Toxicity of photodynamic therapy with photofrin in the normal rat brain

The widespread acceptance of photodynamic therapy (PDT), a potential adjuvant brain tumor therapy under clinical evaluation since 1980, has been partially restrained by its potential toxicity toward normal brain tissue. This study examined PDT-produced injury of normal rat brain as a function of photosensitizer dose. Brain injury was characterized by correlating measurements of the area of cerebral edema using T2-weighted magnetic resonance images, measurement of brain water content at the lesion site, microscopic examination of histological sections through the PDT lesion, and by evaluation of the area of blood brain barrier (BBB) disruption using computerized morphometric analysis of the region of Evans blue (EB) dye-labelled albumin extravasation. Monochromatic red light (630 nm) was delivered intracere-brally using a 5-mm-long cylindrical, diffusion-tip optical fiber at a constant energy dose of 15 joules. A Photofrin dose of 2 mg/kg of body weight produced a transient breakdown in the blood brain barrier around the site of the implanted optical fiber demonstrated by magnetic resonance imaging (MRI), extravasation of EB dye and pallor on hematoxylin and eosin-stained microscopic tissue sections. A much larger area of BBB disruption was seen at a dose of 4 mg/kg of Photofrin, and this drug dose resulted in significant permanent brain injury. In this model, a Photofrin dose of 4 mg/kg body weight is not tolerated by the normal brain. © 1994 Wiley-Liss, Inc.     

The role of bradykinin in the etiology of vasogenic brain edema and perilesional brain dysfunction

Summary The feline infusion model of brain edema was used to evaluate the role of bradykinin in the etiology and pathophysiology of vasogenic brain edema. Bradykinin (3 or 90 ug in 600 L saline) did not alter normocapnic regional cerebral blood flow (rCBF) nor induce specific changes in either the somatosensory (SEP) or motor (MEP) evoked potentials. The mean increases in ICP (from 4.5 to 16.1 mmHg) and peri-infusion white matter water content (from 69.4 to 79.8 ml/100 g tissue), mean decrease in lumped craniospinal compliance (from 0.040 to 0.014 ml/mmHg) and local histological changes were all similar to those after 600 L saline infusion. The interstitial bradykinin infusion caused focal blood-brain-barrier (BBB) opening to Evans Blue dye and was chemotaxic for granulocytes. After the infusion there was a global loss of rCBF CO₂ reactivity but there was no ischemia at normocapnia. These results show that bradykinin in brain edema fluid, at concentrations greater than those found in neuropathological conditions, can open the BBB of normal cerebral parenchymal capillaries and cause vascular dysregulation. In neuropathological conditions bradykinin may therefore potentiate formation of vasogenic brain edema but does not contribute to perilesional brain dysfunction.This work was presented in part at the Brain Edema VIII Meeting, Berne, Switzerland, June, 1990.     

Low power interstitial Nd-YAG laser photocoagulation in normal rabbit brain

The safe, effective, clinical application of interstitial laser irradiation to destroy brain tumour tissue requires a knowledge of the relation of the extent of laser-induced (thermal) necrosis to the delivered laser power and total energy, and to time post-irradiation. We have conducted experiments to determine these relationships in normal rabbit brain. Irradiation by a Nd-YAG laser (1064 nm), at powers of 0.5–3.0 W and exposures of 200–1333 s produced well-defined necrotic lesions whose size increased with both the power and the total energy delivered. Lesions of 6 mm diameter made by 0.75 W for 1000s were well tolerated by animals allowed to recover from anaesthesia following irradiation. The diameter of the lesion was greatest at 48 h after irradiation. Following evolution of a characteristic healing response to necrosis in brain, the residual damage at 4 weeks was no greater in volume than that of the acute lesion. The results suggest that low power interstitial Nd-YAG laser photocoagulation in brain can be reliably and safely effected.     

Treatment of cold injury-induced brain edema with a nonspecific matrix metalloproteinase inhibitor MMI270 in rats

Blood-brain barrier (BBB) disruption is a critical event leading to vasogenic brain edema and secondary brain damage after cold injury-induced brain trauma. Matrix metalloproteinases (MMPs), a family of proteolytic enzymes which degrade the extracellular matrix, are implicated in BBB disruption in this model. The purpose of this study was to examine the effects of MMI270 (N-hydroxy-2(R)-[(4-methoxysulfony) (3-picolyl)-amino]-3-metylbutaneamide hydrochloride monohydrate), a synthetic nonspecific MMP inhibitor, on cold injury-induced brain edema in rats. Cold injury was induced by applying a copper probe cooled with liquid nitrogen on the parietal skull for 30 sec in 38 rats. Treatment with MMI270, a bolus injection at a dose of 30 mg/kg, was started immediately after the induction of cold injury and was continued for 24 h at a dose of 40 mg/kg/day using an intraperitoneal osmotic minipump (n = 7). In the untreated control group (n = 7), rats were administered a vehicle and implanted with a vehicle-containing osmotic pump. Two percent Evans Blue (EB) in saline (1 mL/kg) was administrated intravenously immediately after the cold injury in another group of rats, six of which were untreated and six of which were treated with MMI270 at the above dose. At 24 h after the cold injury, the brain water content and the BBB permeability to EB were determined. To assess the protective effect of MMI270 on secondary brain lesion after the cold injury, the MMI270-treated rats received a bolus injection at a dose of 30 mg/kg, followed by a continuous administration of MMI270 for 7 days at a dose of 40 mg/kg/day using an osmotic minipump (n = 6). In the untreated control group (n = 6), the rats were administered the vehicle and implanted with a vehicle-containing osmotic pump. At 7 days after cold injury, the secondary brain lesion was assessed using hematoxylin and eosin (H-E) staining. Compared with the untreated control group, treatment with MMI270 significantly reduced the brain water content in the ipsilateral core and intermediate areas (p < 0.05 and p < 0.01) and protected the BBB integrity to EB in the ipsilateral core area (p < 0.05) at 24 h after the cold injury. The secondary lesion was significantly smaller in the MMI270-treated animals compared with the untreated animals (p < 0.05) a 7 days after the cold injury. O kur results indicate that treatment with MMI270 in rats exhibits protection in acute brain edema formation and secondary brain damage by attenuating the BBB permeability after cold injury.     

Neuroprotective effects of nimodipine and MK-801 on acute infectious brain edema induced by injection of pertussis bacilli to neocortex of rats

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高功率微波辐射对大鼠血睾屏障的影响

目的:探讨高功率微波(HPM)辐射对血睾屏障(BTB)结构与功能的影响。方法:166只二级雄性Wistar大鼠经0、10、30、100mW/cm2HPM辐射5min,于辐射后6h,1、3、7、14d,采用镧醛(含20g/L硝酸镧,50mg/L戊二醛)心脏灌注和2%伊文思蓝(EB)尾静脉注射,经光镜、电镜和激光共聚焦显微镜(LSCM)观察BTB结构变化及硝酸镧和EB分布。结果:10～100mW/cm2HPM辐射后大鼠睾丸间质水肿伴血管充血、出血;生精小管近腔室内血浆蛋白和红细胞积聚,病变在辐射后6h出现,1～7d明显加重,范围扩大,14d有所减轻;30、100mW/cm2辐射组明显重于10mW/cm2辐射组。电镜下见各辐射组硝酸镧颗粒于近腔室内精母细胞、精子细胞和精子之间沉淀。LSCM观察见生精小管近腔室内弥散分布的EB颗粒。结论:HPM辐射可引起BTB结构破坏,通透性增加。     

An experimental study on the occurrence of brain edema after retrograde cerebral perfusion

To assess the safety of retrograde cerebral perfusion, the occurrence of brain edema after this procedure was investigated. Twenty-eight adult mongrel dogs were divided into three groups that underwent the following treatments: antegrade perfusion (group 1, n=9); retrograde perfusion alone (group 2, n=11); or tetrograde perfusion with drugs (manuitol, thiopental sodium, and methylprednisolone; group 3, n=8). After 90 minutes of cerebral perfusion at 20°C of the pharyngeal temperature, evans blue (EB) was administered to check for disruptions of the blood-brain-barrier (BBB) and brain tissue water content was measured. Intracranial pressure after cerebral perfusion was markedly higher in group 2 than in group 1 (26.4 ± 9.4 vs. 11.2 ± 3.6 mmHg), and brain tissue water content was also significantly higher in group 2 than in group 1 (80.7 ± 2.0 vs. 77.8 ± 0.9%). these data suggested that brain edema was more prominent after retrograde perfusion than after antegrade perfusion. The extent of EB to brain tissue was greater in group 2 than in group 1 (169.8 ± 97.7 vs. 54.7 ± 31.5 μg/dl). The BBB was highly disrupted in group 2 and vasogenic edema appeared after retrograde cerebral perfusion. Maximum intracranial pressure, brain tissue water content and EB concentration were significantly lower in group 3 than in group 2, and did not differ significantly between group 3 and 1. Administration of pharmacologic agents suppressed edema formation and extravasation of EB. We conclude that 90 minutes of retrograde cerebral perfusion at 20°C of the pharyngeal temperature causes brain edema and disrupts the BBB in a manner different from that associated with antegrade perfusion. Mannitol, thiopental sodium, and methylprednisolone prevent these phenomena, indicating that pharmacologic intervention may improve the safety of retrograde cerebral perfusion.     

异丙酚对老年及成年大鼠血脑屏障通透性的影响

目的探讨异丙酚对老年及成年大鼠血脑屏障通透性的影响。方法用依文氏蓝染色及光镜、电镜方法,观察老年及成年大鼠静脉恒速分别输入高浓度和低浓度异丙酚后,其血脑屏障通透性和脑形态结构的变化。结果(1)输入高浓底和低浓度异丙酚1h对老年及成年大鼠血脑屏障通透性无影响;(2)HE染色光镜观察各组脑结构均正常;(3)电镜下见各组的镧离子均在血管腔内,脑组织结构正常。结论能引起脑电图爆发抑制且循环改变不大剂量的异丙酚,对老年及成年大鼠血脑屏障通透性和脑组织结构均无明显影响。     

Altered Expression of Zonula Occludens-2 Precedes Increased Blood–Brain Barrier Permeability in a Murine Model of Fulminant Hepatic Failure

Brain edema secondary to increased blood–brain barrier (BBB) permeability is a lethal complication in fulminant hepatic failure (FHF). Intact tight junctions (TJ) between brain capillary endothelial cells are critical for normal BBB function. However, the role of TJ in FHF has not been explored. We hypothesized that alterations in the composition of TJ proteins would result in increased BBB permeability in FHF. In this study, FHF was induced in C57BL/6J mice by using azoxymethane. BBB permeability was assessed with sodium fluorescein. Expression of TJ proteins was determined by Western blot, and their cellular distribution was examined using immunofluorescent microscopy. Comatose FHF mice had significant cerebral sodium fluorescein extravasation compared with control and precoma FHF mice, indicating increased BBB permeability. Western blot analysis showed a significant decrease in zonula occludens (ZO)-2 expression starting in the precoma stage. Immunofluorescent microscopy showed a significantly altered distribution pattern of ZO-2 in isolated microvessels from precoma FHF mice. These changes were more prominent in comatose FHF animals. Significant alterations in ZO-2 expression and distribution in the tight junctions preceded the increased BBB permeability in FHF mice. These results suggest that ZO-2 may play an important role in the pathogenesis of brain edema in FHF.     

七氟醚对成年及老年大鼠血脑屏障通透性的影响

目的：探讨七氟醚对成年及老年大鼠血脑屏障通透性的影响。方法：用依文氏蓝（EB）染色及光镜、电镜观察成年及老年大鼠吸入1MAC或1.5MAC七氟醚对血脑屏障通透性及神经结构的影响。结果：吸入两种浓度七氟醚的成年及老年大鼠除松果体、后联合等缺乏血脑屏障的部位有轻至中度蓝染外,其它脑组织未见蓝染。HE染色光镜观察见各组脑结构正常。电镜下见各组镧离子均在血管腔内。结论：吸入1MAC或1.5MAC七氟醚1小时不增加成年或老年大鼠血脑屏障通透性,亦不改变脑组织形态和结构。     

Platelet-activating factor and progressive brain damage following focal brain injury

The effects of a platelet-activating factor (PAF) antagonist on brain edema, cortical microcirculation, blood-brain barrier (BBB) disruption, and neuronal death following focal brain injury are reported. A neodymium:yttrium-aluminum-garnet (Nd:YAG) laser was used to induce highly reproducible focal cortical lesions in anesthetized rats. Secondary brain damage in this model was characterized by progressive cortical hypoperfusion, edema, and BBB disruption in the vicinity of the hemispheroid lesion occurring acutely after injury. The histopathological evolution was followed for up to 4 days. Neuronal damage in the cortex and the hippocampus (CA-1) was assessed quantitatively, revealing secondary and progressive loss of neuronal tissue within the first 24 hours following injury. Pretreatment with the PAF antagonist BN 50739 ameliorated the severe hypoperfusion in 12 rats (increasing local cerebral blood flow from a mean +/- standard error of the mean of 40.5% +/- 8.3% to 80.2% +/- 7.8%, p less than 0.01) and reduced edema by 70% in 10 rats (p less than 0.05) acutely after injury. The PAF antagonist also reduced the progression of neuronal damage in the cortex and the CA-1 hippocampal neurons (decrease of neuronal death from 88.0% +/- 3.9% to 49.8% +/- 4.2% at 24 hours in the cortex and from 40.2 +/- 5.0% to 13.2% +/- 2.1% in the hippocampus in 30 rats; p less than 0.05). This study provides evidence to support progressive brain damage following focal brain injury, associated with secondary loss of neuronal cells. In this latter process, PAF antagonists may provide significant therapeutic protection in arresting secondary brain damage following cerebral ischemia and neurological trauma.     

Real-Time Monitoring of Blood–Brain Barrier Disruption Induced by Ultraviolet Laser Irradiation

Ultraviolet laser light of sufficient power can induce focal œdema in the brain. The formation of ultraviolet-induced vasogenic \kdema was monitored by observing real-time changes in the integrity of the blood–brain barrier. The brain surface of guinea-pigs injected with Evans blue was exposed to light from a continuous wave argon laser at 351 nm, delivered via an optical fibre. The integrity of the blood–brain barrier was evaluated by measuring surface reflectance using a separate probing light. The brain was then sectioned and examined using light and electron microscopy. Extravasation of Evans blue following vasodilatation was observed when the irradiation intensity was greater than 0.64 W/cm². The extent of glial and vascular damage could be correlated with the laser power. Irradiated vascular endothelium exhibited lipping at the tight junction, vacuolation and mitichondrial swelling. These results suggest that disruption of the blood–brain barrier induced by ultraviolet light is preceded by vasodilatation. Received for publication May 1997; accepted following revision September 1997.     

Effects of magnesium sulfate on traumatic brain edema in rats

svarietyofneuroprotectiveagentshavebeensynthesized .However ,besidessomeagentspresentlybeingevaluatedinclinicaltrails ,mostofthesecompoundshavelimitedclinicalusebecauseofneurotoxicityandbehavioralsideeffects .Recently ,severalstudiesdemonstratedthattraumaticinjurytothebraincausesadecreaseinmagnesiumconcentrationcorrelatedwithinjuryseverity .1Sincethen ,moreandmoreattentionhasbeen paidtoMgSO4 foritsneuroprotectiveeffects .Magnesiumsulfatehasbeenwidelyusedinclinicalpracticeforalmost 10 0 years.…     

Effects of magnesium sulfate on traumatic brain edema in ats

OBJECTIVE: To investigate the effects of magnesium sulfate on traumatic brain edema and explore its possible mechanism. METHODS: Forty-eight Sprague-Dawley (SD) rats were randomly divided into three groups: Control, Trauma and Treatment groups. In Treatment group, magnesium sulfate was intraperitoneally administered immediately after the induction of brain trauma. At 24 h after trauma, total tissue water content and Na(+), K(+), Ca(2+), Mg(2+) contents were measured. Permeability of blood-brain barrier (BBB) was assessed quantitatively by Evans Blue (EB) dye technique. The pathological changes were also studied. RESULTS: Water, Na(+), Ca(2+) and EB contents in Treatment group were significantly lower than those in Trauma group (P<0.05). Results of light microscopy and electron microscopy confirmed that magnesium sulfate can attenuate traumatic brain injury and relieve BBB injury. CONCLUSIONS: Treatment with MgSO4 in the early stage can attenuate traumatic brain edema and prevent BBB injury.     

脑损伤后不同时间给予高渗盐-羟乙基淀粉液的治疗效应

目的探讨在创伤性脑损伤后不同时间给予高渗盐-羟乙基淀粉液(HSH)对脑损伤的影响。方法选用SD大鼠64只,采用Feeney自由落体损伤模型,于伤后早期(伤后10min)和后期(伤后6h)分别经尾静脉注射HSH、生理盐水(4mg/kg),并据此分为四组,24h后处死动物,干湿重法测定脑组织含水量,伊文氏兰(EB)测定对血脑屏障的影响及应用流式细胞仪测定各组对损伤区周围皮质调亡的影响。结果伤后10minHSH10组的脑组织含水量和EB含量略高于NS10组,而皮层脑细胞调亡数明显低于NS10组(P<0.05);伤后6hHSH6组的脑组织含水量、EB含量和皮层脑细胞调亡数均明显低于NS6组(P<0.05);HSH6组的脑组织含水量、EB含量和皮层脑细胞调亡数均明显低于HSH10组(P<0.05)。结论脑损伤早期给予HSH会加重脑水肿,伤后6h给予HSH不会加重脑水肿;无论伤后早期还是晚期给予HSH均可减少皮层脑细胞调亡数,晚期给药效果更佳。     

Effect of Hyperosmotic Solutions on Human Brain Tumour Vasculature

Summary  Reversible opening of the blood-brain barrier (BBB) has been used to increase delivery of chemotherapeutic agents into brain tumours, but it is complicated and requires general anaesthesia. Without affecting the normal BBB, and avoiding the complications of BBB modification by hyperosmotic solution, we tried an adequate minimal BBB disruption in brain tumours. Although the effect of BBB disruption on normal brain has been described, there are no reports of the effect of an impaired BBB on microcirculation. In this study, four patients underwent surgical resection of a glioblastoma multiforme (GM; n=1), astrocytoma (n=2), or metastatic brain tumour (n=1). Epicerebral microcirculation was observed in the operative field. Serial fluorescein microangiograms of the tumour and peritumoural area were obtained before and after BBB disruption was introduced intra-operatively by retrograde infusion of mannitol introducing a catheter via the temporal superficial artery back to the carotid bifurcation. On the initial microangiogram, staining by the fluorescein dye was observed in the GM and metastatic tumour but not in the astrocytoma; no extravasation of fluorescein dye was observed in the peritumoural areas. After BBB disruption, fluorescein perfusion increased and extravasation of fluorescein dye from the venules was observed in the GM and the metastatic tumour and in the peritumoural area of both lesions; BBB disruption started from venules in the peritumoural area without affecting the normal brain. However, such effects were not observed in the astrocytomas after BBB disruption nor in normal brain tissue in any patient. It appears that the integrity of the BBB is less stable in the peritumoural area of GM and metastatic brain tumours than it is in astrocytomas or normal brain. Osmotic BBB disruption may offer a method for achieving global delivery of therapeutic agents to brain tumours and peritumoural areas.     

Relation between polyporphyrin distribution and blood brain barrier changes in the rat glioma model.

Photofrin (a polyporphyrin mixture) distribution in a rat glioma model was studied in relation to changes in the blood brain barrier (BBB). At selected intervals after intraperitoneal injection of Photofrin, the concentration of polyporphyrins (PP) and Evans Blue Dye, an indicator of BBB permeability, were determined for tumor, brain adjacent to tumor (BAT), and normal brain tissue. Contrary to earlier reports of maximal accumulation at 4-24 hours, tumor levels of PP increased throughout the 96 hour measurement period. During the early stages of tumor development, PP uptake by tumor appeared to be less correlated to BBB disruption. We conclude that passive diffusion through an incompetent BBB does not completely explain PP accumulation in tumor tissue.     

Hyperosmotic blood-brain barrier disruption in brains of rats with an intracerebrally transplanted RG-C6 tumor

To test the results of blood-brain barrier (BBB) disruption in the treatment of brain tumor, RG-C6 glioma was transplanted into the brains of rats. Intracarotid infusions of normal saline and hyperosmotic mannitol were then made, followed by intravenous injection of Evans blue dye plus albumin (EB, MW 68,000), horseradish peroxidase (HRP, MW 40,000), and 5-fluorouracil (5-FU, MW 130). Uptake of the drug and the consistency of drug levels in the normal brain and tumor varied widely among these three agents. Both EB and HRP penetrated the brain tumors but did not stain the normal brain tissues. After BBB opening, penetration of EB and HRP into the normal brain was drastically increased; however, the uptake of EB and HRP in the tumor was not increased. The concentration of 5-FU in the tumor was higher than that in the serum and, although it increased 1.5-fold after BBB opening, the increase was not statistically significant. Conversely, there was a progressive increase in concentrations of 5-FU in the tumor-free brain regions (p less than 0.05). These observations suggest that an intracarotid infusion of hyperosmotic mannitol may increase neurotoxicity because it allows greater delivery of anticancer drugs into the normal brain tissue than into the tumor tissues.     

In vitro analysis of human tooth pulp chamber temperature after low-intensity laser therapy at different power outputs

In vitro studies have provided conflicting evidence of temperature changes in the tooth pulp chamber after low-level laser irradiation of the tooth surface. The present study was an in vitro evaluation of temperature increases in the human tooth pulp chamber after diode laser irradiation (GaAlAs, λ = 808 nm) using different power densities. Twelve human teeth (three incisors, three canines, three premolars and three molars) were sectioned in the cervical third of the root and enlarged for the introduction of a thermocouple into the pulp chamber. The teeth were irradiated with 417 mW, 207 mW and 78 mW power outputs for 30 s on the vestibular surface approximately 2 mm from the cervical line of the crown. The highest average increase in temperature (5.6°C) was observed in incisors irradiated with 417 mW. None of the teeth (incisors, canines, premolars or molars) irradiated with 207 mW showed temperature increases higher than 5.5°C that could potentially be harmful to pulp tissue. Teeth irradiated with 78 mW showed lower temperature increases. The study showed that diode laser irradiation with a wavelength of 808 nm at 417 mW power output increased the pulp chamber temperature of certain groups of teeth, especially incisors and premolars, to critical threshold values for the dental pulp (5.5°C). Thus, this study serves as a warning to clinicians that “more” is not necessarily “better”.     

Nonhyperemic blood flow restoration and brain edema in experimental focal cerebral ischemia

The effect of suppression of postischemic reactive hyperemia on the blood-brain barrier (BBB) and ischemic brain edema after temporary focal cerebral ischemia was studied in cats under ketamine and alpha-chloralose anesthesia. Regional cerebral blood flow (rCBF) was measured by a thermal diffusion method and a hydrogen clearance method. The animals were separated into three groups. In Group A, the left middle cerebral artery (MCA) was occluded for 6 hours. In Group B, the MCA was occluded for 3 hours and then reperfused for 3 hours; postischemic hyperemia was suppressed to the preischemic level by regulating the degree of MCA constriction. In Group C, the MCA was occluded for 3 hours and reperfused for 3 hours without suppressing the postischemic reactive hyperemia. The brain was removed and cut coronally at the site of rCBF measurement. The degree of ischemic edema was assessed by gravimetry in samples taken from the coronal section and correlated with the degree of BBB disruption at the corresponding sites, evaluated by densitometric determination of Evans blue discoloration. The findings showed that 1) ischemic edema was significantly exacerbated by postischemic hyperemia during reperfusion in parallel with the degree of BBB opening to serum proteins, and 2) suppression of postischemic hyperemia significantly reduced the exacerbation of ischemic edema and BBB opening. These findings indicate that blood flow may be restored without significant exacerbation of postischemic edema by the suppression of postischemic hyperemia in focal cerebral ischemia.