Biomedical subjects

M Chopp

Publications and source records attributed to M Chopp.

At least 73 records · Page 4Linked to original sources

PubMed1999

Apoptosis and expression of p53 response proteins and cyclin D1 after cortical impact in rat brain.

We measured the temporal profile and cellular identification of apoptosis in rat brain after cortical contusion injury. Double staining immunohistochemistry was also used to investigate the relationship between apoptotic cell death and selective protein expression associated with DNA damage and repair (p53, Bax, MDM2, WAF1, Gadd45, PCNA) and cell cycle protein, Cyclin D1, in male Wistar rats 48 h after injury. Cortical contusion was induced in male Wistar rats with a pneumatic impactor device. The animals were sacrificed at different times after trauma (1, 2, and 14 h and 1, 2, 4, 7 and 14 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 for temporal profile determination. Additional 11 rats were used for study of protein expression. Coronal brain sections were analyzed using an in situ terminal deoxynucleotdyl transferase-mediated biotinylated deoxyuridine triphosphate nick end labeling (TUNEL), hematoxylin, and immunohistochemical double staining methods. Apoptotic cells were observed as early as 2 h after the impact. Apoptotic cell death peaked at 2 days, gradually tapering off afterward, although scattered apoptotic cells were detected at 2 weeks after the impact. The number of apoptotic cells at 2 days far exceeded their number at other times (p=0.009). Apoptotic cells were observed primarily in the cortex adjacent to the site of injury. In addition, apoptotic cells in conjunction with few injured cells were present in the ipsilateral hippocampus and localized to the granule layer of dentate gyrus. Our data indicate that DNA fragmentation is present in nearly all neurons subacutely after cortical contusion and persists for at least 2 weeks thereafter. Apoptosis is also present in neurons localized to the hilus of the dentate gyrus at a site remote from the area of injury suggesting a selective role for apoptosis in promoting secondary brain damage and dysfunction after traumatic brain injury. Using double staining, we were able to show that a great majority of apoptotic cells (>95%) were neurons and the rest were astrocytes and endothelial cells. Proteins associated with DNA damage and repair (p53, Bax, MDM2, WAF1, Gadd 45, PCNA) were expressed in the cytoplasm of normal cells of naive and sham rats. These proteins were translocated to the nuclei of apoptotic and injured cells at 48 h after cortical contusion. Cyclin D1 was not present in apoptotic cells. The differential expression of proteins associated with DNA damage, repair and the cell cycle protein Cyclin D1 in the contused brain suggest a potential role for these proteins in cell survival and apoptosis after cortical contusion.

Animals↗

PubMed1999

Increased therapeutic efficacy with rt-PA and anti-CD18 antibody treatment of stroke in the rat.

OBJECTIVE: To examine the efficacy of an antileukocyte adhesion antibody (anti-CD18) as an adjuvant for delayed (2 hours and 4 hours) thrombolytic therapy (recombinant human tissue plasminogen activator [rt-PA]) in middle cerebral artery occlusion (MCAO) in rats. BACKGROUND: Thrombolytic therapy with rt-PA is limited in its application by a short therapeutic window. METHODS: Male Wistar rats were subjected to MCAO by a single fibrin-rich clot. The rats were assigned to the following experimental groups: Experiment 1 (treatment 2 hours after embolization), 1) rt-PA, 2) anti-CD18 antibody, 3) rt-PA and anti-CD18 antibody, 4) immunoglobulin (Ig) G, and 5) vehicle; Experiment 2 (treatment 4 hours after occlusion), 1) rt-PA alone, 2) rt-PA and anti-CD18 antibody, and 3) nontreated control group. Neurologic deficits, infarction volume, hemorrhage, and brain myeloperoxidase (MPO) immunoreactivity were measured. RESULTS: Administration of rt-PA and anti-CD18 antibody 2 hours later reduced significantly (p < 0.05) the infarct volume and improved neurologic deficits compared with the vehicle-treated group. Treatment with rt-PA alone improved neurologic deficits significantly and reduced mean infarct volume compared with the vehicle-treated group. However, treatment with anti-CD18 antibody neither reduced infarct volume nor improved neurologic deficits compared with the IgG-treated group. The combination of rt-PA and anti-CD18 antibody treatment at 4 hours reduced significantly the infarct volume and MPO immunoreactive cells compared with rt-PA treatment alone at 4 hours, and reduced neurologic deficits compared with rt-PA treatment alone and compared with the nontreated animals. CONCLUSIONS: The combination of antileukocyte adhesion antibody and thrombolytic therapy may increase the therapeutic window for the treatment of stroke.

Adjuvants, Immunologic↗

PubMed1999

T1 and magnetization transfer at 7 Tesla in acute ischemic infarct in the rat.

T1 and magnetization transfer at a field strength of 7 Tesla were used to discriminate between water accumulation and protein mobilization in tissue undergoing infarction. Twelve rats subjected to acute stroke via intralumenal suture occlusion of the middle cerebral artery, and 19 controls, were studied. In MRI studies to 6 hr post-ictus, serial data acquisition allowed the measurement of cerebral blood flow (CBF), apparent diffusion coefficient of water (ADCw), equilibrium magnetization (M0) and T1, and equilibrium magnetization and T1 under an off-resonance partial saturation of the macromolecular pool (Msat and T1sat). Using these parameters, the apparent forward transfer rate of magnetization between the free water proton pool and the macromolecular proton pool, k(fa), was calculated. Regions of interest (ROIs) were chosen using depressed areas in maps of the ADCw. T1 measurements in bovine serum albumin at 7T were not affected by the mobility of the macromolecular pool (P > 0.2), but magnetization transfer between free water and protein depended strongly on the mobility of the macromolecular pool (P < 0.001). For 6 hr after ictus, k(fa) uniformly and strongly decreased in the region of the infarct (P < 0.0001). Ratios (ischemic/non-ischemic) of parameters M0, Msat, T1, and T1sat all uniformly and strongly increased in the infarct. The ratio T1/T1sat in the region of infarction showed that a progressive accumulation of free water in the region of interest was the major (>80%) contribution to the decrease in k(fa). There also existed a small contribution due to changes at the water-macromolecular interface, possibly due to proteolysis (P = 0.005).

Acute Disease↗

PubMed1999

The clot thickens--thrombolysis and combination therapies.

Stroke in the human is most frequently caused by an intra-arterial clot. In order to investigate human stroke, appropriate and relevant animal models must be selected. Since the only approved treatment of stroke is that of recombinant tissue plasminogen activator (rtPA) the models selected should be amenable to thrombolytic treatment. We therefore describe a new model of embolic stroke in the rat in which a fibrin rich clot is placed via the internal carotid artery (ICA) at the origin of the middle cerebral artery (MCA). Data are summarized describing treatment of embolic stroke with rtPA administered at various times after stroke, the use of combination antiadhesion molecule and rtPA therapy, and the application of MRI to monitor the temporal evolution of physiological changes within ischemic tissue with and without rtPA intervention and to predict therapeutic efficacy.

Animals↗

PubMed1999

High resolution quantitation of microvascular plasma perfusion in non-ischemic and ischemic rat brain by laser-scanning confocal microscopy.

Laser-scanning confocal microscopy (LSCM) was used to measure at high resolution cerebral plasma volumes (perfusion) using two fluorescent plasma markers in a rat model of embolic stroke. This application of LSCM to study the microvascular circulation in embolic stroke was developed as an alternative to autoradiography to measure cerebral perfusion. An additional benefit of LSCM is that it quantitates with great accuracy the structural relationships of the microcirculation to cells and the pathological alterations of the ischemic brain. Autoradiography allows only a quantitative analysis of cerebral perfusion. For example, in order to study the microcirculation and its relationship to blood brain barrier damage, the volume of perfused cerebral capillaries was measured by administering two fluorescent plasma markers (FITC-dextran and Evans blue) intravenously to a rat. Evans blue was administered before cerebral ischemia and FITC-dextran administered post-ischemia 1 min before sacrifice. Volumes of plasma perfusion were analyzed by means of a system developed for 3D analysis of fixed and stained serial brain histologies. Plasma volumes for the non-ischemic cerebral cortex were 1.00%+/-0.38% while plasma volumes in the caudate/putamen were 0.69%+/-0.17% in good agreement with the previously published values using the autoradiography method. The architecture of the capillaries in the ischemic core showed perfusion of Evans blue but there was no flow of FITC dextran. Our work represents a novel application of this technology to investigation of cerebral vascular disease and identifies its potential to become an important tool for investigation of cerebral pathology.

Animals↗

PubMed1999

Expression of cell cycle proteins (cyclin D1 and cdk4) after controlled cortical impact in rat brain.

We measured the expression of Cyclin D1 and its kinase cdk4, 48 h after induction of cortical contusion in the rat. Brain from rats (n = 6) subjected to controlled cortical impact injury and sham-operated (n = 3) and normal (n = 2) rats were processed for dual label immunohistochemical study to identify cellular expression of these cell cycle proteins. Antibodies against neurofilaments 68 and 200 and glial fibrillary acidic protein were employed to identify neurons and astrocytes, respectively, whereas microglia were identified using histochemical detection of IB4-isolectin. Double staining for DNA fragmentation detection, using terminal deoxynucleotdyl transferase mediated biotinylated deoxyuridine triphosphate nick end 3 'OH labeling (TUNEL) and antibodies for expression of Cyclin D1 and cdk4 was also performed. Cyclin D1 and cdk4 were selectively expressed in morphologically intact or injured neurons throughout the rat brain. Apoptotic cells were not immunoreactive to Cyclin D1 and cdk4. The selective expression of cell cycle proteins observed in nonapoptotic postmitotic neurons suggests a role for these proteins in the survival of cells after cortical contusion.

Animals↗

PubMed1999

Quantitation of microvascular plasma perfusion and neuronal microtubule-associated protein in ischemic mouse brain by laser-scanning confocal microscopy.

In an exposition of the technique of calculating distribution volumes from laser-scanning confocal microscopic (LSCM) data, three-dimensional images of the distribution of one or two fluorescent markers in mouse brain specimens were generated by LSCM and processed by a system developed for morphometric analysis of fixed and stained serial brain histologic samples. To determine the volume of perfused cerebral capillaries, one of two fluorescent plasma markers, either fluorescein isothiocyanate (FITC)-dextran or Evans blue, was intravenously administered to mice subjected to 1 hour of embolic middle cerebral artery (MCA) occlusion (n = 9) and to mice that were not operated on (n = 3); after 1 minute of circulation, brains were removed, immersion-fixed, and processed for LSCM. In some of these animals (n = 5), the volume of endogenous microtubule-associated protein-2 (MAP2) fluorescence was also determined using immunohistochemical staining. For mice that were not operated on, this methodology yielded highly localized volumes of (1) microvascular plasma, which agree with those determined for rodents by other techniques, and (2) MAP2 expression, which appears physiologically and morphologically reasonable. After 1 hour of MCA occlusion, the MAP2 volumes of distribution were less than 10% of normal in the ipsilateral hemisphere in which plasma perfusion essentially ceased. In conclusion, precise colocalization and quantitation of early ischemic neuronal damage and cerebral plasma perfusion deficit can be done with this three-dimensional, microphysiologic and microanatomic methodology.

Animals↗

PubMed1999

Thrombolysis with tissue plasminogen activator alters adhesion molecule expression in the ischemic rat brain.

BACKGROUND AND PURPOSE: We tested the hypothesis that treatment of embolic stroke with recombinant human tissue plasminogen activator (rhtPA) alters cerebral expression of adhesion molecules. METHODS: Male Wistar rats were subjected to middle cerebral artery occlusion by a single fibrin-rich clot. P-selectin, E-selectin, and intercellular adhesion molecule-1 (ICAM-1) immunoreactivity was measured at 6 or 24 hours after embolic stroke in control rats and in rats treated with rhtPA at 1 or 4 hours after stroke. To examine the therapeutic efficacy of combined rhtPA and anti-ICAM-1 antibody treatment at 4 hours after embolization, ischemic lesion volumes were measured in rats treated with rhtPA alone, rats treated with rhtPA and anti-ICAM-1 antibody, and nontreated rats. RESULTS: Administration of rhtPA at 1 hour after embolization resulted in a significant reduction of adhesion molecule vascular immunoreactivity after embolization in the ipsilateral hemisphere compared with corresponding control rats. However, when rhtPA was administered to rats at 4 hours after embolization, significant increases of adhesion molecule immunoreactivity in the ipsilateral hemisphere were detected. A significant increase of ICAM-1 immunoreactivity was also detected in the contralateral hemisphere at 24 hours after ischemia. A significant reduction in lesion volume was found in rats treated with the combination of rhtPA and anti-ICAM-1 antibody compared with rats treated only with rhtPA. CONCLUSIONS: The present study suggests that the time of initiation of thrombolytic therapy alters vascular immunoreactivity of inflammatory adhesion molecules in the ischemic brain and that therapeutic benefit can be obtained by combining rhtPA and anti-ICAM-1 antibody treatment 4 hours after stroke.

Animals↗

PubMed1998

P-selectin antibody reduces hemorrhage and infarct volume resulting from MCA occlusion in the rat.

We investigated the effect of an anti-P-selectin antibody (RMP-1) on ischemic cell damage and hemorrhage after transient middle cerebral artery occlusion (MCAo) in the rat. Animals were divided into four groups: (1) antibody (Ab) 1 group (n = 14) RMP-1 (2 mg/kg) was administered to rats 1 h prior to induction of 2 h of MCA occlusion; (2) control-vehicle group Ab2 (n = 12) rats were subjected to the same experimental protocol, except that an isotype-matched control antibody was administered; (3) Abl group (n = 10) rats were subjected to 2 h of MCA occlusion and RMP-1 (2 mg/kg) was administered upon reperfusion; (4) control-vehicle group Ab2 (n = 10) rats were subjected to the same experimental protocol, except that an isotype-matched control antibody was administered. Animals were sacrificed 48 h after onset of the MCAo for histological evaluation of infarction and hemorrhage, and to quantify number of neutrophils. The lesion volume was significantly smaller only in pretreated rats (RMP-1 group, 18.7+/-3.1%) compared to the vehicle-treated (31.6+/-2.6%) group (P<0.01). Total area of hemorrhage (5.94 x 10(3)+/-2.86 x 10(3) microm2) in the pre MCAo RMP-1 treated group animals was significantly reduced (P<0.02) compared to the vehicle group (6.1 x 10(4)+/-3.42 x 10(4) microm2), respectively. Our data demonstrate that administration of the anti-P-selectin antibody before transient focal cerebral ischemia in rat brain reduces ischemic cell damage and petechial hemorrhage.

Animals↗

PubMed1998

Early (1 h) administration of tissue plasminogen activator reduces infarct volume without increasing hemorrhagic transformation after focal cerebral embolization in rats.

We assessed the incidence of hemorrhagic transformation and infarct volume after early intravenous infusion of recombinant human tissue plasminogen activator (rht-PA) in a newly developed rat cerebral embolic model. Male Wistar rats (n=60) were subjected to middle cerebral artery (MCA) occlusion by a single fibrin rich clot. One hour after embolization, rats were assigned to the following groups: (1) rht-PA treated group (n=20); (2) vehicle treated group (n=20); and (3) saline treated group (n=20). Neurological deficits, lodgement of a clot at the origin of the MCA, infarction volume and microscopic hemorrhage were measured. Animals exhibited moderate to severe neurological deficits 1 h after MCA occlusion in all groups. Administration of rht-PA significantly (P<0.05) reduced the incidence of lodgement of a clot at the origin of the MCA (30%) compared with the saline treated group (100%) and the vehicle treated group (80%). A significant (P<0.05) reduction of percent hemispheric infarct volume was detected between the saline (33.2+/-3.71%) and the rht-PA groups (19.4+/-3.3%). However, no significant difference was found in the total area of microscopic hemorrhage of the rht-PA (0.05+/-0.02 mm2), the vehicle (0.02+/-0.01 mm2), and the saline (0.03+/-0.02 mm2) treated groups. No significant difference of percent hemispheric infarct volume (P=0.08) was observed between the vehicle and the rht-PA treated groups. This study demonstrates that treatment with rht-PA reduced infarct volume without increasing intracerebral hemorrhage in rats with large cerebral infarction when treatment was initiated at 1 h of the onset of embolization.

Animals↗

PubMed1998

Preliminary clinical-radiological assessment of a MR tissue signature model in human stroke.

We evaluated the ability of an MR signature model (SM) of cerebral ischemic injury to stage the evolution of cellular damage in human stroke. In 19 patients with ischemic stroke of presumed embolic or non-embolic cause we carried out diffusion-weighted and T2-weighted MR imaging within 48 h of onset, and obtained apparent diffusion coefficient of water (ADCw), and T2 weighted images. We used the signatures obtained from these ADCw/T2 maps to formulate two patterns of damage signifying accelerated or non-accelerated progression of cellular death after stroke onset. Those patients with the accelerated pattern corresponded to those with the neuroradiological (NRC) and clinical diagnosis (TOAST.1 and TOAST.2) of presumed embolic stroke, with clinical diagnosis performed blinded both to NRC and to SM. Agreement between the SM and NRC was substantial (kappa=0.62), moderate (0.60<kappa<0.40) between the SM or NRC and TOAST.2, and fair (0.40<kappa<0.20) among the SM or NRC and TOAST.1. We believe these results constitute a preliminary validation of the MR tissue signature modeling in clinical stroke assessment.

Adult↗

PubMed1998

Intact, injured, necrotic and apoptotic cells after focal cerebral ischemia in the rat.

Middle cerebral artery occlusion (MCAo) leads to brain cell death. However, quantitation of injured brain cells and inflammatory cells after MCAo has not been determined in the rat. Transient (2 h) MCAo was therefore induced in male Wistar rats by means of an intraluminal monofilament. Immunohistochemical and histochemical procedures performed at 46 h after MCAo were used to identify specific cellular populations in ischemic and control rats (n = 11). In the ischemic core of the lesion, approximately 24.7% of cells disappeared. Forty-four point eight percent of parenchymal cells consisted of intact (13.0%) or reversibly injured swollen (7.6%) and scalloped/shrunken dark (24.2%) cells. The percentage of irreversibly damaged cells was 55.2%, and included 49.9% necrotic cells (10.5% red and 39.4% ghost) and 5.4% apoptotic cells. In the inner boundary zone of the lesion, 15.9% of cells disappeared. Viable cells constituted 62.0% of all remaining cells. Neutrophils and macrophages were localized to this area. In the outer boundary zone of the lesion, 9.0% of cells disappeared. Viable cells constituted 91.6% of all remaining cells. The ratio of apoptotic to necrotic cells was 1:9, 1:6, 1:13 in the ischemic core, inner and outer boundary zones, respectively. Our data suggest the presence of three zones within the ischemic lesion: the core, and inner and outer boundaries. At 46 h after 2 h of MCAo the ischemic lesion is highly heterogeneous containing relatively large percentages of morphologically intact cells, suggesting the possibility of an extended window of therapeutic opportunity.

Animals↗

PubMed1998

Neutrophil inhibitory factor treatment of focal cerebral ischemia in the rat.

The present study was designed to determine whether a hookworm-derived recombinant neutrophil inhibitory factor (rNIF) is neuroprotective when administered after initiation of focal cerebral ischemia in the rat. We measured the rNIF dose-response on cerebral infarct volume, the therapeutic time window, the therapeutic response to permanent ischemia, and whether rNIF treatment delays the maturation of the ischemic lesion (2 days), or reduces cerebral infarct volume at 7 days after middle cerebral artery occlusion (MCAO). MCAO was induced by an insertion of intraluminal 4-0 monofilament nylon suture into internal carotid artery (n=195). We demonstrate a significant neuroprotective effect of rNIF administration 48 h after MCAO in a dose-dependent fashion when treatment was initiated upon reperfusion after 2 h MCAO and maintained until 48 h after MCAO. The beneficial effect was lost under conditions of permanent MCAO. The therapeutic time window is 4 h after MCAO. Brief treatment (6 h) is not sufficient to provide protection for the final ischemic damage. Continuous treatment with a high dose of rNIF for a long duration (7 days) is necessary to achieve maximum neuroprotection.

Animals↗

PubMed1998

Diffusion, perfusion, and T2 magnetic resonance imaging of anti-intercellular adhesion molecule 1 antibody treatment of transient middle cerebral artery occlusion in rat.

The effect of anti-intercellular adhesion molecule-1 (anti-ICAM-1) antibody treatment of transient (2 h) middle cerebral artery (MCA) occlusion in the rat was measured using diffusion (DWI)-, T2 (T2I)- and perfusion (PWI)-weighted magnetic resonance imaging. Rats were treated upon reperfusion with an anti-ICAM-1 monoclonal antibody (n=11) or a control antibody (n=7). DWI, T2I and PWI were performed before, during, and after induction of focal cerebral ischemia from 1 h to 7 days. In both groups, the apparent diffusion coefficient of water (ADCw) and cerebral blood flow (CBF) values in the ischemic region significantly declined from the preischemic ADCw values (p<0. 05). The post ischemic increase in T2 of the control group was significantly higher at 48 h than in the anti-ICAM-1 treated group (p<0.05). CBF was not significantly different between the two groups. The temporal profiles of MRI cluster analysis, which combines ADCw and T2 maps into a single image, was significantly different between groups. These data suggest that the neuroprotective effect of anti-ICAM-1 antibody treatment is reflected in reductions of T2 and lesion growth during reperfusion and may not be associated with increased cerebral perfusion.

Animals↗

PubMed1998

The expression of P- and E-selectins in three models of middle cerebral artery occlusion.

The expression and localization of P- and E-selectins in rat brain (n=126) were examined using immunohistochemical techniques at various time points after induction of middle cerebral artery (MCA) occlusion in the suture, thrombotic and embolic models of stroke. Expression of P- or E-selectin was not observed in brain tissue of sham operated control rats (n=9). P-selectin immunoreactivity was detected as early as 15 min and decreased to control level at 1 h after the onset of the MCA occlusion in all three models. P-selectin then slightly increased at 2 h and peaked at 6 h after MCA occlusion. E-selectin immunoreactivity was first observed at 2 h and peaked at 6 h and 12 h of after MCA occlusion in all three models. P- and E-selectin immunoreactivity was colocalized with von Willebrand factor immunoreactive microvessels. 90.4+/-2.0% of all vessels expressing P-selectin immunoreactivity were 7.5 to 30.0 micron in diameter; 3.6+/-1.4% were contained in vessels smaller than 7.5 micron, and 6.0+/-1.8% were localized in vessels greater than 30.0 micron in diameter. The percent distribution of E-selectin immunoreactive vessels were 75.9+/-2.1% in vessels 7.5 to 30.0 micron in diameter; 23.6+/-2.2% were in vessels smaller than 7.5 micron, and 0.6+/-0.4% were localized in vessels greater than 30.0 micron in diameter. These findings indicate that the temporal profiles of P- and E-selectin expression are independent of these models of MCA occlusion and are consistent with the time course of selectin mediated leukocyte infiltration after focal cerebral ischemia in the rat.

Analysis of Variance↗

PubMed1998

Cerebral vessels express interleukin 1beta after focal cerebral ischemia.

Rapid and marked increased levels of expression of interleukin 1beta (IL-1beta) mRNA have been detected in animal models of cerebral ischemia. However, the protein production of IL-1beta and the cellular sources of IL-1beta are largely undefined after cerebral ischemia. In the present study, we have measured the cellular localization of IL-1beta protein in brain tissue from non-ischemic and ischemic mice using immunohistochemistry. Male C57B/6J (n=45) mice were subjected to middle cerebral artery (MCA) occlusion by a clot or a suture. The mice were sacrificed at time points spanning the period from 15 min to 24 h after onset of the MCA occlusion. Non-operated and sham-operated mice were used as control groups. A monoclonal anti-IL-1beta antibody was used to detect IL-1beta. In the non-operated and sham-operated mice, a few IL-1beta immunoreactive cells were detected scattered throughout both hemispheres. IL-1beta immunoreactive cells increased in the ischemic lesion as early as 15 min and peaked at 1 h to 2 h after MCA occlusion. IL-1beta immunoreactivity was detected in the cortex of the contralateral hemisphere 1 h after ischemia. By 24 h after onset of ischemia, IL-1beta immunoreactivity was mainly present adjacent to the ischemic lesion and in the non-ischemic cortex. IL-1beta immunoreactivity was found on endothelial cells and microglia. This study demonstrates an early bilateral expression of IL-1beta on endothelium after MCA occlusion in mice.

Animals↗

PubMed1998

Photodynamic therapy of U87 human glioma in nude rat using liposome-delivered photofrin.

BACKGROUND AND OBJECTIVE: Liposomes as photosensitizer carriers may enhance the photodynamic effect on tumors. STUDY DESIGN/MATERIALS AND METHODS: To test this hypothesis, we treated U87 human glioma in rat brain with photodynamic therapy (PDT) using Photofrin encapsulated in a liposome carrier or Photofrin in dextrose. Nontumored brain was also treated and Photofrin content ratios were measured in tumor and nontumored brain. RESULTS: PDT using the liposome encapsulated photosensitizer significantly increased tumor destruction compared to PDT with Photofrin in dextrose (P = 0.007), whereas no difference in tissue damage was detected in nontumored brain with or without liposome carrier. Photofrin uptake was also significantly elevated in the liposome vehicle group compared to the dextrose (P < 0.05) group. CONCLUSIONS: Our data suggest that Photofrin encapsulated in a liposome may enhance the PDT treatment of human brain tumors.

Animals↗

PubMed1998

Photodynamic therapy using Photofrin in combination with buthionine sulfoximine (BSO) to treat 9L gliosarcoma in rat brain.

BACKGROUND AND OBJECTIVE: The reactive oxygen mechanisms associated with cell damage after photodynamic therapy (PDT) may be exploited to enhance tumor destruction. Pharmacological reduction of glutathione (GSH), an inhibitor of reactive oxygen species, can be induced by administration of buthionine sulfoximine (BSO). STUDY DESIGN/MATERIALS AND METHODS: BSO was administered in combination with Photofrin as the photosensitizer in order to promote PDT induced cell damage. Photofrin (12.5 mg/kg) or Photofrin with BSO (440 mg/kg) were administered to male Fischer rats (n = 27) containing an intracerebral 9L gliosarcoma or to non tumored rats. Brain tumor or non tumored brain was treated with an optical (632 nm) irradiance of 140 J/cm2. Animals were sacrificed 24 h after PDT and the volume of tissue necrosis was measured. Brain Photofrin concentration was measured in tumor and in non tumor bearing animals administered either Photofrin or Photofrin with BSO. GSH was measured by high pressure liquid chromatography in tumor and homologous non tumor tissue in animals administered BSO or control solution. RESULTS: The volume of tumor necrosis was significantly greater in animals administered Photofrin and BSO than in animals administered only Photofrin. No differences were detected in non tumored tissue damage between groups. No differences in Photofrin concentration were detected in tumored or nontumored animals between animals administered Photofrin and animals administered Photofrin and BSO. BSO administration preferentially and significantly reduced GSH in tumor compared to non tumor tissue. CONCLUSIONS: Our data suggest that BSO administration preferentially augments tumor destruction without compromising non tumored tissue.

Animals↗