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Disruption of the blood--brain barrier (BBB) underlies the development of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis. Environmental factors, such as Bordetella pertussis, are thought to sensitize central endothelium to biogenic amines like histamine, thereby leading to increased BBB permeability. B. pertussis-induced histamine sensitization (Bphs) is a monogenic intermediate phenotype of EAE controlled by histamine [H.sub.1] receptor (Hrh1/ [H.sub.1]R). Here, we transgenically overexpressed [H.sub.1]R in endothelial cells of Hrh 1-KO ([H.sub.1]RKO) mice to test the role of endothelial [H.sub.1]R directly in Bphs and EAE. Unexpectedly, transgenic [H.sub.1]RKO mice expressing endothelial [H.sub.1]R under control of the von Willebrand factor promoter ([H.sub.1]RKO-[vWF.sup.H1R] Tg) were Bphs-resistant. Moreover, [H.sub.1]RKO-[vWF.sup.H1R] Tg mice exhibited decreased BBB permeability and enhanced protection from EAE compared with [H.sub.1]RKO mice. Thus, contrary to prevailing assumptions, our results show that endothelial [H.sub.1]R expression reduces BBB permeability, suggesting that endothelial [H.sub.1]R signaling may be important in the maintenance of cerebrovascular integrity. endothelium | experimental autoimmune encephalomyelitis | vasoactive amine sensitization | vascular permeability | multiple sclerosis doi/ 10.1073/pnas.1008816107

The superparamagnetic properties of magnetic nanoparticles (MNPs) allow them to be guided by an externally positioned magnet and also provide contrast for MRL However, their therapeutic use in treating CNS pathologies in vivo is limited by insufficient local accumulation and retention resulting from their inability to traverse biological barriers. The combined use of focused ultrasound and magnetic targeting synergistically delivers therapeutic MNPs across the blood-brain barrier to enter the brain both passively and actively. Therapeutic MNPs were characterized and evaluated both in vitro and in vivo, and MRI was used to monitor and quantify their distribution in vivo. The technique could be used in normal brains or in those with tumors, and significantly increased the deposition of therapeutic MNPs in brains with intact or compromised blood-brain barriers. Synergistic targeting and image monitoring are powerful techniques for the delivery of macromolecular chemotherapeutic agents into the CNS under the guidance of MRI. blood-brain barrier | brain drug delivery | focused ultrasound | magnetic nanoparticles | magnetic targeting doi/ 10.1073/pnas.1003388107

Hibernating mammals use reduced metabolism, hypothermia, and stored fat to survive up to 5 or 6 mo without feeding. We found serum levels of the fat-derived ketone, D-[beta]-hydroxybutyrate (BHB), are highest during deep torpor and exist in a reciprocal relationship with glucose throughout the hibernation season in the thirteen-lined ground squirrel (Spermophilus tridecemlineatus). Ketone transporter monocarboxylic acid transporter 1 (MCT1) is upregulated at the blood-brain barrier, as animals enter hibernation. Uptake and metabolism of [sup.13]C-labeled BHB and glucose were measured by high-resolution NMR in both brain and heart at several different body temperatures ranging from 7 to 38[degrees]C. We show that BHB and glucose enter the heart and brain under conditions of depressed body temperature and heart rate but that their utilization as a fuel is highly selective. During arousal from torpor, glucose enters the brain over a wide range of body temperatures, but metabolism is minimal, as only low levels of labeled metabolites are detected. This is in contrast to BHB, which not only enters the brain but is also metabolized via the tricarboxylic acid (TCA) cycle. A similar situation is seen in the heart as both glucose and BHB are transported into the organ, but only [sup.13]C from BHB enters the TCA cycle. This finding suggests that fuel selection is controlled at the level of individual metabolic pathways and that seasonally induced adaptive mechanisms give rise to the strategic utilization of BHB during hibernation. hibemation; [beta]-hydmxybutyrate; glucose; [sup.13]C magnetic resonance spectroscopy; blood-brain barrier

CNS tissues are protected from circulating cells and factors by the blood--brain barrier (BBB), a specialization of the neurovasculature. Outcomes of the loss of BBB integrity and cell infiltration into CNS tissues can differ vastly. For example, elevated BBB permeability is closely associated with the development of neurological disease in experimental allergic encephalomyelitis (EAE) but not during clearance of the attenuated rabies virus CVS-F3 from the CNS tissues. To probe whether differences in the nature of BBB permeability changes may contribute to the pathogenesis of acute neuroinflammatory disease, we compared the characteristics of BBB permeability changes in mice with EAE and in mice clearing CVS-F3. BBB permeability changes are largely restricted to the cerebellum and spinal cord in both models but differ in the extent of leakage of markers of different size and in the nature of cell accumulation in the CNS tissues. The accumulation in the CNS tissues of CD4 T cells expressing mRNAs specific for IFN-[gamma], and IL-17 is common to both, but iNOS-positive cells invade into the CNS parenchyma only in EAE. Mice that have been immunized with myelin basic protein (MBP) and infected exhibit the features of EAE. Treatment with the peroxynitrite-dependent radical scavenger urate inhibits the invasion of iNOS-positive cells into the CNS tissues and the development of clinical signs of EAE without preventing the loss of BBB integrity in immunized/infected animals. These findings indicate that BBB permeability changes can occur in the absence of neuropathology provided that cell invasion is restricted. experimental allergic encephalomyelitis | neuroimmunology | peroxynitrite-dependent radicals | rabies virus | CNS inflammation

The purpose of this paper is to demonstrate a prototype design of a low-frequency multiple-channel hemispherical focused-ultrasound phased-array system for transcranial disruption of the blood-brain barrier (BBB). A 32-channel ultrasound driving system tunable in the frequency range from 200 to 400 kHz was designed for producing a suitable ultrasound output for BBB disruption. The driving system includes a microcontroller/field-programmable gate-array-based control kernel with multiple-channel driving circuits implemented by a high-voltage switching/LC-resonance/impedance-matching circuit module. Three hemispherical phased arrays comprising 22, 31, and 80 elements were fabricated and tested. The pressure distributions at the geometric center and at off-center positions were tested experimentally. The focal performance of the different hemispherical arrays was also evaluated theoretically. The results showed that the developed phased-array system can successfully drive the hemispherical array with multiple-channel ultrasound signals with independent phase control at 8-bit resolution. Good focusing abilities were evident both at the geometric center and at specific off-center target positions. Preliminary animal experiments show that the BBB in rat can be locally disrupted successfully. The system will serve as a reference platform for developing a focused-ultrasound system for clinical use in brain drug delivery applications. Index Terms--Biomedical ultrasonics, brain, drug delivery systems.

Hypoxia is linked to changes in blood-brain barrier (BBB) permeability, and loss of BBB integrity is characteristic of many pathological brain diseases including stroke. In particular, astrocytes play a central role in brain homeostasis and BBB function. We investigated how hypoxia affects astrocyte survival and assessed whether VEGF release through hypoxia-inducible factor-1[alpha] (HIF-1[alpha]) induction plays a role in tolerance of these cells to insult. Thus primary astrocytes were subjected to normoxic (21% [O.sub.2]), hypoxic (1% [O.sub.2]), or near-anoxic ( oxygen deprivation; glucose withdrawal; blood-brain barrier; glial scarring

Brain edema is an important factor leading to morbidity and mortality associated with primary brain tumors. Dexamethasone, a synthetic glucocorticoid, is routinely prescribed with antineoplastic agents to alleviate pain associated with chemotherapy and reduce intracranial pressure. We investigated whether dexamethasone treatment increased the expression and activity of multidrug resistance (MDR) transporters at the blood-brain barrier. Treatment of primary rat brain microvascular endothelial cells with submicromolar concentrations of dexamethasone induced significantly higher levels of drug efflux transporters such as breast cancer resistance protein (abcg2), P-glycoprotein (P-gp; abcbl a/abcb 1 b), and MDR protein 2 (Mrp2; abcc2) as indicted by protein and mRNA levels as well as by functional activity. The effect of dexamethasone on transporter function was significant within 6 h of treatment, was dose dependent, and was reversible. Dexamethasone-induced upregulation of Bcrp and P-gp expression and function was partially abrogated by the glucocorticoid receptor (GR) antagonist RU486. In contrast, RU486 had no effect on the dexamethasone-induced upregulation of Mrp2, suggesting a GR-independent regulation of Mrp2, and a GR-dependent regulation of P-gp and Bcrp. In addition to the dexamethasone-induced upregulation of MDR transporters, we measured a dose-dependent and reversible increase in the expression of the nuclear transcription factor pregnane xenobiotic receptor (PXR). Administering dexamethasone to rats caused increased expression of PXR in brain microvessels within 24 h. These results suggest that adjuvant therapy with corticosteroids such as dexamethasone in the treatment of brain tumors may increase the expression of MDR transporters at the blood-brain barrier through pathways involving GR and PXR. multidrug resistance proteins; pregnane xenobiotic receptor; breast cancer resistance protein

Leukemia inhibitory factor (LIF) is a proinflammatory cytokine mediating a variety of central nervous system (CNS) responses to inflammatory stimuli. During lipopolysaccharide (LPS)-induced inflammation, blood concentrations of LIF increase, correlating with lethality of sepsis. Circulating LIF crosses the blood-brain barrier (BBB) by a saturable transport system. Here we determine how this transport system is regulated in neuroinflammation. Using transport assays that quantify the influx rate and volume of distribution of LIF in mice, we show that LPS facilitated the permeation of LIF from the blood to the brain without compromising the paracellular permeability of the BBB as determined by coadministration of fluorescein. Concurrently, gp130 (shared by the interleukin-6 family of cytokines), but not gp 190 (the specific receptor for LIF) or cilliary neutrophic factor (CNTF-R[alpha], a unique receptor for cilliary neurotrophic factor that also uses gp130 and gp190), showed increased levels of mRNA and protein expression in cerebral microvessels from the LPS-treated mice. The upregulation of gp130 by LPS was at least partially mediated by vascular tumor necrosis factor receptor (TNFR)1 and TNFR2. This was shown by elevated TNFR1 and TNFR2 mRNA and protein in cerebral microvessels after LPS and by the absence of the LPS effect on gp130 in knockout mice lacking these receptors. The results show that neuroinflammation by LPS induces endothelial signaling and enhances cytokine transport across the BBB. blood-brain barrier; leukemia inhibitory factor; lipopolysaccharide; tumor necrosis factor; nuclear factor- [kappa]B; neuroinflammation

Q My husband had electroconvulsive therapy for depression six years ago. Would this be associated with the fact that he developed normal pressure hydrocephalus (NPH) later in life? A Electroconvulsive [...]