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Biomedical subjects

M Chopp

Publications and source records attributed to M Chopp.

At least 127 records · Page 7Linked to original sources
PubMed1995

Expression of monocyte chemoattractant protein-1 and macrophage inflammatory protein-1 after focal cerebral ischemia in the rat.

Chemoattractant cytokines, the chemokines, play an important role in early events of inflammation at the site of tissue damage. We examined the expression of mRNA and the protein products of two such chemokines; i.e. monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1 alpha (MIP-1 alpha) in the ischemic brain tissue following middle cerebral artery occlusion (MCAo). The mRNA transcripts of MCP-1 and MIP-1 alpha were detected by Northern hybridization and reverse transcriptase polymerase chain reaction (RT/PCR), respectively, and the anatomic distribution of specific proteins was analyzed by immunohistochemistry. We found that MCP-1 mRNA was not expressed in the brains of normal rats or rats sacrificed 2 h after MCAo. 6 h after the induction of cerebral ischemia, weak expression of both mRNAs was detected in the ischemic tissue. mRNAs were expressed up to 48 h, and were markedly attenuated at 96 h. In the rats subjected to MCA occlusion, MCP-1 immunoreactivity was diffusely expressed and localized to the ischemic area, and was most intense at 48 h after MCA occlusion. Endothelial cells and macrophage-like cells expressed MCP-1 protein in the ischemic brain. The distribution and morphology of MIP-1 alpha immunoreactive cells were identical with activated astrocytes. We conclude that MCP-1 and MIP-1 alpha mRNAs and proteins are induced after cerebral ischemia in the rat. They may have a role in promoting inflammatory and/or repair processes in the ischemic brain, possibly by attracting or modulating inflammatory cells in the ischemic area.

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PubMed1995

In situ detection of DNA fragmentation after focal cerebral ischemia in mice.

Brains from 5 mice subjected to focal ischemia (2 hours)--reperfusion (22 h), revealed a significant increase (P < 0.01) in cells exhibiting DNA fragmentation (100-200 per section)--ipsilateral hemisphere compared to 0-3 per section found in the contralateral hemisphere and normal (n = 5) and sham operated (n = 5) mice. Neurons were the predominant cells (90-95%) exhibiting DNA fragmentation, and were primarily located in the inner boundary zone to the infarct. Apoptosis may contribute to the development of infarct after transient focal cerebral ischemia.

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PubMed1995

Temporal profile of in situ DNA fragmentation after transient middle cerebral artery occlusion in the rat.

We measured the temporal profile and anatomic distribution of cells exhibiting DNA fragmentation at various durations of reperfusion after middle cerebral artery (MCA) occlusion in the rat. Focal cerebral ischemia was induced in male Wistar rats (n = 62) using an intraluminal monofilament blockade of the MCA. After 2 h of MCA occlusion, the animals were killed at different durations of reperfusion (0.5, 3, 6, 9, and 12 h and 1, 2, 4, 7, 14, 21, and 28 days, n = 4 per time point). Sham-operated rats (n = 4) and normal rats not subjected to any surgical procedure (n = 4) were used as controls. Coronal brain sections (5 microns) were analyzed, using an in situ ApopTag kit, hematoxylin and eosin, and immunohistochemical double-staining methods. Six rats subjected to 2 h of MCA occlusion were killed at 24 h for measurement of DNA fragmentation by gel electrophoresis. Our data indicate that within a coronal section, DNA fragmentation was present in zero to three cells in each hemisphere of normal and sham-operated rats as well as in the contralateral hemisphere of ischemic rats. The number of cells exhibiting DNA fragmentation increased as early as 0.5 h (8 +/- 6), peaked at 24-48 h (213 +/- 59), and persisted for 4 weeks (10 +/- 2) after onset of reperfusion (p < 0.01). Groups of cells exhibiting DNA fragmentation (> 95% neurons) were located primarily in the inner boundary zone of the infarct. With use of gel electrophoresis, purified DNA obtained from the ischemic tissue exhibited the characteristic nucleosome ladder pattern associated with apoptosis.(ABSTRACT TRUNCATED AT 250 WORDS)

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PubMed1995

Induction of DNA fragmentation after 10 to 120 minutes of focal cerebral ischemia in rats.

BACKGROUND AND PURPOSE: The induction of neuronal necrosis has been studied after various durations of transient middle cerebral artery (MCA) occlusion in the rat. The objective of the present study was to measure the numbers and anatomic distribution of cells exhibiting apoptotic bodies as an indication of DNA fragmentation and apoptotic cell death as a function of duration of transient MCA occlusion in the rat. METHODS: The MCA of male Wistar rats (n = 24) was occluded for 10, 20, 30, 60, 90, and 120 minutes (n = 4 per group) with the use of an intraluminal monofilament, and reperfusion was instituted for 48 hours. DNA fragmentation was measured in paraffin sections with the use of a terminal deoxynucleotidyl-transferase (TdT)-mediated dUTP-biotin nick end-labeling (TUNEL) method. Adjacent sections were stained with hematoxylin and eosin for analysis of ischemic cell damage, and immunohistochemical double staining methods were used for cell identification. Sham-operated rats (n = 4) and normal rats not subjected to any surgical procedure (n = 4) were used as controls for apoptosis detection. RESULTS: Within 5-microns-thick coronal sections, DNA fragmentation was present in 0 to 3 apoptotic cells in each hemisphere of normal, sham-operated rats as well as in the contralateral hemisphere of ischemic rats. After 10 to 20 minutes of MCA occlusion, apoptotic cells exhibiting DNA fragmentation (10 to 20) increased in the regions of selective neuronal necrosis in the preoptic area and in the striatum. After 30 to 60 minutes of ischemia, scattered apoptotic cells (30 to 60) exhibited DNA fragmentation and expanded into areas of selective neuronal necrosis in the cortex. After 90 to 120 minutes of occlusion, groups of apoptotic cells (70 to 200, > 95% neurons) were primarily localized to the inner boundary zone of the infarct. CONCLUSIONS: A range of mild to severe ischemia-reperfusion stimuli induce internucleosomal DNA cleavage. The presence and anatomic location of apoptotic cells exhibiting DNA fragmentation after transient cerebral occlusion indicate that apoptosis accompanies neuronal necrosis.

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PubMed1995

Anti-intercellular adhesion molecule-1 antibody reduces ischemic cell damage after transient but not permanent middle cerebral artery occlusion in the Wistar rat.

BACKGROUND AND PURPOSE: Postischemic cerebral inflammation may contribute to ischemic cell damage. Intercellular adhesion molecule-1 (ICAM-1) is a glycoprotein expressed on endothelial cells that facilitates leukocyte adhesion. We investigated the effect of administration of an anti-ICAM-1 antibody (1A29) on ischemic cell damage after transient (2-hour) or permanent middle cerebral artery (MCA) occlusion in the Wistar rat. METHODS: Groups studied were as follows: (1) transient MCA occlusion: rats were subjected to 2 hours of MCA occlusion, and after 1 hour of reperfusion they were treated with 1A29 (n = 11) or an isotype control antibody (n = 9); and (2) permanent MCA occlusion: rats were treated with 1A29 (n = 9) or an isotype control antibody (n = 7) 2 hours after onset of MCA occlusion. All animals were killed 1 week after onset of ischemia. Brain sections were stained with hematoxylin and eosin for histological evaluation. RESULTS: Significant reductions (P < .05) in both volume (44%) of the ischemic lesion and weight loss were found in animals subjected to transient MCA occlusion and treated with 1A29 compared with vehicle-treated animals. In contrast, in animals subjected to permanent MCA occlusion the lesion and the temporal profile of body weight were not altered by 1A29 administration. CONCLUSIONS: Ischemic cell damage is promoted by postischemic inflammatory response after 2 hours of transient MCA occlusion, and ischemic cell damage is reduced by administration of an anti-ICAM-1 antibody during reperfusion.

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PubMed1995

The effect of hypothermia and hyperthermia on photodynamic therapy of normal brain.

The effect of whole body hyperthermia and hypothermia in conjunction with photodynamic therapy (PDT) was determined on normal rat brain. Hyperthermia animals (Group I, n = 18) were warmed until their core body temperature reached 40 degrees C, (brain temperature, 39.7 +/- 0.5 degree C) and maintained at 40 +/- 1 degree C for 30 minutes prior to and after PDT. Hypothermia (Group II, n = 31) animals were cooled to 30 +/- 1 degree C (brain temperature, 29.3 +/- 0.4 degree C) for 1 hour. PDT treatment was performed, and the body temperature of the animals was maintained at 30 degrees C for 2 hours post-PDT. A population of animals was subjected to PDT under normothermic (Group III, n = 16; body temperature, 37 +/- 1 degree C; brain temperature, 36.7 +/- 0.8 degree C) conditions and treated in a manner identical to that of hyperthermic animals. PDT was performed with 17 J/cm2, 35 J/cm2, or 70 J/cm2 (100 mW/cm2). Photofrin (Quadralogic Technologies Ltd., Vancouver, Canada) (12.5 mg/kg) was injected intraperitoneally 48 hours prior to laser treatment on all three groups. Wet-dry weight measurements were obtained on a separate set of all three groups of animals (n = 27). Cortical lesion depths were measured, and pathological evaluation was made at 24 hours post-PDT. No difference in the wet-dry weight measurements or histopathology was present between the three groups of animals. Lesion depths for Group I animals did not significantly differ from Group III animals.(ABSTRACT TRUNCATED AT 250 WORDS)

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PubMed1995

Ultrastructural and light microscopic evidence of apoptosis after middle cerebral artery occlusion in the rat.

Brains from eight rats subjected to transient focal ischemia (2 hours) and reperfusion (22 hours) revealed an ultrastructural appearance of apoptosis and light microscopic features of cells exhibiting DNA fragmentation. The number of cells exhibiting DNA fragmentation was significantly higher (P < 0.01) in the ipsilateral hemisphere (216 +/- 43 per section) than in the contralateral hemisphere and in normal (n = 4) and sham operated (n = 4) rats (0 to 3 positive cells per section in controls). Cells exhibiting DNA fragmentation were primarily located in the inner boundary zone to the infarct. Cells exhibiting DNA fragmentation provided morphological information of apoptosis. Apoptosis may contribute to the development of infarct after transient focal cerebral ischemia.

Animals↗
PubMed1994

Upregulation of neuronal nitric oxide synthase and mRNA, and selective sparing of nitric oxide synthase-containing neurons after focal cerebral ischemia in rat.

Nitric oxide synthase-containing neurons are presumed to be resistant to neurodegeneration and neurotoxicity, however this resistance has not been demonstrated after focal cerebral ischemia. We therefore measured the temporal profile of neuronal nitric oxide synthase (NOS-I) mRNA and immunoreactivity and NADPH-diaphorase reactivity over a one week period after permanent middle cerebral artery (MCA) occlusion in 48 male Wistar rats and compared these data to ischemic cell damage as evaluated on hematoxylin and eosin (H & E) stained sections by light microscopy. NOS-I mRNA increased as early as 15 min after MCA occlusion in the ipsilateral striatum and maximal expression of NOS-I was found in the ipsilateral cortex and striatum 1 h after MCA occlusion. The numbers of NOS-I-containing neurons in the ipsilateral cortex and striatum were significantly greater (P < 0.05) than NOS-I-containing neurons in the contralateral hemisphere at 2-48 h after the onset of ischemia. The number of NOS-I-containing neurons peaked at 4 h after MCA occlusion. Neurons exhibited shrinkage or were swollen at 1 to 4 h after MCA occlusion. At 24-48 h after ischemia, neurons in the ischemic lesion appeared to be eosinophilic or ghost like on H & E stained sections. However, some of these neurons retained morphological integrity on the NOS-I immunohistochemical sections. At 168 h after ischemia, all neurons within the lesion appeared necrotic on H & E stained sections; however, scatterred neurons expressed NOS-I and NADPH-diaphorase. The rapid upregulation of NOS-I and mRNA in the ischemic lesion suggests that NOS-I is involved in focal cerebral ischemic injury; the expression of NOS-I by neurons that retain their morphological structure in the area of the infarct suggests that NOS-I-containing neurons are more resistant to the ischemic insult. Our data also indicate a close association of NOS-I immunoreactivity and NADPH-diaphorase reactivity in ischemic brain.

Amino Acid Oxidoreductases↗
PubMed1994

Anti-CD11b monoclonal antibody reduces ischemic cell damage after transient focal cerebral ischemia in rat.

We investigated the effect of an anti-CD11b monoclonal antibody (1B6c) on ischemic cell damage after transient middle cerebral artery occlusion. We divided animals into three groups: MAb 1 group (n = 5)--rats were subjected to 2 hours of transient occlusion and 1B6c (1 mg/kg) was administered intravenously at 0 and 22 hours of reperfusion; MAb 2 group (n = 5)--same experimental protocol as MAb 1 group, except that the initial dose of 1B6c was increased to 2 mg/kg; and control group (n = 5)--same experimental protocol as MAb 2 group, except that an isotype-matched control antibody was administered. Animals were weighed and tested for neurological function before and after occlusion of the middle cerebral artery. Forty-six hours after reperfusion, brain sections were stained with hematoxylin and eosin for histology evaluation. We observed a significant reduction of weight loss and improvement in neurological function after ischemia in the MAb 2 animals compared to MAb 1 and vehicle-treated animals (p < 0.05). The lesion volume was significantly smaller in the MAb 2 group (19.5 +/- 1.9%) compared to MAb 1 (29.9 +/- 2.6%) and vehicle-treated (34.2 +/- 5.4%) groups (p < 0.01). Tissue polymorphonuclear cell numbers were reduced in both 1B6c-administered groups. Our data demonstrate that administration of anti-CD11b antibody results in a dose-dependent, significant functional improvement and reduction of ischemic cell damage after transient focal cerebral ischemia in the rat.

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PubMed1994

Temporal profile of ischemic tissue damage, neutrophil response, and vascular plugging following permanent and transient (2H) middle cerebral artery occlusion in the rat.

We investigated the temporal profile of ischemic tissue damage, neutrophil response, and vascular occlusion after permanent and transient middle cerebral artery occlusion in the rat. Focal cerebral ischemia was induced by advancing a nylon monofilament to occlude middle cerebral artery (MCA). Two groups of rats were investigated: (1) those with permanent MCA occlusion (n = 29), and (2) and those having the arterial occlusion released after 2 h (n = 34). Experiments were terminated at 6, 12, 24, 48, 72, 96 and 168 h after the onset of ischemia, and brain sections were stained with hematoxylin and eosin for histological evaluation. Initially, the cortical lesion was smaller in rats subjected to transient MCA occlusion than in rats subjected to permanent MCA occlusion (p < 0.02). The surface area of the lesion was identical in both groups at 48 h after the onset of ischemia. Neutrophil infiltration into tissue and the time of peak neutrophil infiltration occurred earlier after transient MCA occlusion than after permanent MCA occlusion (6 h, 48 h in transient; 12 h, 72 h in permanent). Within the lesions, the number of occluded vessels was significantly lower in the transient ischemia group than in the permanent ischemia group during the time interval between 12-48 h (p < 0.01). Our data suggest that the temporal evolution of the lesion, the pattern of neutrophil infiltration and the chronology of microvascular occlusion differs depending on whether the MCA occlusion is transient (2 h) or permanent; however, significant differences in the size of the brain lesion disappeared 48 h after onset of ischemia.

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PubMed1994

Cerebral blood flow changes during cortical spreading depression are not altered by inhibition of nitric oxide synthesis.

CBF increases concomitantly with cortical spreading depression (CSD). We tested the hypothesis that CBF changes during CSD are mediated by nitric oxide (NO). Male Wistar rats (n = 23) were subjected to KCl-induced CSD before and after administration of nitric oxide synthase (NOS) inhibitors N-nitro-L-arginine (L-NNA) or N-nitro-L-arginine methyl ester (L-NAME) and in nontreated animals. CBF, CSD, and mean arterial blood pressure were recorded. Brain NOS activity was measured in vitro in control, L-NNA, and L-NAME-treated rats by the conversion of [3H]arginine to [3H]citrulline. Our data show that the NOS inhibitors did not significantly change regional CBF (rCBF) during CSD, even though cortical NOS activity was profoundly depressed and systemic arterial blood pressure was significantly increased. Our data suggest that rCBF during CSD in rats is not regulated by NO.

Amino Acid Oxidoreductases↗
PubMed1994

The effect of hypothermia on transient focal ischemia in rat brain evaluated by diffusion- and perfusion-weighted NMR imaging.

The effect of moderate whole-body hypothermia (30 degrees C) on transient middle cerebral artery (MCA) occlusion in the rat was evaluated using diffusion- and perfusion-weighted magnetic resonance imaging. Two hours of transient MCA occlusion was induced by intracarotid insertion of a nylon filament under normothermic (n = 14) and hypothermic (n = 7) conditions. Diffusion- and perfusion-weighted imaging were performed before, during, and after focal ischemia from 30 min up to 7 days. In hypothermic animals, scattered neuronal necrosis was localized to select areas of the caudate putamen and the parietal and insular cortex. In contrast, the normothermic ischemic animals exhibited pan-necrosis and infarct encompassing the damaged area. The diffusion and perfusion data measured from caudate putamen indicate that hypothermia causes a significant reduction in the apparent diffusion coefficient of water (ADCw) and CBF values from normothermic control values (p < 0.01). In both normothermic and hypothermic animals after onset of MCA occlusion, ADCw and CBF values in the core of the ischemic region (striatum) significantly declined from the preischemic and homologous contralateral control ADCw and CBF values (p < 0.05). However, ADCw and CBF in the hypothermic group returned toward control more rapidly than in the normothermic group. These results suggest that the protective effect of hypothermia on ischemic cell damage is reflected in the early return of ADCw during reperfusion and the reduction of ischemic cell damage by hypothermia may be mediated by the improved CBF during acute reperfusion.

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PubMed1994

p53-immunoreactive protein and p53 mRNA expression after transient middle cerebral artery occlusion in rats.

BACKGROUND AND PURPOSE: We investigated the temporal distribution of the p53-immunoreactive protein in conjunction with cellular damage and the expression of the p53 mRNA after focal cerebral ischemia in rats. METHODS: Male Wistar rats (n = 66; controls, n = 7) were subjected to 2 hours of middle cerebral artery occlusion and were killed at various times of reperfusion (0.5 to 168 hours) for p53 immunohistochemistry and Northern blot analysis. RESULTS: A cellular expression of mutant p53-immunoreactive protein was found localized to anatomic sites exhibiting severe neuronal damage. A maximal induction of mutant p53-immunoreactive protein was found at 12 hours after reperfusion and subsequently declined. No wild-type p53 protein expression was detected after ischemia. A time-dependent expression of p53 mRNA was observed in both hemispheres. The peak level of p53 mRNA occurred at 24 hours after reperfusion. CONCLUSIONS: Our data indicate that the expressions of p53-immunoreactive protein and p53 mRNA are upregulated after transient focal cerebral ischemic insult in rats. The concomitant appearance of p53 and cell damage in ischemic brain suggests that p53 expression may impact cell biological response to an ischemic insult.

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PubMed1994

Postischemic administration of an anti-Mac-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in rats.

BACKGROUND AND PURPOSE: Postischemic cerebral inflammation may contribute to ischemic cell damage. The CD11b/18 (Mac-1) integrin mediates stimulated neutrophil binding to endothelia. We therefore investigated the effect of administration of an anti-Mac-1 monoclonal antibody on cerebral ischemic cell damage in the rat. METHODS: Rats (n = 10) were subjected to 2 hours of middle cerebral artery occlusion; the anti-Mac-1 antibody was administered at a dose of 2 mg/kg i.v. at 1 hour of reperfusion and 1 mg/kg i.v. at 22 hours of reperfusion or an isotype-matched control antibody (n = 10) was administered using the same experimental protocol. Rats were killed at 46 hours of reperfusion, and brain sections were stained with hematoxylin and eosin for histological evaluation. In a separate population of rats given either vehicle (n = 8) or anti-Mac-1 antibodies (n = 9), intraparenchymal neutrophils were measured by means of a myeloperoxidase assay. RESULTS: The lesion volume was significantly smaller (28%) in the anti-Mac-1 antibody group compared with the vehicle control group (P < .01). Numbers of intraparenchymal polymorphonuclear cells were significantly reduced (P < .05) in the cortex of the anti-Mac-1 antibody group compared with the vehicle control group. CONCLUSIONS: Our data demonstrate that administration of anti-Mac-1 antibody 1 hour after onset of reperfusion results in significant reductions of ischemic cell damage and intraparenchymal neutrophils after transient (2-hour) focal cerebral ischemia in the rat.

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PubMed1994

Magnetic resonance imaging assessment of evolving focal cerebral ischemia. Comparison with histopathology in rats.

BACKGROUND AND PURPOSE: This study was performed to document the progression of ischemic brain damage after middle cerebral artery occlusion in the rat using magnetic resonance imaging and histopathologic methods. METHODS: Cerebral ischemia was induced through permanent tandem occlusion of ipsilateral middle cerebral and common carotid arteries. The evolution of magnetic resonance imaging and histopathologic parameter changes was studied, both short term (1.5 to 8 hours) and long term (24 to 168 hours), in five specific brain regions within the middle cerebral artery territory. RESULTS: Significant changes in proton nuclear magnetic resonance spin-lattice and spin-spin relaxation times and the "apparent" diffusion coefficient of water could be detected within hours after the onset of permanent focal cerebral ischemia, whereas significant alterations in proton spin-density ratios were not apparent until approximately 48 hours. Histological changes were evident within 12 hours, with a significant loss of neurons seen in the most severely damaged regions at 7 days. Diffusion-weighted imaging was the most sensitive technique for visualizing acute ischemic alterations. The water diffusion coefficient was the only magnetic resonance imaging parameter studied to indicate significant alterations within the first 4 hours after arterial occlusion in all five brain regions. CONCLUSIONS: The degree of change for a particular magnetic resonance imaging parameter appeared to be related to the location and extent of neuronal injury, with the most dramatic changes occurring within the areas displaying the most severe histological damage. These results indicate that complete specification of all brain regions affected by ischemic brain injury may require a combination of imaging strategies applied over a period of days and suggest the possibility of using magnetic resonance imaging to distinguish between permanent and reversible cell damage.

Animals↗
PubMed1994

Anti-ICAM-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in the rat.

Intercellular adhesion molecule-1 (ICAM-1) is a glycoprotein expressed on endothelial cells that facilitates leukocyte adhesion. To test the hypothesis that reduction of leukocytes in an ischemic lesion reduces ischemic brain damage, we measured the effect of administration of an anti-ICAM-1 monoclonal antibody on ischemic brain damage after transient middle cerebral artery occlusion in the rat. ICAM-1 expression increased in the ischemic lesion, and the lesion volume was significantly reduced by 41% in the anti-ICAM-1 antibody group compared with the control group (p < 0.05). Numbers of polymorphonuclear leukocytes (PMNs) were significantly reduced in the cortices of the anti-ICAM-1 antibody group compared with the control animals (p < 0.05). Our data indicate that administration of anti-ICAM-1 antibody results in a significant reduction of ischemic brain damage concomitant with a reduction of PMNs in the lesion after transient focal cerebral ischemia in the rat.

Animals↗
PubMed1994

[Magnetoencephalographic observation of cortical spreading depression elicited by experimental focal brain ischemia in rats].

It has recently been reported that focal ischemia induced by occlusion of unilateral middle cerebral artery provoked direct current (DC) potential deflection in the cortical infarct rim. DC potential deflection is suggested to be one of the deteriorating factors for ischemic damage. We aimed to elucidate whether a direct current magnetoencephalography (MEG) can noninvasively record DC potential deflection in focal brain ischemia or not. Fourteen male Wistar rats were used for this study. After anesthesia with pentobarbital, rats were subjected to transcranial occlusion of left middle cerebral artery by electrocauterization. Three rats showed recurrent DC potential deflections, like cortical spreading depression (CSD). The direct current MEG deflections always followed DC potential obtained by electrically recorded electrocorticograms. Mean repetition interval of DC potentials was 574 +/- 178 (SD) seconds, and their mean amplitude was 1266 +/- 789 fT. Time course of DC potentials induced by focal ischemia resembles to CSD induced by KCl application to cerebral cortex. Our observation suggests that DC magnetoencephalography is one of the useful tools for non invasive recording direct current potential deflections which are impossible to be obtained by conventional EEG techniques, and that this method will be a powerful diagnostic tool for focal brain ischemia.

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