The blood-brain barrier (BBB) restricts molecular and cellular trafficking between the blood and the CNS. Although astrocytes are known to control BBB permeability, the molecular determinants of this effect remain unknown. We show that angiotensinogen (AGT) produced and secreted by astrocytes is cleaved into angiotensin II (AngII) and acts on type 1 angiotensin receptors (AT 1 ) expressed by BBB endothelial cells (ECs). Activation of AT 1 restricts the passage of molecular tracers across human BBB-derived ECs through threonine-phosphorylation of the tight junction protein occludin and its mobilization to lipid raft membrane microdomains. We also show that AGT knock-out animals have disorganized occludin strands at the level of the BBB and a diffuse accumulation of the endogenous serum protein plasminogen in the CNS, compared with wild-type animals. Finally, we demonstrate a reduction in the number of AGT-immunopositive perivascular astrocytes in multiple sclerosis (MS) lesions, which correlates with a reduced expression of occludin similarly seen in the CNS of AGT knock-out animals. Such a reduction in astrocyte-expressed AGT and AngII is dependent, in vitro, on the proinflammatory cytokines tumor necrosis factor-␣ and interferon-␥. Our study defines a novel physiological role for AngII in the CNS and suggests that inflammation-induced downregulation of AngII production by astrocytes is involved in BBB dysfunction in MS lesions.

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Multidrug resistance (MDR) is associated with the expression of P-glycoprotein (P-gp), an ATP-dependent transporter which expels anti-cancer drugs from cells. In the present study, MDR1 P-gp was immunodetected by Western blot analysis in 60 human brain tumors, including meningiomas, schwannomas, low-grade gliomas (astrocytomas, pilocytic astrocytomas) and high-grade gliomas (anaplastic astrocytomas, glioblastomas and anaplastic oligodendrogliomas). Most samples from primary tumors expressed P-gp at the same levels as normal brain tissue except for schwannomas, in which levels were reduced by 65%, and meningiomas, in which levels were more than 10-fold higher in 7 of 10 samples. P-gp levels were 70% and 95% lower in brain metastases from melanomas and lung adenocarcinomas, respectively, than in normal brain tissue. These results indicate that the majority of primary brain tumors express MDR1 P-gp and that its high expression levels in meningiomas may be a marker for this type of brain tumor.

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The existence of a dopamine (DA) projection from nucleus raphe dorsalis (RD) to neostriatum was demonstrated in the rat by combined tyrosine hydroxylase (TH) immunohistochemistry and radioautography after retrograde axonal transport of [3H]noradrenaline ([3H]NA). Intrastriatal injections of [3H]NA were carried out in normal rats or after ipsilateral destruction of the nigrostriatal DA system by injection of 6-hydroxydopamine (6-OHDA) into the substantia nigra. Some 1,000 TH-positive nerve cell bodies were counted within the confines of RD as defined by its content in serotonin (5-HT) neurons. These DA neurons occupied the upper third of the RD and they were part of its small cell population. In all cases, a small proportion of the TH-immunoreactive nerve cell bodies in RD were retrogradely radiolabeled. Radiolabeled but immunonegative cells were exceedingly rare. The double-labeled neurons were generally more numerous after elimination of the nigrostriatal DA innervation than in normal rats. They mostly lay within the ventral portion of the medial subdivision of RD and always predominated on the [3H]NA- injected side. Some were also present in nucleus linearis caudalis. It was concluded that [3H]NA had been taken up and retrogradely transported exclusively by catecholamine neurons; part of the DA cell group in RD projects to the neostriatum; and that most if not all non-5-HT neurons projecting from RD to neostriatum are likely to be dopaminergic.

Malignant brain tumors and brain metastases present a formidable clinical challenge against which no significant advances have been made over the last decade. Multidrug resistance (MDR) is one of the main factors in the failure of chemotherapy against central nervous system tumors. The MDR1 gene encoding P-glycoprotein (P-gp), a drug efflux pump which plays a significant role in modulating MDR in a wide variety of human cancers, is highly expressed in the blood-brain barrier (BBB). The BBB controls central nervous system exposure to many endogenous and exogenous substances. The exact molecular mechanisms by which the BBB is involved in the resistance of brain tumors to chemotherapy remain to be identified. The purpose of this review is to summarize reports demonstrating that P-gp, one of the most phenotypically important markers of the BBB, is present in primary brain tumors and thus plays a crucial role in their clinical resistance to chemotherapy.

Haemorrhagic complications can occur following aneurysm treatment with flow diverters (FD), but the underlying mechanism remains unknown. We describe a case where deformation of the device may have contributed to the complication. A patient with a giant, previously unruptured cavernous aneurysm that extended intracranially to cause oedema of the internal capsule was treated with flow diversion. Treatment was followed by multiple episodes of peri-aneurysmal haemorrhages within eight days. A deformation of the device which occurred where it curved to cross the aneurysm neck created residual flows which, in the presence of a stent stenosis immediately beyond the neck, may have contributed to the observed ruptures. Following multiple haemorrhages the patient subsequently died. Autopsy demonstrated early red thrombus partially bridging the struts of the flow diverter, and intra-aneurysmal thrombus of various ages. Microscopic pathology showed an aneurysm wall consisting of collagen infiltrated with neutrophils, but the wall was absent near the cerebral peduncle, adjacent to the brain haemorrhage. Radiographs of the extracted specimen confirmed deformation of the FD construct, located at the transition zone of the stent, leading to increased pore size and porosity. The site of the deformation correlated with the angiographic presence of a continued blood inflow jet into the aneurysm. Stent deformation at the transition zone may promote persistent blood entry into the aneurysm, and in turn potentially contribute to haemorrhagic complications.

Astrocytic tumors are the most common human brain tumors. Establishment of tumor grade is a key determinant both in the choice of a therapeutic approach and in the prognosis. The diagnosis of astrocytic tumors is currently determined following histopathological analysis. The identification of molecular markers would offer a complementary tool for characterizing tumors with respect to their clinical behavior. In this study we determined the expression levels of 3 small GTP binding proteins (RhoA, RhoB and Rac1), of their inhibitor RhoGDI and of caveolin-1 in 24 human astrocytic tumors of grades I to IV. Our results demonstrated that the expression of RhoA and RhoB decreased significantly in all brain tumors studied and was inversely related with tumor of grade II to IV malignancy. The amount of caveolin-1 immunodetected was not significantly different from normal brain samples while the Rac1 expression level was diminished in astrocytic tumors of grades III and IV. Our finding that RhoA and RhoB expression levels are correlated to tumor malignancy suggests that they may serve as novel and efficient diagnostic markers for astrocytic brain tumors of histological grade II to IV and complement currently applied histopathological analysis.