Biomedical subjects

M Chopp

Publications and source records attributed to M Chopp.

At least 163 records · Page 9Linked to original sources

PubMed1992

Immunocytochemical detection of the 72-kDa heat shock protein in halothane--induced hepatotoxicity in rats.

Liver sections removed from phenobarbital induced rats 24 to 48 hours after a 2 hour exposure to 1.0% halothane with 10% oxygen and subjected to immunocytochemical treatment showed evidence of centrilobular damage as well as evidence of the production of a protein which has immunoreactivity with anti HSP 72 antibodies. The cells showing evidence of immunoreactivity were within the area of the centrilobular lesion. The level of immunoreactive protein varied directly with the intensity of the lesion. Liver sections from animals treated with phenobarbital alone, phenobarbital plus 10% oxygen, or phenobarbital plus 20% oxygen and 1.0% halothane all were without lesions as well as the immunoreactive protein.

Animals↗

PubMed1992

The effect of hypothermia on transient middle cerebral artery occlusion in the rat.

We investigated the effect of moderate whole body hypothermia (30 degrees C) on transient middle cerebral artery occlusion (MCAO) in the rat. Male Wistar rats were subjected to 2 h of ischemia by inserting a suture into the lumen of the internal carotid artery and occluding the origin of the MCA. Experimental groups were (a) MCAO induced at 37 degrees C body temperature (n = 15); (b) 30 degrees C body temperature induced prior to ischemia and maintained for 2 h of MCAO and 1 h of reperfusion (n = 12); and (c) MCAO with regional brain and body temperatures measured in normothermic (n = 3) and hypothermic MCAO rats (n = 2). Histopathological evaluation was performed 96 h after reperfusion. All normothermic MCAO animals exhibited ischemic infarct involving the ipsilateral cortex and basal ganglia with infiltration of neutrophils, macrophages, and microvascular proliferation. Hypothermic MCAO animals exhibited minor ischemic damage ranging from selective neuronal injury to small focal areas of infarct with minimal inflammatory response. Our data demonstrate that transient ischemia induced by using the intra-arterial suture method to occlude the MCA results in a reproducible brain lesion and that moderate hypothermia has a profound protective effect on the brain injury after transient MCAO.

Animals↗

PubMed1992

Photoactivated Photofrin II: astrocytic swelling precedes endothelial injury in rat brain.

Light activation of circulating hematoporphyrin derivatives has been used in the treatment of selected brain tumors. The effects of this photodynamic therapy on the non-neoplastic, adjacent brain tissue are incompletely characterized. We studied in adult Fisher rats the time-dependent (1 hour to 7 days) effects of photoactivated Photofrin II. Our protocol was comparable to that used in the treatment of human brain tumors. Structural and functional changes spread from the treatment surface and from the center to the periphery to involve the entire cerebral cortex exposed under a 5 mm craniectomy. The sequential changes spreading from the surface to the deepest cortical layer involve first astrocytes (1 hour), then endothelial cells and, ultimately, neurons. Thrombi were first noted in the microvasculature after 18 hours and coagulation necrosis of the entire area at risk occurred only after 48 hours. The results suggest that the photosensitizing agent crosses the intact blood-brain barrier and enters the astrocytic compartment where it becomes cytotoxic upon light activation. A comparison between the focal brain lesions of photodynamic therapy and those induced by middle cerebral artery occlusion suggests that cell damage evolves along different paths in these two forms of brain injury.

Animals↗

PubMed1992

Effects of light beam size on fluence distribution and depth of necrosis in superficially applied photodynamic therapy of normal rat brain.

The light fluence distributions of 632.8 nm light incident on the exposed surface of normal rat brain in vivo have been measured using an interstitial, stereotactically-mounted optical fiber detector with isotropic response. The dependence of the relative fluence rate on depth and the spatial distribution of fluence were compared for incident beam diameters of 3 and 5 mm. The fluence rate at depth of 1-6 mm along the optical axis within the brain tissue was approximately 70% greater for a 5 mm diameter beam than for a 3 mm beam, at the same incident fluence rate, although the plots of the relative fluence rate vs depth were parallel over the depth range 1-6 mm. The depths of necrosis resulting from photodynamic treatment of brain tissue using the photosensitizer Photofrin and irradiation by 632 nm light with 3 and 5 mm incident beams were also measured. The observed difference in necrosis depths was consistent with the measured difference in fluence. The importance of beam size in photodynamic treatment with small diameter incident light fields is discussed.

Animals↗

PubMed1992

Hypothermia reduces 72-kDa heat-shock protein induction in rat brain after transient forebrain ischemia.

BACKGROUND AND PURPOSE: We examined the influence of concurrent moderate hypothermia (30 degrees C) and transient forebrain ischemia on the induction of 72-kDa heat-shock protein and neuronal damage in male Wistar rats. SUMMARY OF REPORT: Experimental groups included: normothermic with 8 minutes of transient forebrain ischemia (group 1, n = 7), hypothermic without ischemia (group 2, n = 9), and hypothermic (30 degrees C) with 8 minutes of transient forebrain ischemia (group 3, n = 5). Intense 72-kDa heat-shock protein immunoreactivity was demonstrated in rat forebrain 48 hours after induction of normothermic forebrain ischemia (group 1); it was not detected in the brain of animals subjected to hypothermia without ischemia (group 2), and hypothermia during ischemia (group 3) significantly inhibited its expression compared with that in normothermic ischemia animals (group 1). CONCLUSIONS: These observations suggest that 72-kDa heat-shock protein induction is not the mechanism by which moderate hypothermia protects against ischemic cell damage.

Animals↗

PubMed1992

Distribution of the 72-kd heat-shock protein as a function of transient focal cerebral ischemia in rats.

BACKGROUND AND PURPOSE: The significance and physiological implications of the expression of the 72-kd heat-shock protein in ischemic tissue are unknown. To enhance our understanding of the relation between ischemic cell damage and 72-kd heat-shock protein expression, we evaluated the cellular expression and the anatomic distribution of 72-kd heat-shock protein in conjunction with the morphological analysis of rat brain, as a function of the duration of a single arterial occlusion. METHODS: Adult Wistar rats were subjected to graded transient middle cerebral artery occlusion (for a duration of 10, 20, 30, 60, 90, and 120 minutes and sham; n = 4 per group). Forty-eight hours after reopening the artery, brain tissue sections were analyzed to determine the extent of neuronal damage (hematoxylin and eosin staining), the extent of astrocytic reactivity (immunohistochemistry, using anti-glial fibrillary acidic protein), and the distribution of 72-kd heat-shock protein (immunohistochemistry, using a monoclonal antibody to 72-kd heat-shock protein). RESULTS: We found that 72-kd heat-shock protein was sequentially expressed in morphologically intact neurons, microglia, and endothelial cells with increasing duration of ischemia; 72-kd heat-shock protein immunoreactivity was not detected in astrocytes. The duration of ischemia required to evoke a 72-kd heat-shock protein response in neurons was dependent on the anatomic site and followed a pattern of increasing neuronal sensitivity to ischemic cell damage with duration of ischemia: 72-kd heat-shock protein and neuronal damage were sequentially detected in the caudate putamen, globus pallidus, cerebral cortex, amygdala, and hippocampus with increasing duration of ischemia. With ischemia of long duration (greater than or equal to 90 minutes), neurons expressing 72-kd heat-shock protein were localized to a zone peripheral to the severely damaged ischemic core. CONCLUSIONS: These studies suggest that 1) the expression of 72-kd heat-shock protein in neurons precedes the development of ischemic cellular alterations detectable by conventional hematoxylin and eosin light microscopy methods; 2) there is a hierarchy of cell types and anatomic sites that express 72-kd heat-shock protein, and this hierarchy reflects cellular and anatomic vulnerability to ischemic cell damage; and 3) 72-kd heat-shock protein induction in neurons bordering a necrotic ischemic core may be the morphological equivalent of the ischemic penumbra.

Animals↗

PubMed1992

Magnetoencephalography of focal cerebral ischemia in rats.

BACKGROUND AND PURPOSE: The purpose of this study was to use magnetoencephalography to record magnetic field changes in the brain during middle cerebral artery occlusion. METHODS: A direct-current electrocorticogram (two channels) and a direct-current magnetoencephalogram (seven channels) were simultaneously recorded from five rats subjected to middle cerebral artery occlusion for 1-2 hours. RESULTS: Direct-current electrocorticographic and direct-current magnetoencephalographic signal deflections were observed after the onset of middle cerebral artery occlusion and occurred repeatedly throughout the ischemic period, with a mean +/- SD time interval of 12 +/- 5 minutes. A one-to-one correspondence of the electrocorticographic and magnetoencephalographic signal deflections was demonstrated. CONCLUSIONS: Direct-current magnetoencephalography can provide a new noninvasive technique for studying depolarization and/or spreading depression in focal cerebral ischemia.

Animals↗

PubMed1992

The effect of light fluence rate in photodynamic therapy of normal rat brain.

This paper reports the effect of incident light fluence rate on the depth to which necrotic lesions are produced by photodynamic therapy (PDT) in the brains of normal Fisher rats. The rats were injected intraperitoneally with Photofrin (12.5 mg kg-1) 48 h prior to PDT with a fixed incident fluence of 35 J cm-2. The treatment was performed at 10, 50, 100, and 200 mW cm-2 and also in a periodic manner (30 s "on" at 100 mW cm-2, 30 s "off"). The depth to which necrosis occurred was determined 24 h after treatment by microscopic examination of tissue sections. No differences were found in the depth to which necrosis was produced by any of the five irradiation schedules. This finding is discussed in the context of other published dose-rate experiments.

Animals↗

PubMed1992

Neuronal injury after photoactivation of photofrin II.

Photodynamic therapy has been used in the management of patients with malignant brain tumors even though the effects of this form of treatment on the adjacent normal brain are incompletely characterized. The authors examined, in sequential experiments, morphologic alterations affecting the cerebral cortex in rats injected with Photophrin II and exposed to light. Initially, minimal cell alterations, including cisternal swelling of both endoplasmic reticulum and Golgi apparatus, involved only neurons located in the superficial layers of the cerebral cortex exposed to light. These changes spread, over a period of several hours, from the surface to the bottom of the cortex and eventually involved the entire cortical segment exposed to light. The earliest structural signs of lethal injury to neurons developed over a period of 18 hours after porphyrins had been photoactivated and astrocytes had been severely damaged. Signs of lethal injury to neurons included an increase in the number of mitochondrial cristae and appearance of amorphous electron-dense deposits within swollen mitochondria. The appearance of these alterations was followed by segregation of intracytoplasmic organelles and fragmentation of nuclear and cytoplasmic membranes. The tissue changes, including those involving neurons, eventually progressed to coagulation necrosis at 48 hours. These observations suggest that prophyrins injected to rats (48 hours before photoactivation) cause swelling and necrosis of astrocytes. This is followed by neuronal necrosis, which appears at two time intervals; the initial neuronal necrosis occurs after the astrocytic disintegration. A second type of neuronal alteration appears after microvessels become thrombosed and ischemia is likely to develop.

Animals↗

PubMed1992

Variations in pO2 and pH response to hyperthermia: dependence on transplant site and duration of treatment.

It has been clearly established that changes in intratumor pO2 and pH occur following hyperthermia, and it has been hypothesized that these changes may, in some way, be related to the ultimate response (i.e., cure) of the lesion. The purpose of this study was twofold: first, to examine the changes in intratumor pH during the course of a hyperthermia treatment at biologically related end point "doses"; second, to examine the response of pO2 after treatment in a different lesion transplant site. During hyperthermia treatment of the tumor transplanted in the leg, intratumor pH was found to drop from a control value of 6.74 +/- 0.17 to 6.47 +/- 0.13 within 15 min following the start of treatment. The values then remained relatively constant throughout the remainder of the treatment (either 1 or 2 h at 43.5 degrees C). Following the subcurative (10% tumor cures at 30 days; 60 min at 43.5 degrees C) treatment the pH began to rise immediately, while after the higher dose (60% tumor cures at 30 days; 120 min at 43.5 degrees C) a slight rise in pH was followed by a continuous drop in pH for up to 4 h, as we have reported previously. Oxygen response in the two transplant sites (leg and flank) was found to be remarkably different even though the tumor cure rate was identical for a given hyperthermia "dose" in terms of time and temperature. In the leg, only very low levels of oxygen can be measured in the tumor 24 h after treatment with either "dose" studied (all measured pO2 values less than or equal to 5 mm Hg). In the flank, the tumor response is dependent on hyperthermia "dose." Only 28% of measured oxygen values are less than or equal to 5 mm Hg 24 h following a subcurative "dose," while 4 h following the higher "dose" there is a nonsignificant trend toward hypoxia (approximately 65% of values less than or equal to 5 mm Hg) with a subsequent shift toward reoxygenation. These latter observations are contrary to results reported previously and tend to contradict some current theories regarding the physiological mechanisms associated with hyperthermia treatment.

Adenocarcinoma↗

PubMed1991

Magnetic fields associated with anoxic depolarization in anesthetized rats.

We have performed simultaneous measurements of the DC-magnetoencephalogram (DC-MEG) and DC-electrocorticogram (DC-ECoG) in rats (n = 6) subjected to 90 s of reversible anoxia. The onset of major shifts of electric and magnetic signals occurred at 52 +/- 18 (S.D.) and 68 +/- 14 (S.D.), respectively, and reached a peak at 83 +/- 27 and 102 +/- 19 (S.D.) s, respectively, after termination of mechanical ventilation. DC-ECoG signal deflections were always associated with DC-MEG deflections. The time of onset and peak signals in both DC-MEG and DC-ECoG changes caused by asphyxia were highly correlated (r + 0.83, 0.94; P less than 0.05, 0.001; respectively). Our observations suggest that the non-invasive technique of DC-MEG is reliable and may provide insight into the mechanisms of anoxic cerebral depolarization.

Anesthesia, General↗

PubMed1991

Neuronal injury and expression of 72-kDa heat-shock protein after forebrain ischemia in the rat.

We evaluated the relationship between the induction of the 72-kDa heat-shock protein (hsp 72) and the presence of necrotic neurons in the rat hippocampus, 48 h after an 8-min episode of forebrain ischemia in eight rates. Hsp 72 was detected using the monoclonal antibody C92 on vibratome brain tissue sections. Hematoxylin and eosin (H&E) staining on adjacent paraffin-embedded sections was used to determine histopathological features. All morphologically intact CA1/2 neurons, 70% of which are destined to become necrotic 7 days after ischemia, exhibited intense hsp 72 staining, while necrotic or damaged neurons were devoid or low in hsp 72. Hsp 72 was also detected in CA3 neurons destined to survive 7 days after ischemia. Blood vessels positive for hsp 72 were detected in focal brain regions, in which severely damaged neurons were either devoid or low in hsp 72 staining. Occasional glial cells expressed hsp 72 in both normal and damaged brain regions. Hsp 72 response to a transient forebrain ischemia seemingly reflects differences in the selective ischemic vulnerability of CA1/2 and CA3 neurons. Further, the presence of hsp 72 within a neuron is likely only a marker of stress and is not necessarily indicative of eventual neuronal survival.

Animals↗

PubMed1991

Chronic changes in the brain Mg2+ concentration after forebrain ischemia in the rat.

Brain Mg2+ ion concentrations, [Mg2+], were evaluated in three groups of animals subjected to either 8 minutes (n = 10), or 12 minutes (n = 10) of near-complete forebrain ischemia, or sham operation (n = 10), from their 31P NMR spectra. No significant differences were observed in [Mg2+] among sham operated animals prior to or at any time point after surgery. In the 8-min ischemia group, mean [Mg2+] were significantly lower at 48 (0.28 +/- 0.06 mM, p = 0.014) and 72 (0.29 +/- 0.07 mM, p = 0.005) hours post-ischemia when compared to their mean pre-ischemia levels (0.39 +/- 0.08 mM). [Mg2+] was restored to pre-ischemia values at 96 hours after induction of ischemia. In the 12 min ischemia group, [Mg2+] were lower at all time points post-ischemia when compared to their pre-ischemia levels. Our data shows that forebrain ischemia causes a chronic decline of cerebral Mg2+ concentration, and the observed reduction of this cation can be partially attributed to concurrent brain tissue alkalosis.

Animals↗

PubMed1991

1H magnetic resonance imaging of normal brain tissue response to photodynamic therapy.

1H Magnetic resonance imaging (MRI) was used to study the effects of photodynamic therapy (PDT) on normal rat brain (n = 5) using T1-, T2-, diffusion-, and proton density (rho)-weighted images. Rats received intraperitoneal injections of 12.5 mg/kg of Photofrin II, and 48 hours later the dural area over the frontal cortex was treated with 35 J/cm2 of light (632 +/- 1 nm). The T1-, T2-, and diffusion-weighted images revealed an evolving high contrast region of brain that corresponded to the PDT-treated area. Lesioned brain exhibited significant increases in T1 and T2 relaxation times at 1 day (P less than 0.01) and 3 days (T1, P = 0.018; T2, P less than 0.01) after treatment, compared with the contralateral equivalent volume of nonlesioned brain. Water proton diffusion coefficient (DW) in the lesioned area decreased at 1 day (P = 0.026) and increased at 3 days (P = 0.012) compared with nonlesioned brain. An increase in the proton density ratio (rho D/rho O) from PDT (rho D) versus nonlesioned side (rho O) was found 3 days after PDT treatment (P = 0.03). The data indicate that the biophysical parameters obtained from magnetic resonance imaging scans, T1, T2, DW, and proton density, can be used to monitor changes in an evolving photochemically induced lesion.

Animals↗

PubMed1991

Depth measurements and histopathological characterization of photodynamic therapy generated normal brain necrosis as a function of incident optical energy dose.

The response of normal brain to photodynamic therapy (PDT) was investigated in 62 Fisher rats. The animals were injected i.p. with Photofrin II (12.5 mg/kg). Forty-eight hours following injection, an area of dura 5 mm in diameter over the frontal cortex was photoactivated with red light (632 +/- 2 nm) at 100 mW cm-2, with no contributing thermal increases, at optical energy doses ranging from 1-140 J cm-2 from an argon-pumped dye laser. Appropriate controls were also prepared. Brain tissue samples for histological analysis were taken 24 h following PDT treatment. Maximum lesion depth perpendicular to the pial brain surface, was measured using an eyepiece micrometer. Lesions of increasing depth were generated as the incident optical energy dose was increased. Fitting the depth of necrosis to a natural log dependence of incident optical dose yielded a slope of 0.83 mm/ln J cm-2 (r2 = 0.99). The intercept of 1.47 J cm-2 indicated the energy dose below which no normal tissue damage would occur at the incident laser intensity of 100 mW cm-2. The smallest lesions consisted almost exclusively of isolated neuronal injury and neuropil vacuolation, suggestive of an early ischemic lesion. Damage at the upper energy levels (35-140 J cm-2) consisted of complete coagulative necrosis identical to that induced by an arterial occlusion. The existence of viable tissue alongside neurons in various stages of necrosis at low energy levels (less than 35 J cm-2) is suggestive of reversible injury and possibly clinically relevant treatment levels.

Animals↗

PubMed1991

In vivo 31P NMR study of combined hyperthermia and photodynamic therapies of mammary carcinoma in the mouse.

Although the sequence and time interval effects of combined photodynamic therapy (PDT) and hyperthermia tumor treatments have been studied using survival curves, tumor regrowth, and cloning assays, the metabolic response to combined treatment measured by nuclear magnetic resonance (NMR) spectroscopy has not yet been clarified. In this study, mammary carcinoma in the flank of C3H mice was subjected to PDT (12.5 mg/kg Photofrin II, 632 +/- 1 nm at 200 J/cm2) and water bath hyperthermia (43.5 degrees C, 30 min) with no delay or 4 h delay between treatments. In vivo 31P-NMR spectroscopy was employed to measure energy metabolism and pH of the tumors before and serially after treatment for up to 1 week. The data revealed significant differences in the time course of high energy phosphate levels between treatment combinations, which may reflect the biological effectiveness of the combined treatments. Our observations indicate that 31P-NMR spectroscopy can be used to evaluate the metabolic response of tumors to treatment with combined PDT and hyperthermia.

Animals↗

PubMed1991

Mild hypothermic intervention after graded ischemic stress in rats.

We investigated the effect of mild (34 degrees C) postischemic hypothermia on hippocampal neuronal damage in 43 rats as a function of the duration of forebrain ischemia. Two temperatures and two durations were investigated. In two normothermic groups ischemia lasted 8 (n = 15) and 12 (n = 10) minutes, respectively. In two hypothermic groups ischemia lasted 8 (n = 9) and 12 (n = 9) minutes, respectively, and was followed immediately by the lowering and maintenance of rectal temperature to 34 degrees C for 2 hours. Seven days after the ischemic insult, the rats were sacrificed and the brains were prepared for histologic analysis; the percentage of necrotic neurons among the total neuronal population in selected CA1/2 sectors of the hippocampus was determined. There was a significant decrease in the percentage of necrotic neurons in the central (77.5% versus 55.5%, p = 0.006) and lateral (62.5% versus 38.9%, p=0.005) areas and in the overall CA1/2 sector of the hippocampus (71.8% versus 52.2%, p = 0.008) for the 8-minute hypothermic group compared with the 8-minute normothermic group. In contrast, no differences were detected in any area of the hippocampus between the 12-minute normothermic and the 12-minute hypothermic groups (p = 0.29-0.49). Our data indicate that mild postischemic whole-body hypothermia ameliorates neuronal survival when ischemia lasts 8 minutes but not 12 minutes.

Animals↗

PubMed1991

Temporal evolution of ischemic damage in rat brain measured by proton nuclear magnetic resonance imaging.

We studied the effect of focal cerebral ischemia on the "state" of brain water using proton nuclear magnetic resonance imaging. Focal cerebral ischemia was induced in five halothane-anesthetized rats via tandem occlusion of the left common carotid artery and the left middle cerebral artery. The proton transverse relaxation time, the proton density, and the water diffusion coefficient were measured at various times from the same region of brain tissue from 1.5 to 168 hours after occlusion. Early measurements indicated significant changes in the transverse relaxation time (p = 0.004) and water diffusion coefficient (p = 0.002) of ischemic brain tissue compared with a homologous region from the contralateral hemisphere. However, the transverse relaxation time, proton density, and water diffusion coefficient in ischemic brain tissue showed different temporal evolutions over the study period. Diffusion coefficient weighting was superior to relaxation time and proton density weighting for the visualization of early cerebral ischemia. Our data suggest that nuclear magnetic resonance imaging is sensitive in detecting changes in proton-associated parameters during early cerebral ischemia and confirm significant changes (p less than or equal to 0.01) in the temporal evolution of transverse relaxation times, proton densities, and diffusion coefficients following middle cerebral artery occlusion.

Animals↗