Effects of adrenal cortical steroids and osmotic blood-brain barrier opening on methotrexate delivery to gliomas in the rodent: the factor of the blood-brain barrier.

The effect of adrenal cortical steroids and osmotic blood-brain barrier modification on methotrexate delivery to normal and glioma-bearing rats was studied. In animals with the avian sarcoma virus-induced glioma, osmotic blood-brain barrier modification resulted in significantly increased delivery of methotrexate to the tumor-bearing hemisphere (including the tumor, the brain around the tumor, and the brain distant to the tumor), compared to the nonmodified hemisphere or to control animals. The administration of adrenal steroids, followed by intracarotid methotrexate, resulted in slightly decreased chemotherapeutic agent (methotrexate) delivery to the tumor, the brain around the tumor, and the brain distant to the tumor. When adrenal steroids were given prior to barrier modification and methotrexate therapy, the level of methotrexate was significantly less in the tumor. These studies provide evidence that the blood-brain barrier exists in tumors and is a factor in drug delivery to tumors. Steroid administration greatly interferes with the enhancement of drug delivery to tumors that can be achieved with osmotic blood-brain barrier modification.     

不同时间微创颅内血肿清除对血脑屏障功能及预后影响的研究

目的 探讨不同时间颅内血肿微创清除术对高血压脑出血患者血脑屏障指数(BBB)、血清髓鞘碱性蛋白(MBP)及预后日常生活能力评分(ADL)的影响. 方法观察时间≤3.0 h 30例,3.1～8.0 h 32例,8.1～24.0 h 28例,＞24.0 h 22 例,对照分析其BBB、MBP及ADL的变化.结果 ≤3.0 h、3.1～8.0 h微创血肿清除术组BBB和MBP[(6.57±0.69)×10 3和(3.12±0.40)μg/L、(7.37±1.29)×10 3和(3.25±0.60)μg/L]均明显低于8.1～24.0 h、＞24.0 h组[(12.02±1.51)×10-3和(4.60±0.48)μg/L、(14.68±2.07)×10-3和(5.88±0.64)μg/L,Q＞13.8,P＜0.05];≤3.0 h,3.1～8.0 h微创血肿清除术组[(2.60±1.07)分、(3.06±0.91)分]均明显高于8.1～24.0h、＞24.0 h组[(4.00±0.67)分、(3.68±1.32)分,Q＞3.1,P＜0.05]. 结论≤8.0 h实施微创血肿清除术可减轻高血压脑出血患者细胞毒性对血脑屏障的损伤,从而减轻脑水肿,提高患者的生存质量.

Abstract：

Objective To explore the effects of minimally invasive removal of intracranial hematoma on blood-brain barrier (BBB) index, serum myelin basic protein (MBP) and activity of daily living (ADL) in hypertensive patients with cerebral hemorrhage.Methods Through observing 30cases operated within 3.0 hours, 32 case operated between 3. 1-8. 0 hours, 28 cases operated between 8. 1 to 24.0 hours and 22 cases operated over 24 hours, the changes of BBB index, serum MBP and ADL were analyzed. Results The BBB index and serum MBP were significantly lower in patients operated within 8. 0 hours than in patients operated over 8. 1 hours [≤3.0 hours group:(6.57±0.69)×10-3 and (3. 12±0.40)μg/L;3. 1-8.0 hours group: (7. 37±1.29)×10-3 and (3.25±0.60)μg/L;8. 1-2.0 hours group: ( 12. 02± 1.51 ) × 10 3 and (4. 60±0. 48)μg/L;over 24.0 hours group: ( 14. 68±2.07)×10-3 and (5.88±0.64)μg/L,Q＞13.8,P＜0. 05]. And the ADL was lower in patients operated within 8. 0 hours than in patients operated over 8. 1 hours [≤3.0 hours group: (2. 60± 1.07)scores; 3.1-8.0 hours group: (3. 06±0. 91 )scores;8. 1-24.0 hours group: (4.00±0.67) scores;over 24.0 hours group:(3.68±1.32)scores,Q＞3. 1,P＜0.05].Conclusions The minimally invasive surgery of intracranial hematoma within 8.0 hours can mitigate the cytotoxicity-damaged BBB so as to lighten brain edema and improve the patients quality of life.     

Regulation of blood-brain barrier permeability

The blood-brain barrier minimizes the entry of molecules into brain tissue. This restriction arises by the presence of tight junctions (zonulae occludens) between adjacent endothelial cells and a relative paucity of pinocytotic vesicles within endothelium of cerebral arterioles, capillaries, and venules. Many types of stimuli can alter the permeability characteristics of the blood-brain barrier. Acute increases in arterial blood pressure beyond the autoregulatory capacity of cerebral blood vessels, application of hyperosmolar solutions, application of various inflammatory mediators known to be elevated during brain injury, and/or activation of blood-borne elements such as leukocytes can produce changes in permeability of the blood-brain barrier. The second messenger systems that account for increases in permeability of the blood-brain barrier during pathophysiologic conditions, however, remain poorly defined. This review will summarize studies that have examined factors that influence disruption of the blood-brain barrier, and will discuss the contribution of various cellular second messenger pathways in disruption of the blood-brain barrier during pathophysiologic conditions.     

The blood-brain barrier in neuroAIDS

Nearly every aspect of blood-brain barrier (BBB) function is involved in or affected by HIV-1. The disruption of the BBB tends to be minimal and is not likely the mechanism by which infected immune cells and virus enter the brain. Instead, immune cells, virus and viral proteins likely activate brain endothelial cells and enable their own passage across the BBB by way of highly regulated processes such as diapedesis and adsorptive endocytosis. Viral proteins and cytokines can enter the CNS from the blood and provide a mechanism by which HIV-1 can affect CNS function independent of viral transport. Brain endothelial cells can also secrete neuroimmunoactive substances when stimulated by HIV-1, gp120, and Tat. Efflux systems such as p-glycoprotein transport anti-virals in the brain-to-blood direction, thus hampering effective accumulation of drug by the CNS. Overall, the BBB plays a major role in establishing and maintaining virus within the CNS and neuroAIDS.     

Human blood-brain barrier transferrin receptor

The kinetics of binding and endocytosis of 125I-human holotransferrin by isolated human brain capillaries was examined using this system as a model of the human blood-brain barrier (BBB). Both binding and endocytosis of the peptide by human brain capillaries was temperature-dependent and the binding was saturated by holotransferrin, but not by insulin, somatostatin, or vasopressin. Scatchard analysis of the binding reaction revealed a dissociation constant of 448 +/- 110 ng/mL (5.6 +/- 1.4 nmol/L) and a maximal binding constant (Ro) of 8.0 +/- 1.5 ng/mg protein. Thus, the affinity and capacity of the BBB transferrin receptor is within the same order of magnitude as the affinity and capacity of the BBB receptors for insulin, insulinlike growth factor-I, or insulinlike growth factor-II. The human brain capillary transferrin receptor was also detected with a mouse monoclonal antibody to the receptor using the avidin/biotin/peroxidase technique. In conclusion, these studies characterize the human BBB transferrin receptor and support the hypothesis that this receptor acts as a transport system which mediates the transcytosis of transferrin-bound iron through the brain capillary endothelial cell in man.     

Crossing the blood-brain barrier with AAV vectors

Metabolic Brain Disease - Central nervous system (CNS) diseases are some of the most difficult to treat because the blood-brain barrier (BBB) almost entirely limits the passage of many therapeutic...     

周细胞在血脑屏障中的作用

周细胞是血脑屏障的一种重要细胞成分,在脑微血管生成、内皮细胞紧密连接形成、血脑屏障分化、微血管动态运动和结构稳定性方面起调节作用.周细胞在一些疾病,如脑血管病、神经退行性疾病、神经免疫性疾病和外伤性脑损伤中,呈现很独特的功能特性.文章对周细胞在血脑屏障中的作用做了综述.     

周细胞在血脑屏障中的作用

周细胞是血脑屏障的一种重要细胞成分,在脑微血管生成、内皮细胞紧密连接形成、血脑屏障分化、微血管动态运动和结构稳定性方面起调节作用.周细胞在一些疾病,如脑血管病、神经退行性疾病、神经免疫性疾病和外伤性脑损伤中,呈现很独特的功能特性.文章对周细胞在血脑屏障中的作用做了综述.     

Permeation of growth hormone across the blood-brain barrier

Exogenous GH can affect central nervous system function when given peripherally to animals and as a supplemental therapy to humans. This study tested whether GH crosses the blood-brain barrier (BBB) by a specific transport system and found that both mice and rats have small but significant uptake of GH into the brain without a species difference. Determined by multiple-time regression analysis, the blood-to-brain influx transfer constants of 125I-labeled rat GH in mice (0.23+/-0.07 microl/g.min) and rats (0.32+/-0.04 microl/g.min) were comparable to those of some cytokines of similar size, with a half-time disappearance of 125I-GH of 3.8-7.6 min in blood. Intact 125I-GH was present in both serum and brain homogenate 20 min after iv injection. At this time, about 26.8% of GH in brain entered the parenchyma, whereas 10% was entrapped in endothelial cells. Neither excess GH nor insulin showed acute modulation of the influx, indicating lack of a saturable transport system for GH at the BBB. Binding and cellular uptake studies in cultured cerebral microvessel endothelial cells (RBE4) further ruled out the presence of high-capacity adsorptive endocytosis. The brain influx of GH by simple diffusion adds definitive value to the long-disputed question of whether and how GH crosses the BBB. The central nervous system effects of peripheral GH can be attributed to permeation of the BBB despite the absence of a specific transport system.     

Targeted delivery of proteins across the blood-brain barrier

Treatment of many neuronal degenerative disorders will require delivery of a therapeutic protein to neurons or glial cells across the whole CNS. The presence of the blood-brain barrier hampers the delivery of these proteins from the blood, thus necessitating a new method for delivery. Receptors on the blood-brain barrier bind ligands to facilitate their transport to the CNS; therefore, we hypothesized that by targeting these receptors, we may be able to deliver proteins to the CNS for therapy. Here, we report the use of the lentivirus vector system to deliver the lysosomal enzyme glucocerebrosidase and a secreted form of GFP to the neurons and astrocytes in the CNS. We fused the low-density lipoprotein receptor-binding domain of the apolipoprotein B to the targeted protein. This approach proved to be feasible for delivery of the protein and could possibly be used as a general method for delivery of therapeutic proteins to the CNS.     

Studies on the permeability of the blood-brain barrier in experimental diabetes

Whether the increased capillary permeability characteristic of diabetes extends to the blood-brain barrier is presently unclear. We have examined in streptozotocin-diabetic rats the permeability of the blood-brain barrier at the level of 12 discrete brain regions employing 3 intravenous tracers of different molecular weight: sucrose, insulin and horseradish peroxidase. In animals killed 5 min after tracer injection both the sucrose and the inulin spaces were similar to controls. In order to assess whether more prolonged circulation of tracers would uncover leakage, we studied brain spaces at longer intervals after tracer injections. When inulin was allowed to circulate for 15 min prior to killing, animals with 4 weeks of diabetes (but not 2 weeks) exhibited larger inulin spaces at the level of the medio-basal hypothalamus (p less than 0.01), medio-dorsal hypothalamus (p less than 0.05) and periaqueductal gray (p less than 0.01). Horseradish peroxidase, even after 75 min of perfusion, remained confined in both diabetic and control animals to central nervous system areas devoid of blood-brain barrier. Thus, after a relatively short duration of diabetes the blood-brain barrier manifests an increased permeability. It is subtle, limited to some brain regions and selective for low molecular weight tracers.     

Uptake and hydrolysis of glycylglutamine at the blood-brain barrier.

Using an organ balance technique in dogs, we recently found that liver, skeletal muscle, kidney, and intestine participate in clearance of glycylglutamine from plasma. The purpose of the present study was to investigate whether brain does the same. The study of arteriovenous differences of glycylglutamine across brain, during continuous infusion of this dipeptide (12 mumol.min-1.kg-1) in dogs, showed an arteriovenous difference that was never significantly different from zero. To establish a basis for this lack of clearance, we investigated uptake and hydrolysis of glycylglutamine at the blood-brain barrier. The study of brain uptake index of glycylglutamine in rats showed that it was not significantly different from that of sucrose, an impermeable marker (3.2 +/- 0.4 v 3.5 +/- 0.4, n = 4 to 5). When isolated brain capillaries were incubated with glycylglutamine, uptake was only modestly above background activity and appeared to be due to nonspecific binding. Finally, the plasma membrane of brain capillaries lacked hydrolase activity against glycylglutamine. In conclusion, brain appears to be unique among organs in lacking any mechanism for clearance of glycylglutamine from plasma.