Radiation-induced permeability and leukocyte adhesion in the rat blood-brain barrier: modulation with anti-ICAM-1 antibodies

We assessed the acute effects of radiation on the rat blood-brain barrier. A cranial window model and intravital microscopy were used to measure changes in permeability and leukocyte adhesion in pial vessels after a localized, single dose of 20 Gy. Permeability was assessed using five sizes of fluorescein isothiocyanate (FITC)-dextran molecules (4.4-, 10-, 38.2-, 70-, and 150-kDa) with measurements performed before and 2, 24, 48, 72 and 96 h after irradiation for the 4.4 and 38.2-kDa molecules and before and 24 h after irradiation for the other three molecules. To demonstrate the nature of blood-brain barrier permeability, we concurrently studied the permeability of microvessels in the cremaster muscle. In both tissues, permeability to FITC-dextran was significantly greater 24 h after irradiation than before (P<0.05). The exception was that radiation did not affect the permeability of pial vessels to the 150-kDa molecule. The particle-size dependence of the permeability changes in the brain were indicative of altered integrity of endothelial tight junctions and occurred concomitantly with an increase in cell adhesion which was determined by fluorescent labeling of leukocytes with rhodamine 6G. An early inflammatory response to irradiation was apparent in the brain 2 h after irradiation. The numbers of rolling and adherent leukocytes increased significantly and peaked at 24 h. Injection with the anti-ICAM-1 mAb significantly reduced leukocyte adhesion and permeability thereby linking the two processes. These findings provide a target to reduce radiation-related permeability and cell adhesion and potentially the side effects of radiation in the CNS.     

双源CT三维血管成像技术在脑膜瘤术前评估中的应用

目的 探讨双源CT三维血管成像技术在脑膜瘤术前评估中的应用价值。方法 回顾性分析26例颅底或窦旁脑膜瘤患者的临床资料,术前行双源CT三维血管成像检查明确肿瘤与颅底血管或矢状窦之间的关系,根据肿瘤与血管关系切除肿瘤。结果 所有病例均能清晰显示脑膜瘤与周围血管、静脉窦之间的关系（包裹或推挤）,术中所见与术前检查所见符合。术中对血管保护完全,无大出血,术后无脑梗死、脑出血。根据Simpson切除标准:2级切除16例,3级切除5例,4级切除4例。术后Karnofsky评分较术前平均提高20分。术后随访6~24个月,22例患者无复发;4例患者残留肿瘤复发,再次手术。结论 双源CT三维血管成像能够清晰显示脑膜瘤与周围血管、静脉窦的关系,有利于术中血管的保护,在脑膜瘤术前评估中具有重要的参考价值。     

Effects of aging on the structural and permeability characteristics of cerebrovasculature in normotensive and hypertensive strains of rats

Summary This study demonstrates that markedly different patterns of age-related changes in blood pressure and body weight occur among normotensive Wistar-Kyoto (WKY) and Sprague-Dawley (SD) rats and spontaneously hypertensive rats (SHR). In addition, a variety of age-related structural alterations occurred in the walls of arterioles, capillaries, and venules of the frontal cortex. These changes include: (1) an increase in the thickness of the vascular wall by deposits of collagen and basal lamina which, in some cases, extended into the surrounding neuropil; (2) the presence of a flocculent material in the adventitia of intracerebral arterioles; (3) vesicular inclusions in perivascular macrophages, pericytes and smooth muscle cells which were labelled with i.v. administered horseradish peroxidase (HRP); (4) fragmentation of smooth muscle cells; and (5) accumulation of lipofuscin-like pigments in perivascular glial processes. The hypertensive rats exhibited these changes, but they were more advanced and more widely distributed throughout the cerebral cortex. The aged hypertensive rats occasionally had large bundles of 10 nm diameter, intermediate filaments in the endothelial cells. Whereas no change in blood-brain barrier permeability to HRP was observed in the aged normotensive rats, all age groups of the hypertensive rats exhibited increased permeability to HRP in the initial segment of penetrating arterioles in laminae I and II of the cerebral cortex.     

Proliferation of epineurial capillaries and smooth muscle cells in angiopathic peripheral neuropathy

Summary Proliferation of epineurial capillaries and smooth muscle cells in human sural nerves has been documented. These are basically independant changes, although both can occur in the same nerve. Proliferated epineurial capillaries were seen in association with arterial stenosis or occlusion with or without granulating or granulomatous inflammatory reactions. Although non-specific they appear to be of considerable diagnostic value indicating compensatory hypervascularisation subsequent to peripheral focal ischemia. Separation and numerical increase of epineurial smooth muscle cells, on the other hand, was also recognised as a significant though non-specific alteration occurring in various inflammatory, immunogenetic, or other, non-inflammatory angiopathies. The youngest (1.3 years) and the oldest individual (104 years) studied, as well as many other documented and non-documented cases, did not show this type of change. Smooth muscle cells may survive isolated or focally separated from adjacent vessel walls in the epineurium.Dedicated to Prof. F. Seitelberger on the occasion of his seventieth birthdaySupported in part by Deutsche Forschungsgemeinschaft (Schr 195/5-6)Presented in part at the XIth Meeting of Swiss Neuropathologists with International Participation, St. Moritz, Switzerland, March 15th–19th, 1986     

Cerebral circulation and histamine: 2. Responses of pial veins and arterioles to receptor agonists

H2-receptors predominantly mediate pial arteriolar dilatation in response to histamine, but the reaction of pial veins to histamine has not been clearly identified. In anesthetized cats, we examined responses of pial veins and arterioles to perivascular microapplication of histamine and specific histamine H1 and H2 receptor agonists. Arterioles were very sensitive to the H2-receptor agonist impromidine, with significant dilatation (+16%) occurring at concentrations as low as 10(-10) M. Arteriolar responses to H1 receptor stimulation by 2.2-pyridylethylamine were small, even at high concentrations. The order of potency and maximum dilatations found for the receptor agonists were: H2 (43%) greater than histamine (28%) greater than H1 (17%). By contrast, pial veins did not respond to histamine or the receptor agonists. The results indicate that pial venomotor activity to histamine is negligible, and suggest a sparse distribution of histamine receptors on the outer surfaces of pial veins.     

Parasympathetic innervation of cephalic arteries in rabbits: Comparison with sympathetic and sensory innervation

We investigated the distribution of parasympathetic, sympathetic, and sensory perivascular nerve fibers in rabbit cephalic arteries supplying the brain, exocrine glands, nasal mucosa, masseter muscles, tongue, and skin in the face and also examined cranial autonomic and sensory ganglia. NADPH diaphorase (NADPHd)-positive and vasoactive intestinal peptide–like immunoreactive (VIP-LI) neurons were located in the cranial parasympathetic ganglia. Neuropeptide Y (NPY)-LI neurons occurred mainly, and dopamine β-hydroxylase (DBH)-LI neurons occurred exclusively, in the superior cervical (sympathetic) ganglion. Substance P (SP)-LI and calcitonin gene-related peptide (CGRP)-LI neurons occurred only in the trigeminal (sensory) ganglion. Therefore, it was assumed that NADPHd-positive and VIP-LI perivascular nerve fibers in cephalic arteries were parasympathetic, all DBH-LI and most NPY-LI fibers were sympathetic, and SP-LI and CGRP-LI fibers were sensory in nature. In the cerebral arteries, NADPHd-positive and VIP-LI varicose fibers were more numerous in the rostral than in the caudal half of the Circle of Willis. In the extracranial arteries, NADPHd-positive and VIP-LI fibers were most abundant in the lingual, lacrimal, and supraorbital arteries; sparse in the parotid and submandibular arteries; and absent in the ear artery. There was an obvious proximal-to-distal density gradient along individual cephalic arterial trees. In contrast, DBH-LI, NPY-LI, SP-LI, and CGRP-LI varicose nerve fibers were similar in density in all cephalic arteries and their branches. These neuroanatomical findings suggest that differential parasympathetic innervation in cephalic arteries may play a role in the partitioning of blood flow between different cephalic tissues. J. Comp. Neurol. 389:484–495, 1997. © 1997 Wiley-Liss, Inc.     

Ependymal lining of infundibular recess in perinatal rats: Relationships with portal capillaries and permeability

Structure and permeability of the ependymal lining the infundibular recess were studied in perinatal rats with silver impregnation, electron microscopy, radioautography, and tracer techniques. According to our data basal processes of ependymal cells reach the primary portal plexus linking the 3rd ventricle and the hypophysial portal system all through the perinatal period. After birth, some of the processes penetrate into the perivascular space of the primary portal plexus and abut there on the endothelium of capillaries. Ependymal cells of fetuses and neonates are joined by specialized junctions (tight junctions, gap junctions and zonulae adhaerentes). Intraventricularly injected ionic lanthanum crosses the ependymal lining of fetuses both trans- and extra-cellularly everywhere in the infundibular recess. By postnatal day 9 only the rostral portion of the recess remains readily permeable. Caudally, extracellular leakage becomes highly restricted, apparently due to the appearance of circumferential tight junctions. Finally, [3H]dopamine seems to penetrate through the ependymal lining in the same way as ionic lanthanum entering the portal capillaries. These findings suggest that the adenohypophysiotropic neurohormones can penetrate from the cerebrospinal fluid into the portal circulation from the very beginning of the establishment of the hypothalamo-hypophysial functional relationships during ontogenesis.     

Prostanoid release from ex vivo perfused canine arteries and veins: effects of prolonged perfusion, intermittent perfusion, as well as exposure to exogenous arachidonic acid, thrombin and bradykinin

Regulation of prostanoid release from ex vivo perfused vessel segments is not fully understood. A series of perfusion experiments were performed with canine arteries and veins to define certain regulatory phenomena. Arteries were perfused with pulsatile flow of 90 ml/min at a pressure of 100 mmHg, and veins with nonpulsatile flow of 90 ml/min at a pressure of 7 mmHg. Segments were perfused with Hanks' balanced salt solution for five 15-min periods with the perfusate exchanged after each study period. With onset of perfusion, there was an initial burst of prostacyclin release to 127 +/- 40 pg/mm2, declining to 32 +/- 10 pg/mm2 after 60 minutes (p less than 0.005). If perfusion continued for 5.5 hours, there was a stable release period between 1 and 3 hours, followed by a very slow decline. At that time addition of arachidonic acid (AA) increased prostacyclin release six-fold (p less than 0.01). Vessels perfused for 1 hour and then rested for another hour, responded to reperfusion at the second onset of flow with a two-fold increase in prostacyclin release (p less than 0.01). Vessels perfused with thrombin, bradykinin or AA (either added to each perfusate or only to the last perfusate) exhibited greater prostacyclin release than did control segments. Release of thromboxane steadily declined with time in all parts of the study, and only increased with the addition of AA to the perfusate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Autoradiographic localization of 5-HT1 receptors to human and canine basilar arteries

Autoradiographic techniques were used to identify serotonergic binding sites in human and canine basilar artery segments. 5-HT1, but not 5-HT2, receptors could be localized to the medial layer of the vascular wall using both [3H]LSD and [3H]5-HT. The identification of 5-HT1 binding sites in human and canine basilar arteries provides anatomical evidence that the 5-HT1 receptor mediates vasoconstriction in these major intracranial vessels.     

Distribution of amyloid deposits in the cerebral white matter of the Alzheimer’s disease brain: relationship to blood vessels

The relationship between blood vessels and amyloid β (Aβ)-protein deposits in the cortex of the Alzheimer’s disease (AD) brain is still controversial. It is difficult to distinguish whether the Aβ deposits are associated with blood vessels or neurons because of their widespread and complicated distribution. In this study, we investigated the distribution of Aβ deposits in the cerebral white matter of the AD brain as a means of removing the bias of neuronal distribution. An immunohistochemical study of 100 serial sections, after pretreatment with formic acid for 24 h, revealed the presence of Aβ deposits in the cerebral white matter of the AD brain. There are various morphological types of plaques containing Aβ deposits in the white matter, the same as in the gray matter. While the majority of Aβ deposits was of a circumscribed type such as “classic” and “primitive” plaques, “compact” and “diffuse” plaques were also observed in the white matter. The location of the Aβ deposits was, for the most part, immediately beneath the gray matter. The distribution of Aβ deposits in the white matter was found to correspond to the orientation of the blood vessels. Serial sections also revealed that these Aβ deposits were distributed along a single blood vessel. These findings suggest that the deposition of Aβ in the cerebral white matter is primarily related to the blood vessels. Received: 7 March 1996 / Revised: 10 October 1996     

Increased p75 neurotrophin receptor expression in the canine distemper virus model of multiple sclerosis identifies aldynoglial Schwann cells that emerge in response to axonal damage

Gliogenesis under pathophysiological conditions is of particular clinical relevance since it may provide regeneration-promoting cells recruitable for therapeutic purposes. There is accumulating evidence that aldynoglial cells with Schwann cell-like growth-promoting properties emerge in the lesioned CNS. However, the characterization of these cells and the signals triggering their in situ generation have remained enigmatic. In the present study, we used the p75 neurotrophin receptor (p75(NTR) ) as a marker for Schwann cells to study gliogenesis in the well-defined canine distemper virus (CDV)-induced demyelination model. White matter lesions of CDV-infected dogs contained bi- to multipolar, p75(NTR) -expressing cells that neither expressed MBP, GFAP, BS-1, or P0 identifying oligodendroglia, astrocytes, microglia, and myelinating Schwann cells nor CDV antigen. Interestingly, p75(NTR) -expression became apparent prior to the onset of demyelination in parallel to the expression of β-amyloid precursor protein (β-APP), nonphosphorylated neurofilament (n-NF), BS-1, and CD3, and peaked in subacute lesions with inflammation. To study the role of infiltrating immune cells during differentiation of Schwann cell-like glia, organotypic slice cultures from the normal olfactory bulb were established. Despite the absence of infiltrating lymphocytes and macrophages, a massive appearance of p75(NTR) -positive Schwann-like cells and BS-1-positive microglia was noticed at 10 days in vitro. It is concluded that axonal damage as an early signal triggers the differentiation of tissue-resident precursor cells into p75(NTR) -expressing aldynoglial Schwann cells that retain an immature pre-myelin state. Further studies have to address the role of microglia during this process and the regenerative potential of aldynoglial cells in CDV infection and other demyelinating diseases.     

Endovascular treatment of blood blister-like aneurysms of internal carotid artery: Stent-assisted coiling and pipeline flow diversion

ObjectiveTo report the stent-assisted coil embolization and flow diversion treatments of blood-blister-like aneurysms based on the theory of acute dissection of the internal carotid artery.Patients and methodsFrom July 2016 through July 2020, 27 patients presenting with subarachnoid hemorrhage (SAH) due to rupture of internal carotid artery blood blister-like aneurysms were subjected to endovascular treatment with stent-assisted coiling or Pipeline flow diversion. Clinical outcomes were evaluated using modified Rankin Scale score (mRS).ResultsA proximal stenosis caused by angiopathology adjacent to aneurysms were found on internal carotid artery angiograms in all 27 cases. The angiopathology combining with the aneurysms implement that acute dissection of the supraclinoid segment of the internal carotid artery indicated the pathogenesis of blood blister-like aneurysm formation. All aneurysms were treated successfully with alleviation of the adjacent angiopathology after stenting on angiograms. During 1–12 months, mean 3.5 months, complete aneurysm obliteration without adjacent stenosis were found in 25(92.6%) patients. Two (7.4%) cases of recanalization were retreated with complete obliteration at 1 week and 3 months after initial treatment. Clinical mRS 0 and 1 outcomes were observed in 23(85.2%) patients, mRS 2 in 3(11.1%) patients and mRS 6 in 1(3.7%) not related to aneurysm treatment during follow-up.ConclusionsAcute focal dissection of supraclinoid segment of internal carotid artery underlies the development of blood blister-like aneurysm. Stent-assisted coiling and flow diversion treatments constitute appropriate treatment based on the arterial dissection pathology.     

Dissection and atherosclerosis of carotid arteries in the young: role of the apolipoprotein E polymorphism

Twenty-seven young (<50 years old) patients with spontaneous carotid artery dissection in 11 cases and carotid atherosclerosis in 16 cases were evaluated to determine the apolipoprotein E polymorphism. At the DNA analysis the epsilon3/epsilon3 genotype was observed in all patients with dissection, in 13 of 16 (81.2%) patients with atherosclerosis and in 27 of 30 (90%) controls. Three of 16 (18.8%) patients with atherosclerosis and 3 of 30 (10%) controls presented with the epsilon4/epsilon3 genotype, and this difference was not statistically significant. Moreover, observation of the epsilon4/epsilon3 genotype was not significantly higher in patients with atherosclerosis compared with those with dissection. No homozygote epsilon4/epsilon4, epsilon2/epsilon2 or heterozygote epsilon2 genotype was observed. No correlation was found between the presence of the epsilon4/epsilon3 genotype and vascular risk factors. Therefore, the epsilon4 allele seems to be involved in carotid premature atherosclerosis development whereas it may appear to be protective for artery dissection occurrence. A larger sample size is needed to support this suggestion.     

Ultracytochemical distribution of myelin basic protein after injection into the cerebrospinal fluid. Evidence for transport through the blood-brain barrier and binding to the luminal surface of cerebral veins

Distribution of myelin basic protein (MBP) in the central nervous system (CNS) following injection into the cerebrospinal fluid (CSF) was studied by different qualitative and quantitative immunelectron -microscopic techniques. Endogenous MBP was present in myelin sheaths in injected as well as in control animals. After injection of exogenous MBP into CSF this protein was present in the subarachnoid space, on the surface of meningeal cells, on the surface of collagen fibers, in the basement membrane of the glia limitans, in vessel walls, and in the extracellular space of spinal roots. In meningeal veins, endothelial vesicles filled with peroxidase reaction product were found on the abluminal side of endothelial cells, in the endothelial cytoplasm and sometimes opening into the vascularllumen . In addition patchy staining of the luminal surface of endothelial cells was noted, indicating binding of antigen at this location. Quantitative immunelectron microscopy (an indirect technique with rabbit anti-MBP serum as primary layer and gold-labeled anti-rabbit IgG as secondary layer) revealed highly significant MBP binding on the luminal surface of endothelial cells after injection of this antigen into the CSF. The present results indicate that MBP, when liberated in CNS is transported through the blood-brain barrier and presented on the luminal surface of endothelial cells of the cerebral and meningeal veins. This observation may be important in interpretation of pathogenesis of initial inflammatory infiltrates in experimental allergic encephalitis (EAE).     

Evidence for vasopressin V1 receptors of rostrodiencephalic neurons: Iontophoretic studies in the in vivo rat. Responses to oxytocin and to angiotensin

Extracellular recordings were obtained in anaesthetized rats from single neurons located in various structures around the rostral end of the third ventricle, known to harbour integrative neurons sensing deficiencies in and originating corrective responses for water-electrolyte balance. Once arginine vasopressin (AVP) responsive neurons were located, a selective antidiuretic agonist (binding to V2 receptors) and either V1 (presser response related) or V2 (antidiuretic) antagonists were iontophoretically applied. Neurons in this region did not respond to the V2 agonist and only the VI antagonist was able to block the response to AVP. It is assessed that the investigated region has neurons equipped only with receptors of the VI type. Interestingly, a number of these neurons also responded to angiotensin II (All), oxytocin and to blood pressure changes. The integrative neuronal population of parasagittal rostrodiencephalic neurons seem therefore to sense indices of haemodynamic changes including their neuro-hormonal signals within the brain such as All and AVP which bind to V1 (pressor response related) receptors.     

The kinetics of platelet and fibrin deposition on to damaged rabbit carotid arteries in vivo: involvement of platelets in the initial deposition of fibrin

Thrombus formation in the rabbit carotid artery has been studied kinetically in vivo using a minimally invasive technique utilising radioisotopes. Clamping of the carotid artery for 5 min resulted in the simultaneous accumulation of platelets and fibrin at the site of injury over the next 45 min. Under the electron microscope the response was seen to range from platelet monolayer adhesion to mural thrombus formation with fibrin deposition. In animals rendered thrombocytopenic, fibrin deposition was impaired during the first 15-20 minutes after injury. Basic coagulation times and fibrinogen concentration were within normal limits. In addition the injured vessels in these animals accumulated more radiolabelled albumin, but not erythrocytes, than injured vessels in control animals. The results may imply a role for platelets in the enhancement of fibrin deposition during the early part of the response to injury and in contributing to the maintenance of normal permeability following vessel injury.     

Immune mechanisms of stress susceptibility and resilience: Lessons from animal models

Stress has an impact on the brain and the body. A growing literature demonstrates that feedback between the peripheral immune system and the brain contributes to individual differences in the behavioral response to stress. Here we examine preclinical literature to demonstrate a holistic vision of risk and resilience to stress. We identify a variety of cellular, cytokine and molecular mechanisms in adult animals that act in concert to produce a stress susceptible individual response. We discuss how cross talk between immune cells in the brain and in the periphery act together to increase permeability across the blood brain barrier or block it, resulting in susceptible or stress resilient phenotype. These preclinical studies have importance for understanding how individual differences in the immune response to stress may be contributing to mood related disorders such as depression, anxiety and posttraumatic stress disorders.     

Numbers of neurons and glia in mature rat somatosensory cortex: effects of prenatal exposure to ethanol

Stereological methods were used to examine the consequences of prenatal exposure to ethanol on the structure of area 3, primary somatosensory cortex, of the mature hooded rat. Pregnant rats were fed a liquid diet containing 6.7% (v/v) ethanol (Et), pair-fed an isocaloric liquid control diet (Ct), or fed a diet of chow and water (Ch). Cresyl violet-stained sections of 3-month-old pups were examined. The corrected mean size of the cell bodies of neurons in layers other than layer V was significantly smaller in the Et-treated rats; conversely, the mean somatic size of glia in each layer was significantly larger in the Et-treated rats. The laminar cell packing density for neurons and glia, however, was similar in rats from both treatment groups. The overall volume of area 3 and the volume of individual layers were about 33% smaller in Et-treated rats than in the pair-fed controls. Thus, the estimated total number of neurons in Et-treated rats (1.79 X 10(6] was significantly fewer than in Ch-treated rats (2.77 X 10(6] and in Ct-treated rats (2.66 X 10(6]. The total number of glia also was about 30% fewer in Et-treated rats than in the controls. Not all layers were affected equivalently. The space occupied by the neuropil was significantly greater in Et-treated rats, but only in layers II/III, IV, and VI; hence, the cell body/neuropil ratio in these layers was less in Et-treated rats than in the controls. Therefore, microcephaly caused by prenatal exposure to ethanol results not only from a miniaturization of the brain, but also from a permanent abnormal organization of cerebral cortex.     

Naturally occurring canine distemper virus encephalitis: distribution and expression of viral polypeptides in nervous tissues

Summary Formalin-fixed brain tissues from 16 dogs with naturally occurring canine distemper virus (CDV) infection were investigated immunohistochemically by a panel of eight monoclonal antibodies (mAb) directed against four structural CDV proteins. Three mAb recognizing different epitopes of the polymerase (P-1, P-2, P-3) protein, two clones identifying different epitopes on each, the nucleocapsid (NP-1, NP-2) and fusion (F-2, F-3) protein, and one mAb directed against the hemagglutinin (H-2) protein were used. The immunoreactivity of the clones was tested on formalin-fixed, paraffin-embedded Vero cells, which were lytically infected with the neurotropic R252 (R252-CDV) or the Onderstepoort (CDV/Ond) strain of CDV. Clones directed against the H-2 and F-3 epitope recognized CDV/Ond but not R252-CDV. The remaining six clones showed positive immunoreaction with both CDV strains. In vivo expression and distribution of the individual proteins and their epitopes varied substantially between animals and within lesions from the same animal. The NP-2 epitope showed positive immunostaining in all 16 cases. The P-2 epitope was demonstrated in 13, the NP-1 epitope in 12, the P-3 epitope in 9, and the P-1 epitope in 3 brains, but staining was severely reduced compared with the NP-2 epitope and restricted to areas with strong NP-2 expression. Immunostaining was prominent in early and subacute and reduced in chronic demyelinating lesions. mAb directed against the H and F protein showed no immunoreaction in diseased brains.Supported by a grant from the Deutsche Forschungsgemeinschaft