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Biomedical subjects

M Chopp

Publications and source records attributed to M Chopp.

At least 109 records · Page 6Linked to original sources
PubMed1996

ARL 17477, a potent and selective neuronal NOS inhibitor decreases infarct volume after transient middle cerebral artery occlusion in rats.

We tested the effects of administration of a selective neuronal nitric oxide synthase (nNOS) inhibitor, ARL 17477, on ischemic cell damage and regional cerebral blood flow (rCBF), in rats subjected to transient (2 h) middle cerebral artery (MCA) occlusion and 166 h of reperfusion (n = 48) and in rats without MCA occlusion (n = 25), respectively. Animals were administered ARL 17477 (i.v.): 10 mg/kg; 1 mg/kg; 3mg/kg; N-nitro-L-arginine (L-NA) 10 mg/kg L-NA 1 mg/kg; and Vehicle. Administration of ARL 17477 1 mg/kg, 3 mg/kg and 10 mg/kg reduced ischemic infarct volume by 53 (p < 0.05), 23, and 6.5%, respectively. L-NA 1 mg/kg and 10 mg/kg increased infarct volume by 2 and 15%, respectively (p > 0.05). Administration of ARL 17477 (10 mg/kg) significantly (p < 0.05) decreased rCBF by 27 +/- 5.3 and 24 +/- 14.08% and cortical NOS activity by 86 +/- 14.9 and 91 +/- 8.9% at 10 min or 3 h, respectively, and did not alter mean arterial blood pressure (MABP). L-NA (10 mg/kg) significantly reduced rCBF by 23 +/- 9.8% and NOS activity by 81 +/- 7% and significantly (p < 0.05) increased MABP. Treatment with 3 mg/kg and 1 mg/kg ARL 17477 reduced rCBF by only 2.4 +/- 4.5 and 0%, respectively, even when NOS activity was reduced by 63 +/- 13.4 and 45 +/- 15.7% at 3 h, respectively, (p < 0.05). The data demonstrate that ARL 17477 inhibits nNOS in the rat brain and causes a dose-dependent reduction in infarct volume after transient MCA occlusion.

Amidines↗
PubMed1996

E-selectin in focal cerebral ischemia and reperfusion in the rat.

The selectin family of glycoproteins facilitates the early phase of polymorphonuclear leukocyte adhesion to the endothelial cell and, thus, may promote ischemic cell damage. To evaluate E-selectin in the pathogenesis of focal cerebral ischemia and reperfusion injury, we cloned rat E-selectin cDNA and measured the temporal profiles E-selectin mRNA (Northern blot) and protein (immunohistochemistry) during (1 h of ischemia) and after (up to 1 week) transient (2 h) middle cerebral artery (MCA) occlusion in the male Wistar rat. We also tested the effect on these rats of administration of CY-1503, an analog of sialyl Lewis(x) (SLe(x)), on ischemia cell damage. mRNA for E-selectin was first detected in the ischemic hemisphere at 2 h of reperfusion and persisted to 46 h of reperfusion. E-selectin (protein) was localized to microvessels within the ischemic lesion at 0 h of reperfusion and persisted to 70 h of reperfusion. Treatment of the ischemic animals with CY-1503 (50 mg/kg) (n = 8) significantly reduced infarct volume by 42% (p < 0.05) and significantly reduced myeloperoxidase immunoreactive cells in the ischemic lesion by 60% (p < 0.05). These findings provide the first direct evidence for the involvement of E-selectin in transient MCA occlusion in rats and suggest that the E-selectin may facilitate neutrophil adhesion and subsequent cerebral ischemic cell damage.

Amino Acid Sequence↗
PubMed1996

Damage threshold of normal rat brain in photodynamic therapy.

Normal brain tissue response to photodynamic therapy (PDT) must be quantified in order to implement PDT as a treatment of brain neoplasm. We therefore calculated the threshold for PDT-induced tissue necrosis in normal brain using Photofrin (porfimer sodium, Quadralogic Technologies Inc., Vancouver, BC) as the photosensitizer. The absolute light fluence-rate distribution for superficial irradiation and effective attenuation depth were measured in vivo using an invasive optical probe. Photosensitizer uptake in cerebral cortex was measured with chemical extraction and fluorometric analysis. Photodynamic therapy-induced lesion depths at various drug dose levels were measured as a biological end point. The PDT threshold for normal brain necrosis was calculated as in the magnitude of 10(16) photons/cm3. Thus normal rat brain is extremely vulnerable to PDT damage. This suggests that extra precautions must be exercised when PDT is used in brain.

Animals↗
PubMed1996

Photodynamic therapy of human glioma (U87) in the nude rat.

We measured the response of normal brain and the human U87 glioma implanted in the brain of rats (n = 65) to photodynamic therapy (PDT) using Photofrin as the sensitizer. Normal brain and U87 tumor implanted within brain of athymic (nude) rats were subjected to PDT (12.5 mg/kg of Photofrin) at increasing optical energy doses (35 J/cm2, 140 J/cm2, 280 J/cm2) of 632 nm light. Photofrin concentration in tumor, brain adjacent to tumor and normal brain were measured in a separate population of rats. Twenty-four hours after PDT, the brains were removed, sectioned, stained with hematoxylin and eosin (H&E), and the volumes of the PDT-induced lesion measured. Photofrin concentration in tumor greatly exceeded that of normal brain and brain adjacent to tumor (> 20x). Both normal brain and U87 tumor exhibited superficial tissue damage with PDT at 35 J/cm2. However, both normal and tumor-implanted brain exhibited tissue damage with increasing optical dose. A heterogeneous pattern of pannecrosis along with a uniform volume of pannecrosis was detected in the tumor. In contrast, normal brain exhibited a uniform sharply demarcated volume of necrosis. Our data indicate that the U87 human brain tumor model and the normal brain in the athymic rat are sensitive to PDT and Photofrin with an optical dose-dependent response to treatment.

Animals↗
PubMed1996

DNA damage and repair in central nervous system injury: National Institute of Neurological Disorders and Stroke Workshop Summary.

BACKGROUND AND PURPOSE: DNA damage and repair are areas of research with important implications for stroke and cerebral trauma. DNA damage is present in central nervous system (CNS) injury, and defects in repair mechanisms are associated with neurodegenerative disease. METHODS: A workshop, DNA Damage and Repair in CNS Injury, was organized by the National Institute of Neurological Disorders and Stroke in Bethesda, Md, on September 11, 1995. The objective of this workshop was to promote inquiry and to foster application of research in DNA damage and repair after stroke and trauma. RESULTS: The participants discussed the connection between the fields of DNA damage and repair and stroke and trauma and identified gaps in knowledge to be filled to expand research of DNA damage and repair in CNS injury. Specific recommendations were made targeting research opportunities in the areas of DNA repair and damage in stroke and trauma. CONCLUSIONS: Research in the science of DNA injury and repair will likely provide new and important information on mechanisms of cell damage and provide opportunities for the development of novel and effective therapies to reduce CNS injury in stroke and trauma.

Animals↗
PubMed1996

Synthetic peptide derived from the Bordetella pertussis bacterium reduces infarct volume after transient middle cerebral artery occlusion in the rat.

We explored the therapeutic potential of a peptide (F20) derived from the filamentous hemagglutinin of Bordetella pertussis in a model of ischemic cell injury after transient (2 hours) middle cerebral artery (MCA) occlusion in the rat. Animals were divided into two groups-(1) F20 peptide group: rats (n = 11) were subjected to 2 hours of transient MCA occlusion, and F20 peptide was administered intravenously (50 nmol) at 0 hours of reperfusion and intraperitoneally (150 nmol/dose) at 2, 4, 6, 8, 22, and 30 hours of reperfusion; (2) control group: rats (n = 10) were administered peptide F23 (a scrambled version of peptide F20) with the same experimental protocol as the F20 peptide group. Forty-six hours after reperfusion, animals were sacrificed, and brain tissue was stained with triphenyltetrazolium chloride for evaluation of tissue damage. To measure neutrophil numbers in ischemic tissue, myeloperoxidase (MPO) immunostaining was performed on a coronal cerebral section in each animal. There was a significant reduction of ischemic infarct volume (36%, p < 0.05) in the F20 group of animals compared with the F23 group. The area of the ischemic lesion was highly correlated with the numbers of the immunoreactive MPO cells (r = 0.78, p < 0.001). The data demonstrate that the F20 peptide significantly reduces infarct volume and intraparenchymal neutrophil numbers after transient MCA occlusion.

Adhesins, Bacterial↗
PubMed1996

Delayed intravenous administration of basic fibroblast growth factor (bFGF) reduces infarct volume in a model of focal cerebral ischemia/reperfusion in the rat.

Basic fibroblast growth factor (bFGF) is a potent neurotrophic and vasoactive peptide. Previous studies have shown that intraventricularly-administered bFGF reduces the size of cerebral infarcts following focal ischemia. In the current study, we tested the effects of intravenously-administered bFGF in a model of focal ischemia/reperfusion. The right middle cerebral artery of mature male Wistar rats was occluded by intraluminal suture. After 2 h of occlusion, the suture was removed and intravenous infusion of bFGF in vehicle (45 micrograms/kg/h) or vehicle alone was begun, lasting 3 h. Animals were weighed and evaluated neurologically until sacrifice 7 days after ischemia. The volume of cerebral infarcts was then determined by H and E staining and image analysis. We found a 40% reduction in infarct volume in bFGF- vs. vehicle-treated rats (n = 11 vs. 11, P < 0.05). Reduction in infarct volume was associated with improved neurological outcome and regained body weight in bFGF-treated animals (both P < 0.05). No change in blood pressure was found during bFGF treatment. These results show that the delayed intravenous administration of bFGF reduces infarct size in this model of focal ischemia/reperfusion. The mechanisms of infarct reduction may include direct cytoprotective and/or vasoactive effects.

Animals↗
PubMed1996

Sensitivity of 9L gliosarcomas to photodynamic therapy.

Photodynamic therapy (PDT) has been used clinically for the treatment of malignant brain gliomas. However, the efficacy of this treatment to date has remained equivocal. This study focused on determining the sensitivity of 9L glio sarcoma in Fischer 344 rats to PDT with increasing doses of 632 nm light and making a comparison of the responses of normal and tumor tissue in the brain at these doses. This sensitivity was then correlated with the concentrations of Photoforin present in these tissues at the time of treatment. Our study indicates that the level of Photofrin in the tumor was 13 times that present in normal brain 48 h after injection. However, this selective localization of the photosensitizer was not reflected in a selective tissue response to PDT. There was minimal tumor response to a dose of 35 J cm-2, which has been reported previously to cause necrosis to the normal brain. Increasing energy dose levels resulted in an increased tumor response to PDT; however, normal tissue remained more sensitive than tumor tissue at all energy dose levels examined. These data indicate that, although Photofrin is retained to a significantly higher degree in the tumor than in the normal brain tissue, the normal brain is more sensitive than the tumor to PDT under the conditions outlined in this study.

Animals↗
PubMed1995

Postischemic treatment (2-4 h) with anti-CD11b and anti-CD18 monoclonal antibodies are neuroprotective after transient (2 h) focal cerebral ischemia in the rat.

We investigated the effects of F(ab')2 fragments of anti-CD11b and anti-CD18 monoclonal antibodies on ischemic cell damage in the rat when administered upon reperfusion and at 2 h of reperfusion after transient (2 h) middle cerebral artery (MCA) occlusion. 2 h of MCA occlusion was induced by intraluminal insertion of a monofilament. The following groups of animals were investigated. Anti-CD11b groups (n = 15): an intact anti-CD11b antibody (1B6c) and an anti-CD11b F(ab')2 fragment of 1B6c were infused upon reperfusion (4 mg/kg i.v.). Anti-CD18 group (n = 8): an anti-CD18 F(ab')2 fragment of CL26 was infused upon reperfusion (2 mg/kg i.v.), and at 22 h of reperfusion (1 mg/kg i.v.). Anti-CD11b delayed group (n = 9): an anti-CD11b F(ab')2 fragment of 1B6c was infused at 2 h of reperfusion (4 mg/kg i.v.), and at 22 h after reperfusion (2 mg/kg i.v.). Control groups (n = 18): an isotype-matched control antibody (mouse IgG1) was administered: (a) upon reperfusion (n = 13), and (b) at 2 h and 22 h of reperfusion (n = 5). Rats were sacrificed at 7 days of reperfusion. In a separate population of rats subjected to 2 h of MCA occlusion (n = 9), brain myeloperoxidase (MPO) activity was measured at 46 h of reperfusion. The vehicle groups had infarct volumes of 35.21 +/- 2.82% to 41.39 +/- 2.73% of the contralateral hemisphere, respectively. Infarct volume was significantly reduced after treatment with: the intact anti-CD11b antibody upon reperfusion (19.0 +/- 6.6%) (P < 0.05), the fragments of mAbs of anti-CD11b administered upon reperfusion (19.7 +/- 2.7%) (P < 0.05), and at 2 h of reperfusion (22.2 +/- 4.8%) (P < 0.05), and anti-CD18 administered upon reperfusion (20.4 +/- 4.8%) (P < 0.05). Anti-CD11b treatment significantly (P < 0.05) inhibited the increase of MPO activity in the ischemic hemisphere. Our data demonstrate that anti-CD11b and anti-CD18 mAb fragments significantly reduce infarct volume and inhibit the increase of MPO activity in the ischemic lesion; administration of anti-CD11b mAb fragment even at 2 h of reperfusion significantly reduces infarct volume. These data support importance of the beta 2 integrin CD11b/CD18 in ischemia/reperfusion injury and indicate that the therapeutic window for intervention to reduce ischemic cell damage in this model is at least 4 h from the onset of MCA occlusion.

Animals↗
PubMed1995

The temporal profiles of ICAM-1 protein and mRNA expression after transient MCA occlusion in the rat.

Leukocytes may contribute to ischemic cell damage. ICAM-1 expression on endothelial cells facilitates the migration of leukocytes into tissue. Therefore, we measured the temporal profiles of ICAM-1 mRNA and protein in rat brain after transient (1 or 2 h) of middle cerebral artery (MCA) occlusion. Male Wistar rats (n = 86) were subjected to 1 or 2 h MCA of occlusion, or 2 h of MCA occlusion followed by reperfusion for a variety of durations ranging from 1 h to 1 week. 10 additional control animals were employed. ICAM-1 mRNA and protein were measured during ischemia and reperfusion, and immunohistochemical methods were used to identify specific cell types expressing ICAM-1. ICAM-1 mRNA was detected 1 h after the onset of ischemia. mRNA maximized at 10 h of reperfusion and persisted out to 1 week of reperfusion. ICAM-1 significantly increased in microvascular endothelial cells at 2 h of reperfusion, maximized at 46 h and persisted out to 1 week of reperfusion (P < 0.05). ICAM-1 mRNA and protein are present in ischemic brain early after the onset of ischemia and reperfusion, respectively. These data provide support for the role of ICAM-1 in mediating leukocyte-endothelial adhesion after transient MCA occlusion in the rat.

Animals↗
PubMed1995

Neutrophil inhibitory factor is neuroprotective after focal ischemia in rats.

We tested the neuroprotective potential of neutrophil inhibitory factor (rNIF), a novel 41-kd recombinant glycoprotein derived from a hookworm, in a model of focal cerebral ischemia in the rat. Male Wistar rats were assigned to treatment with rNIF and vehicle. Middle cerebral artery occlusion (MCAO) for 2 hours was induced by insertion of an intraluminal suture. Infusion of the drug was initiated at the onset of reperfusion. Infarct volume was determined 48 hours after reperfusion. Neutrophils were measured within the ischemic tissue by myeloperoxidase (MPO) staining. Treatment with rNIF resulted in a 48% reduction in cerebral infarction compared with control animals (p < 0.01). Neutrophil accumulation in the ischemic brains of rNIF-treated rats was reduced significantly (p < 0.01) compared with control animals. The number of neutrophils within the infarcted tissue correlated positively with the size of the area of infarction (p < 0.001, r = 0.6) within representative cerebral coronal sections. We demonstrated a significant neuroprotective effect of rNIF with continuous treatment for 48 hours following 2 hours of MCAO. The neuroprotective effect was correlated with a reduced number of neutrophils within the ischemic tissue. These results demonstrate potential therapeutic properties of rNIF in the management of stroke.

Animals↗
PubMed1995

Adhesive glycoproteins CD11a and CD18 are upregulated in the leukocytes from patients with ischemic stroke and transient ischemic attacks.

Leukocytes may have an important role in the pathogenesis of brain injury after ischemia. Expression of adhesion molecules on leukocytes and/or endothelia is needed for leukocytes to adhere to endothelia and infiltrate into the injured brain. The purpose of the present pilot study is to delineate whether the expression of leukocyte adhesion molecules, CD11a and CD18, are upregulated in patients with ischemic stroke and transient ischemic attack. Ten patients with ischemic stroke, 6 with transient ischemic attack (TIA), and 11 age and risk factor matched controls were studied. Using immunofluorescence phenotyping and flow cytometry, leukocyte membrane expression of CD11a and CD18 were measured within 72 h after onset of ischemia. Follow-up measurements were performed at 5-7 days after ictus in 6 patients with stroke, and at 3-5 days after ictus in 3 patients with TIA. CD11a immunofluorescence (IF) was significantly increased within 72 h after onset of symptoms in patients with stroke as well as TIA compared with the control group (p < 0.017). IF of CD18 also increased in both patient groups, but significance was reached only in the TIA group (p < 0.05). No difference of CD11a and CD18 IF was detected between stroke and TIA groups. Follow-up measurement of CD11a and CD18 showed a trend of decrease, but CD11a IF remained significantly elevated compared with the control group (p < 0.017). Expression of leukocyte adhesion molecules CD11a, and CD18 are upregulated in patients with ischemic stroke and TIA. Although these data are preliminary, our data suggest that these molecules are associated with cerebrovascular disorders including ischemic stroke and TIA.

Aged↗
PubMed1995

Nitric oxide changes in the rat brain after transient middle cerebral artery occlusion.

Using a porphyritic microsensor, we measured the cortical NO concentration within ischemic tissue during 2 h of middle cerebral artery (MCA) occlusion and 1 h of reperfusion in the rat (n = 36). Local cerebral blood flow was simultaneously measured by laser Doppler flowmetry to verify MCA occlusion and reperfusion. Baseline concentration of NO was < 10(-8) M. The maximum concentrations of NO during MCA occlusion and reperfusion were, respectively, 1.47 +/- 0.45 microM and 0.54 +/- 0.24 microM. Administration of N-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase, prior to ischemia, significantly (p < 0.05) reduced NO release to 0.04 +/- 0.02 microM during MCA occlusion and completely inhibited NO release during 1 h of reperfusion. Administration of L-arginine 30 min after administration of L-NAME restored NO release (3.45 +/- 1.14 microM) during MCA occlusion; however, administration of L-arginine did not overcome the effect of L-NAME on mean arterial blood pressure. Our data indicate that NO is released in the brain after the onset of ischemia and NO levels can be modulated by administration of NO substrate and NO antagonists.

Amino Acid Oxidoreductases↗
PubMed1995

High dose methylprednisolone therapy reduces expression of JE/MCP-1 mRNA and macrophage accumulation in the ischemic rat brain.

The effects of glucocorticoid (GC) on ischemic brain remain to be investigated. Since GC modulates immunological system, it also may inhibit macrophage accumulation in the ischemic brain. The GC effect, if any, on macrophages in ischemic brain, may be mediated through modulation of JE/MCP-1 gene, a strong monocyte attractant, which is expressed in the rat brain after ischemia. The purpose of the present study is to elucidate the effect of high dose methylprednisolone (MP) treatment on (1) macrophage infiltration, (2) histopathology of the ischemic lesion, and (3) expression of JE/MCP-1 mRNA, in a focal cerebral ischemia model of the rat. Thirty Wistar rats were used in this study. Focal cerebral ischemia was induced by advancing a nylon monofilament into the internal carotid artery until the origin of the middle cerebral artery (MCA) was occluded. For JE/MCP-1 mRNA study, animals (n = 9) were randomly injected with MP 75 mg/kg (x 3) (n = 3), 100 mg/kg (x 3) (n = 3), or same volume of saline (n = 3) and killed 24 h after onset of MCA occlusion. Three animals were used as a normal control, and a section of the liver from one rat was used as an internal control for JE/MCP-1 mRNA. Northern blot analysis was performed using murine JE c-DNA. For the histopathological study, animals (n = 17) were randomly divided into a MP group (MP 100 mg/kg x 3, n = 9) and a control group (saline treated, n = 8), and killed 72 h after onset of MCA occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Expression of glial fibrillary acidic protein in areas of focal cerebral ischemia accompanies neuronal expression of 72-kDa heat shock protein.

We examined the astrocytic GFAP and neuronal HSP-72 responses to transient middle cerebral artery (MCA) occlusion in the rat. Three groups of rats (n = 79) were studied: (1) fixed duration of MCA occlusion (120 min) and variable durations of reperfusion (0.5, 3, 6, 9, 12, 24, 48, 96 and 168 h); (2) variable durations of MCA occlusion (10, 20, 30, 60, 90, and 120 min) and a fixed duration of reperfusion (48 h); and (3) controls: sham operated rats and normal rats. Coronal sections from each brain were reacted with appropriate antibodies to GFAP and HSP-72 and stained with H&E for evaluation of cellular response to ischemia. Our data show that after MCA occlusion: (1) GFAP expression was found in the boundary zone to the infarct or in areas of selective incomplete ischemic necrosis; (2) GFAP expression was localized to the same areas where neurons express HSP-72 and are destined to survive the ischemic insult; and (3) HSP-72 expression was not found in astrocytes in any of the experimental groups. These studies suggest that after transient focal ischemia in the rat: areas where both GFAP and HSP-72 expression are lost are destined to become necrotic, even though cells may appear morphologically intact in the H&E preparations, and expression of GFAP and HSP-72 reflects astrocytic and neuronal viability, respectively.

Animals↗
PubMed1995

Effects of moderate hyperglycemia on the temporal profile of brain tissue intracellular pH and [Mg2+] after global cerebral ischemia in rats.

In an attempt to understand the mechanisms by which preischemic plasma glucose (pg) worsens neurologic and neuropathologic outcomes, we investigated the effect of moderate preischemic hyperglycemia (200 mg/dl < mean plasma glucose < 360 mg/dl) on postischemic energy metabolism, tissue intracellular pH (pHi) and tissue free intracellular pMg (= -log[Mg2+]) over a one week period after transient global cerebral ischemia in the rat. In vivo 31P nuclear magnetic resonance spectroscopy was performed prior to and daily up to 1 week (wk) in rats after 12 min of forebrain ischemia, induced by bicarotid occlusion concurrent with systemic hypotension. Preischemic plasma glucose significantly affected 1 wk postischemic survival (p = 0.05, Fisher's exact test). The temporal profile of the brain tissue pHi was significantly different (p < 0.03) between the moderate hyperglycemic (H-1wk, n = 7, mean pg = 266.0 +/- 47.3 mg/dl) and the normoglycemic (N-1wk, n = 8, mean pg = 91.2 +/- 23.7 mg/dl) ischemic animals over 1 wk. Postischemic tissue alkalosis was measured at 24 (p = < 0.006) and 48h (p = 0.001) postischemia in the N-1wk group. A single marginally significant (p = 0.011) mean pHi upshift was measured at 72h postischemia in the H-1wk group. The mean change in pHi at 24h postischemia from the baseline values in moderate hyperglycemic animals that survived only 48h after ischemia (H-48h, n = 6, mean pg = 298.8 +/- 70.1 mg/dl) was significantly lower (p = 0.02) than that of the N-1wk ischemic animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkalosis↗