with a transient improvement of clinical deficits and MRI abnormalities in select patients with acute ischemic stroke. Further studies are warranted to investigate the safety and efficacy of hyperoxia as a stroke therapy.

Adult↗
PubMed2005

Normobaric hyperoxia extends the reperfusion window in focal cerebral ischemia.

A major limitation in thrombolysis for acute ischemic stroke is the restricted time window for safe and effective therapy. Any method that can extend the reperfusion time window would be important. In this study, we show that normobaric hyperoxia extends the time window for effective reperfusion from 1 to 3 hours in rats subjected to focal cerebral ischemia. Normobaric hyperoxia did not increase cellular markers of superoxide generation or brain levels of matrix metalloproteinase-9. Normobaric hyperoxia may be a clinically feasible adjunct method for significantly increasing the time window for effective thrombolytic therapy in acute ischemic stroke.

Animals↗
PubMed2005

Advances in stroke neuroprotection: hyperoxia and beyond.

Refinements in patient selection, improved methods of drug delivery, use of more clinically relevant animal stroke models, and the use of combination therapies that target the entire neurovascular unit make stroke neuroprotection an achievable goal. This article provides an overview of the major mechanisms of neuronal injury and the status of neuroprotective drug trials and reviews emerging strategies for treatment of acute ischemic stroke. Advances in the fields of stem cell transplantation, stroke recovery, molecular neuroimaging, genomics, and proteomics will provide new therapeutic avenues in the near future. These and other developments over the past decade raise expectations that successful stroke neuroprotection is imminent.

Brain↗