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PubMed2003

Blood-brain barrier drug targeting: the future of brain drug development.

As human longevity increases, the likelihood of the onset of diseases of the brain (and other organs) also increases. Clinical therapeutics offer useful long-term treatments, if not cures, if drugs can be delivered appropriately and effectively. Unfortunately, research in drug transport to the brain has not advanced very far. Through better characterization of the transport systems utilized within the blood-brain barrier, a greater understanding of how to exploit these systems will lead to effective treatments for brain disorders. Pardridge reviews the functions of the various known transport systems in the brain and discusses how the development of BBB drug-targeting programs in pharmaceutical and academic settings may lead to more efficacious treatments.

Animals↗
PubMed1987

Neocortical transplants in the mammalian brain lack a blood-brain barrier to macromolecules.

In order to determine whether the blood-brain barrier was present in transplants of central nervous tissue, fetal neocortex, which already possesses blood-brain and blood-cerebrospinal fluid barriers to protein, was grafted into the undamaged fourth ventricle or directly into the neocortex of recipient rats. Horseradish peroxidase or a conjugated human immunoglobulin G-peroxidase molecule was systemically administered into the host. These proteins were detected within the cortical transplants within 2 minutes regardless of the age of the donor or postoperative time. At later times these compounds, which normally do not cross the blood-brain barrier, inundated the grafts and adjacent host brain and also entered the cerebrospinal fluid. Endogenous serum albumin detected immunocytochemically in untreated hosts had a comparable although less extensive distribution. Thus, transplants of fetal central nervous tissue have permanent barrier dysfunction, probably due to microvascular changes, and are not integrated physiologically within the host. Blood-borne compounds, either systemically administered or naturally occurring, which should never contact normal brain tissue, have direct access to these transplants and might affect neuronal function.

Animals↗
PubMed1994

Semliki Forest virus infects mouse brain endothelial cells and causes blood-brain barrier damage.

Induction of experimental allergic encephalomyelitis is facilitated in a genetically resistant BALB/c mouse strain by a nonpathogenic strain of a neurotropic alphavirus, Semliki Forest virus (SFV-A7). One possible explanation for this enhancement is virus infection of endothelial cells (EC), causing increased permeability of the blood-brain barrier. We have now sought evidence for virus infection of EC in vivo by immunocytochemistry and in situ hybridization. SFV-A7 antigens and RNA were detected in vascular EC and perivascular neurons in cerebellar and spinal cord white matter. Expression of viral antigens was followed by fibrinogen leakage from the blood vessels into brain parenchyma. This was shown by immunoperoxidase staining detecting fibrinogen extravascularly in central nervous system sections of infected mice. Simultaneously, expression of ICAM-1 (intercellular adhesion molecule 1) was induced on brain EC. SFV-A7 replicated in mouse brain microvascular EC in vitro and caused lysis of the cells. SFV-A7 did not induce ICAM-1 expression of mouse brain microvascular EC in vitro, while ICAM-1 was readily induced by gamma interferon and interleukin 1 beta. The observed increase of ICAM-1 expression on EC is immune mediated and not a direct effect of the virus infection. We conclude that SFV-A7 infection causes cerebral microvascular damage which contributes to the facilitation of experimental allergic encephalomyelitis in BALB/c mice.

Animals↗
PubMed2001

Release of biochemical markers of damage to neuronal and glial brain tissue is associated with short and long term neuropsychological outcome after traumatic brain injury.

OBJECTIVES: The present study aimed at the analysis of release patterns of neurobiochemical markers of brain damage (neuron specific enolase (NSE) and protein S-100B) in patients with traumatic brain injury and their predictive value with respect to the short and long term neuropsychological outcome. METHODS: Serial NSE and S-100B concentrations were analysed in blood samples taken at the first, second, and third day after traumatic brain injury. In 69 patients who fulfilled the inclusion criteria (no history of neurological or psychiatric disorder or alcohol or drug dependency, blood sampling according to the scheduled time scale, aged between 16 and 65 years) standardised neurological examinations and qualitative and quantitative evaluation of CT were performed. Comprehensive neuropsychological assessment was performed in 39 subjects 2 weeks after admission and in 29 subjects at a 6 month follow up examination. RESULTS: Most patients presented with minor head injuries (GCS>/=13) at the time of admission. Six months later most patients were fully independent in activities of daily living. Two thirds of the patients, however, still had neuropsychological dysfunction. Patients with short and long term neuropsychological disorders had significantly higher NSE and S-100B serum concentrations and a significantly longer lasting release of both markers. A comparative analysis of the predictive value of clinical, neuroradiological, and biochemical data showed initial S-100B values above 140 ng/l to have the highest predictive power. CONCLUSIONS: The analysis of post-traumatic release patterns of neurobiochemical markers of brain damage might help to identify patients with traumatic brain injury who run a risk of long term neuropsychological dysfunction.

Biomarkers↗
PubMed2005

Alterations in blood-brain barrier ICAM-1 expression and brain microglial activation after lambda-carrageenan-induced inflammatory pain.

Previous studies showed that peripheral inflammatory pain increased blood-brain barrier (BBB) permeability and altered tight junction protein expression and the delivery of opioid analgesics to the brain. What remains unknown is which pathways and mediators during peripheral inflammation affect BBB function and structure. The current study investigated effects of lambda-carrageenan-induced inflammatory pain (CIP) on BBB expression of ICAM-1. We also examined the systemic contribution of a number of proinflammatory cytokines and microglial activation in the brain to elucidate pathways involved in BBB disruption during CIP. We investigated ICAM-1 RNA and protein expression levels in isolated rat brain microvessels after CIP using RT-PCR and Western blot analyses, screened inflammatory cytokines during the time course of inflammation, assessed white blood cell counts, and probed for BBB and central nervous system stimulation and leukocyte transmigration using immunohistochemistry and flow cytometry. Results showed an early increase in ICAM-1 RNA and protein expression after CIP with no change in circulating levels of several proinflammatory cytokines. Changes in ICAM-1 protein expression were noted at 48 h. Immunohistochemistry showed that the induction of ICAM-1 was region specific with increased expression noted in the thalamus and frontal and parietal cortices, which directly correlated with increased expression of activated microglia. The findings of the present study were that CIP induces increased ICAM-1 mRNA and protein expression at the BBB and that systemic proinflammatory mediators play no apparent role in the early response (1-6 h); however, brain region-specific increases in microglial activation suggest a potential for a central-mediated response.

Animals↗
PubMed1992

Growth velocity of some fetal parameters. I. Brain weight and brain dimensions.

In this study, fetal growth velocities of the brain weight (whole brain and infratentorial part) and of the right and left fronto-occipital diameters were established from 420 normal fetuses and neonates. The age of the subjects ranged from 10 to 41 gestational weeks. Growth rates were computed by time intervals, and velocity curves were plotted with their 95% confidence intervals. The whole brain displays an accelerating pattern of growth until 35 weeks; thereafter, the growth rate breaks down. The growth velocity of the infratentorial part of the brain increases throughout fetal life, without a fall at 35 weeks. Moreover, it grows faster than the whole brain after 24 weeks. The lengths of the hemispheres present a steady decreasing pattern of growth velocity throughout pregnancy.

Brain↗
PubMedDate not supplied

Ischemic brain edema following occlusion of the middle cerebral artery in the rat. II: Alteration of the eicosanoid synthesis profile of brain microvessels.

Using the rat middle cerebral artery occlusion model, alterations in the eicosanoid synthetic capacity of brain microvessels following ischemia were studied by radiochromatography. Brain microvessels of normal rats predominantly produced hydroxyacids with relatively small amounts of PGD2 and PGE2 from exogenous arachidonic acid. Confirmation that hydroxyacids and prostaglandins were products respectively of lipoxygenase(s) and cyclooxygenase was obtained by experiments using indomethacin and eicosatetraynoic acid. The eicosanoid synthetic capacity of the brain microvessel, especially of hydroxyacids, was significantly enhanced 24 and 72 hours after the onset of ischemia. Because this is the phase of maximum edema in the present model, enhanced eicosanoid production in the brain microvessel may be involved in the mechanisms that underly ischemic brain edema.

Animals↗
PubMed1992

Effects of retrograde perfusion of the brain with combined drug therapy after focal ischemia in rat brain.

BACKGROUND AND PURPOSE: The ischemic edema associated with blood-brain barrier permeability changes and the excess production of free radicals are serious complications in prolonged cerebral ischemia. We examined the efficacy of transvenous perfusion of the brain, starting treatment 5 hours after occlusion of the middle cerebral artery for a period of 2 hours in rats with the combined agents mannitol (10 ml/2 hr) and dexamethasone (1 mg/2 hr) to counter edema and verapamil (0.05 mg/kg/2 hr) for vasodilation. METHODS: In experiment 1, blood-brain barrier permeability changes were examined in five groups with six rats each: group C rats underwent 7 hours of middle cerebral artery occlusion with no treatment; group V, treatment with verapamil alone; group VD, treatment with verapamil and dexamethasone; group VM, treatment with verapamil and mannitol; and group VDM, treatment with verapamil, dexamethasone, and mannitol. In experiment 2, we examined local cerebral blood flow, ischemic tissue damage volume, and water content of cerebral hemispheres in two groups of 16 rats each subjected to the same treatment as groups C and VDM rats in experiment 1. RESULTS: There was a significant reduction of blood-brain barrier permeability changes in the ischemic cortex of rats in group VDM compared with rats in the other groups. In the group undergoing transvenous perfusion of the brain with the three combined agents, there was a significant improvement of cerebral blood flow (39-58%, p < 0.05) in the ischemic cortex and reduction of ischemic cerebral damage volume (22%, p < 0.01) and water content of the ischemic hemisphere (p < 0.05) compared with the control group. CONCLUSIONS: The therapeutic approach using combined agents is effective treatment when initiated within 5 hours of focal cerebral ischemia in rats.

Analysis of Variance↗
PubMed1992

Effect of flunarizine on electroencephalogram recovery and brain temperature in gerbils after brain ischemia.

BACKGROUND AND PURPOSE: This study was designed to determine whether flunarizine enhances the rate of brain recovery as measured by electroencephalography after cerebral ischemia and whether these effects are attributable to changes in brain temperature. METHODS: Male gerbils (n = 81) were treated with either 10 mg/kg flunarizine or its vehicle, beta-cyclodextrin, intraperitoneally, 60 minutes before bilateral carotid occlusion of either 4 or 6 minutes' duration. The electroencephalogram was continuously recorded in the preischemic, ischemic, and postischemic stages of the experiment and rated for the time necessary for the return of 4-6, 7-10, and 11-15 Hz activity. In a second set of experiments, intracerebral temperature was monitored for 60 minutes before ischemia, during 10 minutes of carotid occlusion, and for 60 minutes after ischemia. RESULTS: Flunarizine pretreatment resulted in significantly more rapid return of electroencephalographic activity in each of the three frequency categories monitored when compared with those animals pretreated with vehicle alone (p less than 0.001). Flunarizine had no effect on brain temperature before, during, or up to 60 minutes after termination of ischemia. CONCLUSIONS: Flunarizine, which has been of efficacy in reducing neuronal death, mortality, and functional impairment when administered after ischemic insults, may have prophylactic value in accelerating brain recovery from ischemia, but does not have this effect as a result of altered brain temperature.

Animals↗
PubMed1998

Matrix metalloproteinases and TIMPs are associated with blood-brain barrier opening after reperfusion in rat brain.

BACKGROUND AND PURPOSE: Reperfusion disrupts cerebral capillaries, causing cerebral edema and hemorrhage. Middle cerebral artery occlusion (MCAO) induces the matrix-degrading metalloproteinases, but their role in capillary injury after reperfusion is unknown. Matrix metalloproteinases (MMPs) and tissue inhibitors to metalloproteinases (TIMPs) modulate capillary permeability. Therefore, we measured blood-brain barrier (BBB) permeability, brain water and electrolytes, MMPs, and TIMPs at multiple times after reperfusion. METHODS: Adult rats underwent MCAO for 2 hours by the suture method. Brain uptake of 14C-sucrose was measured from 3 hours to 14 days after reperfusion. Levels of MMPs and TIMPs were measured by zymography and reverse zymography, respectively, in contiguous tissues. Other rats had water and electrolytes measured at 3, 24, or 48 hours after reperfusion. Treatment with a synthetic MMP inhibitor, BB-1101, on BBB permeability and cerebral edema was studied. RESULTS: Brain sucrose uptake increased after 3 and 48 hours of reperfusion, with maximal opening at 48 hours and return to normal by 14 days. There was a correlation between the levels of gelatinase A at 3 hours and the sucrose uptake (P<0.05). Gelatinase A (MMP-2) was maximally increased at 5 days, and TIMP-2 was highest at 5 days. Gelatinase B and TIMP-1 were maximally elevated at 48 hours. The inhibitor of gelatinase B, TIMP-1, was also increased at 48 hours. Treatment with BB-1101 reduced BBB opening at 3 hours and brain edema at 24 hours, but neither was affected at 48 hours. CONCLUSIONS: The initial opening at 3 hours correlated with gelatinase A levels and was blocked by a synthetic MMP inhibitor. The delayed opening, which was associated with elevated levels of gelatinase B, failed to respond to the MMP inhibitor, suggesting different mechanisms of injury for the biphasic BBB injury.

Animals↗
PubMed1985

Distribution of renin activity and angiotensinogen in rat brain. Effects of dietary sodium chloride intake on brain renin.

The purpose of this study was to investigate the biochemistry and the regulation of the brain renin-angiotensin system in the Sprague-Dawley rat. Renin activity and angiotensinogen concentrations (direct and indirect radioimmunoassays) were measured in several brain areas and in neuroendocrine glands. Regional renin activities were measured in separate groups of rats on high and low NaCl diets. Mean tissue renin activities ranged from 2.2 +/- 0.6 to 54.4 +/- 19.7 fmol/mg protein per h (mean of 7 +/- SD), with the highest amounts in pineal, pituitary, and pons-medulla. NaCl depletion increased renin activity in selected regions; based on estimates of residual plasma contamination (despite perfusion of brains with saline), increased renin activity of pineal gland and posterior pituitary was attributed to higher plasma renin. To eliminate contamination by plasma renin, 16-h-nephrectomized rats were also studied. In anephric rats, NaCl depletion increased renin activity by 92% in olfactory bulbs and by 97% in anterior pituitary compared with NaCl-replete state. These elevations could not be accounted for by hyperreninemia. Brain renin activity was low and was unaffected by dietary NaCl in amygdala, hypothalamus, striatum, frontal cortex, and cerebellum. In contrast to renin, highest angiotensinogen concentrations were measured in hypothalamus and cerebellum. Overall, angiotensinogen measurements with the direct and the indirect assays were highly correlated (n = 56, r = 0.96, P less than 0.001). We conclude that (a) NaCl deprivation increases renin in olfactory bulbs and anterior pituitary of the rat, unrelated to contamination by plasma renin; and (b) the existence of angiotensinogen, the precursor of angiotensins, is demonstrated by direct radioimmunoassay throughout the brain and in neuroendocrine glands.

Angiotensinogen↗
PubMed2002

Brain lesions in patients visiting a memory clinic with postconcussional sequelae after mild to moderate brain injury.

Postconcussional disorder after a relatively mild head injury is common. Although a partial organic etiology is presumed, little imaging evidence exists for this assumption. In this study, patients with mild to moderate brain injury (median Glasgow Coma Scale score of 14) had more parenchymal brain lesions than control subjects (P=0.02). Additionally, the authors investigated the potential of quantifying brain injury by the magnetization transfer ratio (MTR). The curve amplitude of the MTR histogram was used as a measure of normal white matter. Patients had a lower curve amplitude than control subjects (P=0.008). This study provides evidence of persistent traumatic brain alterations in patients who sustained a relatively mild traumatic brain injury.

Adult↗
PubMed2006

Effects of ischemic preconditioning on blood-brain barrier permeability and MMP-9 expression of ischemic brain.

The study was designed to investigate the effects of ischemic preconditioning (IP) on permeability of blood-brain barrier (BBB) and expression of matrix metalloproteinase-9 (MMP-9) in subsequent ischemic hemisphere. Rats were divided into four groups, one group was used as control, and the other three groups were given three different pretreatments: the first group received a saline injection into the right internal carotid artery (SI), the second group underwent both left and right carotid arteries occlusion (BCAO), and the third group was treated with BCAO and SI simultaneously (BS). After 24 hours of pretreatments, the focal cerebral ischemia was induced by inserting a thread into the right middle cerebral artery causing occlusion (MCAO). Brain water content, BBB permeability and MMP-9 expression of ischemic hemisphere brains were measured at 24 and 48 hours after MCAO. After 24 and 48 hours MCAO, averages for brain water content were 82.92 and 83.12% in BS group, 85.19 and 85.73% in SI group and 86.06 and 85.88% in BCAO group. Evans blue content of ischemic hemispheres were 14.01 and 11.74 microg/mm(3) at 24 and 48 hours after MCAO in BS group, which were lower than the other two groups, 16.22, 15.01 and 16.61, 15.58 microg/mm(3), respectively (p<0.01). The expression levels of MMP-9 in ischemic hemisphere in BS were lower than that in other two groups (p<0.01). Therefore, ischemic preconditioning could ameliorate brain edema and BBB disruption caused by subsequent cerebral ischemia. Ischemic preconditioning could decrease MMP-9 protein and mRNA expression, which may be an important mechanism of cerebral ischemic tolerance.

Analysis of Variance↗
PubMed2004

Osmotic blood-brain barrier modification for the treatment of malignant brain tumors.

The blood-brain barrier (BBB) is a physiologic barrier that protects the brain from toxic substances, including most of the chemotherapeutic agents used today. The BBB may be partly responsible for the poor efficacy of chemotherapy for malignant primary or metastatic brain tumors. A technique of osmotic modification of the BBB, known as BBB disruption (BBBD), is used to increase the delivery of chemotherapy to the brain. This article discusses the technique of osmotic opening of the BBB, the national BBBD program, the role of nurses in the care and management of patients undergoing BBBD treatment, outcomes of this technique with a variety of brain tumors, and the future directions of the BBBD program.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

The effects of bilirubin on brain energy metabolism during hyperosmolar opening of the blood-brain barrier: an in vivo study using 31P nuclear magnetic resonance spectroscopy.

Despite intensive investigation it remains uncertain how bilirubin enters the brain and how it exerts a toxic effect on neurones. Studies of induced hyperbilirubinemia in animal models in vivo have failed to reproduce bilirubin encephalopathy without additional factors such as hypoxia, asphyxia, hypercapnia, and disruption of the blood-brain barrier. The aim of this study was to investigate, using 31P NMRS, whether hyperbilirubinemia alone or in association with hyperosmolar opening of the blood-brain barrier caused any disturbance of cerebral energy metabolism in vivo. Spectra were acquired using a surface coil positioned over the right cerebral hemisphere of anaesthetized adult rats placed in the bore of a 1.9 Tesla magnet. Hyperbilirubinemia alone at a maximum mean serum concentration of 1063 +/- 175 mumol/L (mean +/- SD, n = 7) caused no apparent disruption in brain energy metabolism. However, in combination with hyperosmolar blood-brain barrier opening a serum bilirubin concentration of 483 +/- 52 mumol/L (mean +/- SD, n = 9) was associated with a reduction in PCr/(PCr + Pi) ratio from 0.68 +/- 0.06 to 0.44 +/- 0.14 (mean +/- SD, p less than 0.001). A significant correlation was demonstrated between cerebral hemisphere bilirubin content and the reduction in PCr/(PCr + Pi) (r = 0.84, n = 9, p less than 0.01). These results demonstrate in vivo a disruptive effect of bilirubin on cerebral energy metabolism in the presence of an open BBB. This mode of entry and mechanism of toxicity may be factors in the pathophysiology of bilirubin encephalopathy in the newborn infant.

Animals↗
PubMed1990

Blood-brain barrier permeability to bilirubin in the rat studied using intracarotid bolus injection and in situ brain perfusion techniques.

It has generally been assumed that free unconjugated bilirubin gains access to the brain because of its lipid solubility. However, no measurements of the blood-brain barrier permeability to free bilirubin exist. The aim of these experiments was to determine the blood-brain barrier permeability in the rat to free bilirubin using single-pass (Oldendorf) and in situ perfusion (Takasato) techniques. Studies were performed on adult rats under sodium pentobarbitone anesthesia. [3H]bilirubin IX-alpha-ZZ (sp act 6.2 Ci/mmol) was synthesized by reduction of biliverdin with sodium boro-[3H]hydride. Blood-brain barrier permeability to albumin-bound and free bilirubin was determined using injectates/perfusates containing a molar excess of human serum albumin with or without the addition of the displacing agent sulphadimethoxine. For free bilirubin, the brain uptake index was 28.5 +/- 9.3 (mean +/- SD, n = 18), and the permeability surface area product was 54.84 +/- 36.38 x 10(-4) mL/s/g (mean +/- SD, n = 13). These results demonstrate that the behavior of free bilirubin in vivo in relation to the cerebral microvasculature corresponds to that of a "lipid soluble" molecule.

Animals↗
PubMed2003

Administration of drugs known to inhibit P-glycoprotein increases brain bilirubin and alters the regional distribution of bilirubin in rat brain.

P-glycoprotein (P-gp) is an ATP-dependent integral plasma membrane efflux pump, expressed in abundance in brain capillary endothelial cells and astrocytes. P-gp contributes to the blood-brain barrier in limiting the influx and retention of a variety of lipophilic compounds, including unconjugated bilirubin. Several drugs block P-gp function and thereby enhance intracellular accumulation of P-gp substrates. In this study we proposed that pretreatment with drugs known to inhibit P-gp function in clinically relevant doses would alter the uptake of bilirubin in the brain of 32- to 36-d-old rats. In the first arm of the study, the animals received pretreatment with an i.v. infusion of either propanolol, erythromycin, verapamil, ceftriaxone, rifampin, or saline, 10 min before an i.v. bolus of 50 mg/kg bilirubin was given. Except for the erythromycin-treated rats, all treatment groups had significantly higher brain-to-serum bilirubin ratios than control animals (p < 0.05, Welch's t test). In the second arm of the study, treatment with either ceftriaxone or rifampin or saline i.v. preceded a 50 mg/kg i.v. bolus of radioactive bilirubin. Analysis of seven different brain regions by scintillation counting showed that the distribution patterns differed significantly between the study groups (p < 0.001, ANOVA), however, not in accordance with a kernicteric staining pattern. Because of limited knowledge of expression and function of P-gp and other membrane transport proteins in the newborn, the implications of this study remain to be seen. We speculate that drugs known to inhibit P-gp function may increase the risk of bilirubin encephalopathy in the hyperbilirubinemic infant.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity.

Brain-derived neurotrophic factor has been associated previously with the regulation of food intake. To help elucidate the role of this neurotrophin in weight regulation, we have generated conditional mutants in which brain-derived neurotrophic factor has been eliminated from the brain after birth through the use of the cre-loxP recombination system. Brain-derived neurotrophic factor conditional mutants were hyperactive after exposure to stressors and had higher levels of anxiety when evaluated in the light/dark exploration test. They also had mature onset obesity characterized by a dramatic 80-150% increase in body weight, increased linear growth, and elevated serum levels of leptin, insulin, glucose, and cholesterol. In addition, the mutants had an abnormal starvation response and elevated basal levels of POMC, an anorexigenic factor and the precursor for alpha-MSH. Our results demonstrate that brain derived neurotrophic factor has an essential maintenance function in the regulation of anxiety-related behavior and in food intake through central mediators in both the basal and fasted state.

Animals↗