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PubMed1981

Cerebral blood flow and glucose utilization following opening of the blood-brain barrier and during maturation of the rat brain.

This paper reviews that relation between regional cerebral blood flow (rCBF) and local cerebral glucose utilization (LCGU) under normal conditions of altered functional activity, following disruption of the blood-brain barrier by osmotic stress or hypertension, and during development and maturation of the rat brain. rCBF usually increases in parallel with LCGU when neuronal activity in the central nervous system increases. However, disruption of the blood-brain barrier disturbs this coupling between rCBF and LCGU. the blood-brain barrier, which is located at the continuous cerebrovascular endothelium, protects against brain edema and helps to maintain normal cerebral metabolism. When the barrier is disrupted by osmotic stress or by hypertension, LCGU increases markedly, due to increased neuronal activity, and brain edema develops. rCBF does not increase, however, possibly because brain edema prevents cerebral vasodilatation. rCBF and LCGU follow separate time courses during development and maturation of the rat brain. Both parameters increase between the ages of 1 and 3 months, but rCBF continues to rise from 3 to 12 months when LCGU simultaneously falls. The divergent time courses of these two parameters of brain functional activity may reflect an age-related change in the sensitivity of the cerebrovascular bed to metabolic factors that regulate rCBF.

Aging↗
PubMed1994

[Breakdown of the blood-brain barrier and clearance of extravasated proteins after experimental brain injury].

It is well recognized that extravasation of circulating proteins is contributed to the formation of vasogenic brain edema after traumatic brain injury. However, clearance of the extravasated proteins from brain tissue remains unclear. In the present study we therefore identified the clearance procedure by evaluating extravascular localization of endogenous serum albumin and exogenous protein tracer, horseradish peroxidase (HRP), after experimental brain injury in rats. Adult male Wistar rats were subjected to a lateral fluid percussive injury. In study 1, HRP was given intravenously 10 minutes before sacrifice. Animals were sacrificed at 1, 2, 24, 72 hours and 7 days after injury in order to determine re-establishment of the blood-brain barrier. In study 2 extravascular accumulation of serum albumin and HRP given before impact was examined at 1, 6, 24, 72 hours and 7 days after injury to evaluate the clearance of these extravasated proteins. Localization of each protein was assessed in injured brain sections at the microscopic level. In study 1, breakdown of the blood-brain barrier was noted in various regions of the injured brain at 1 hour. This barrier disruption was restored in almost regions by 2 hours. Impact site, however, remained permeable upto 72 hours. In study 2, the distribution of extravasated proteins was similar between albumin and HRP at 1 hour post-injury. Pronounced extravasation of both proteins occurred in discrete regions through the injured brain. After 6 hours post-injury a differential accumulation was noted between albumin and HRP. The diffuse extracellular accumulation of albumin was most widespread at 24 hours and less intense at 72 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1999

Ultrastructural pathology of Golgi apparatus of nerve cells in human brain edema associated to brain congenital malformations, tumours and trauma.

The alterations induced by ischemia and anoxia upon smooth endoplasmic membranes are studied in 38 patients with congenital malformations, brain tumours and brain trauma. The effects of vasogenic and cytotoxic brain edema are examined in the Golgi apparatus of nerve and endothelial cells. Samples of cortical biopsies were conventionally processed for transmission electron microscopy. Cortical biopsies were performed according to the basic principles of Helsinki declaration. Slices of 2 to 5 mm were immediately fixed in the surgical room in 4% glutaraldehyde-0.1 M sodium phosphate buffer, pH 7.4 at 4 degrees C, and postfixed in 1% osmium tetroxide in similar buffer. The pathological alterations of the Golgi complex were studied in samples with moderate and severe brain edema. Moderate edema was mainly found in congenital malformations and severe edema in brain trauma and tumours. In some severely edematous neurons, observed in hydrocephalus associated to Arnold-Chiari malformation, small vesicular type Golgi complexes and atrophic ones were observed, characterized mainly by partial or total disappearance of stacked Golgi cisternae and presence of congregated vesicular profiles. In brain trauma and tumours the Golgi complex showed enlargement and fragmentation of the stacked cis- medial- and trans-Golgi cisternae and vacuolization of trans-Golgi network. In addition, an increased formation of Golgi and coated vesicles was observed in the cis- and trans-Golgi regions. Most Golgi and clathrin coated vesicles were observed throughout the cytoplasm suggesting an increased vesicular transport. In severe edema the nerve cell plasma membranes appeared fragmented, presumably due to an interference of the protein insertion process into the plasma membrane. In brain trauma, a hypertrophic Golgi complex was observed in some nerve cells and endothelial cells of cortical capillaries, with increased formation of Golgi and coated vesicles. The ischemia and anoxia associated to the vasogenic and cytotoxic brain edema induced enlargement, fragmentation and disappearance of stacked Golgi cisternae.

Adolescent↗
PubMed2004

Influence of the course of brain inflammation on the endogenous IL-1beta/IL-1Ra balance in the model of brain delayed-type hypersensitivity response to bacillus Calmette-Guérin in Lewis rats.

Interleukin-1beta (IL-1beta) is a key player in the pathogenesis of acute and chronic inflammatory diseases at the periphery and in the brain. Its action is regulated by interleukin-1 receptor antagonist (IL-1Ra), the specific endogenous antagonist of IL-1 receptors. The ratio between local concentrations of IL-1Ra and IL-1beta is known to influence the initiation and progression of many inflammatory and autoimmune diseases at the periphery. In order to determine whether this is also the case in the brain, brain and plasma concentrations of IL-1beta and IL-1Ra were measured by ELISA in a model of chronic brain inflammation in Lewis rats, the hippocampal delayed-type hypersensitivity (DTH) response to bacillus Calmette-Guérin (BCG). Brain IL-1beta increased rapidly after intracerebral (i.c.) injection of BCG and came back to baseline concentrations 1 week later, whereas IL-1Ra increased gradually over time and remained elevated during the last 2 weeks post-BCG intracerebral injection. Following peripheral BCG challenge, brain IL-1beta increased at the site of the brain BCG and peaked 12 days later before decreasing on day 16 post-challenge. Brain IL-1Ra remained elevated during the first days post-challenge and then decreased from the 12th day post-challenge. The same temporal variations were observed in the plasma concentrations of IL-1beta and IL-1Ra. The increase in the IL-1beta/IL-1Ra ratio that was apparent from day 3 to day 12 post-challenge might be correlated with the invasion of peripheral inflammatory cells at the site of intracerebral injection. Besides showing that the course of inflammation alters the brain IL-1beta/IL-1Ra ratio, these findings point to the importance of monitoring plasma IL-1beta/IL-1Ra ratio to predict the course of brain inflammation.

Analysis of Variance↗
PubMed1999

The blood-brain barrier efflux transporters as a detoxifying system for the brain.

The role played by efflux transport systems across the blood-brain barrier (BBB) in the disposition of xenobiotics in the brain is described. Several drugs and organic anions are transported across the BBB via P-glycoprotein and other carrier-mediated efflux transport systems. Studies using in vitro cultured brain capillary endothelial cells, kinetic analysis, and mdr1a gene knock-out mice have shown that P-glycoprotein, located on the BBB, restricts the entry of vincristine and quinidine to the brain. Brain microdialysis studies have demonstrated that the brain interstitial fluid (ISF) concentrations of quinolone antibiotics are significantly lower than their corresponding unbound serum concentrations. A distributed model analysis supports the finding that efflux transport systems on the BBB restrict distribution of 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxyinosine (DDI), and quinolone antibiotics. A brain efflux index (BEI) method has been developed to provide direct evidence of an efflux transport system for carrying substrates from the cerebrum to the circulating blood across the BBB. The BEI method revealed the existence of carrier-mediated efflux organic anion transport systems for compounds such as p-aminohippuric acid, AZT, DDI, taurocholic acid, BQ-123, and estron sulfate. Moreover, cerebral neurotransmitters such as gamma-aminobutyric acid, L-glutamic acid, and L-aspartic acid are transported from brain to the circulating blood in the intact form via a carrier-mediated efflux transport system. The BBB not only restricts nonspecific permeation from the circulating blood to the brain, but also functions as an active efflux transport system for xenobiotics. Accordingly, the BBB plays a very important role by pumping xenobiotics and some endogenous compounds out of the brain, acting as a central nervous system (CNS)-specific detoxifying system supporting and maintaining normal cerebral function.

Journal Article↗
PubMed2003

Serum S100beta: a noninvasive marker of blood-brain barrier function and brain lesions.

BACKGROUND: S100beta protein is expressed constitutively by brain astrocytes. Elevated S100beta levels in cerebrospinal fluid and serum reported after head trauma, subarachnoid hemorrhage, and stroke were correlated with the extent of brain damage. Because elevated serum S100beta also was shown to indicate blood-brain barrier (BBB) dysfunction in the absence of apparent brain injury, it remains unclear whether elevation of serum levels of S100beta reflect BBB dysfunction, parenchymal damage, or both. METHODS: The authors conducted a prospective study of serum S100beta levels in six patients who underwent hyperosmotic BBB disruption (BBBD) with intraarterial chemotherapy for primary central nervous system lymphoma. In addition, 53 serum S100beta samples were measured in 51 patients who had a variety of primary or metastatic brain lesions at the time of neuroimaging. RESULTS: S100beta was correlated directly with the degree of clinical and radiologic signs of BBBD in patients who were enrolled in the hyperosmotic study. In patients with neoplastic brain lesions, gadolinium enhancement on a magnetic resonance image was correlated with elevated S100beta levels (n = 45 patients; 0.16 +/- 0.1 microg/L; mean +/- standard error of the mean) versus nonenhancing scans (n = 8 patients; 0.069 +/- 0.04 microg/L). Primary brain tumors (n = 8 patients; 0.12 +/- 0.08) or central nervous system metastases also presented with elevated serum S100beta levels (n = 27 patients; 0.14 +/- 0.34). Tumor volume was correlated with serum S100beta levels only in patients with vestibular schwannoma (n = 6 patients; 0.13 +/- 0.10 microg/L) but not in patients with other brain lesions. CONCLUSIONS: S100beta was correlated directly with the extent and temporal sequence of hyperosmotic BBBD, further suggesting that S100beta is a marker of BBB function. Elevated S100beta levels may indicate the presence of radiologically detectable BBB leakage. Larger prospective studies may better determine the true specificity of S100beta as a marker for BBB function and as an early detection or follow-up marker of brain tumors.

Adult↗
PubMed2006

Heparanase mechanisms of melanoma metastasis to the brain: Development and use of a brain slice model.

Heparanase (HPSE-1) is an endo-beta-D-glucuronidase that cleaves heparan sulfate (HS) chains of proteoglycans (HSPG), and its expression has been associated with increased cell growth, invasion, and angiogenesis of tumors as well as with embryogenesis and tissue development. Since metastatic cancer cells express HPSE-1, we have developed an orthotopic brain slice model to study HPSE-1 involvement in brain-metastatic melanoma. This model allows for the characterization of tumor cell invasion at both quantitative and qualitative levels. Brain-metastatic melanoma cells (B16B15b) showed augmenting levels of HPSE-1 protein expression in a time-dependent manner. Secondly, B16B15b cells pre-treated with HPSE-1 showed a significant increase in the number of cells that invaded into the brain tissue. Finally, HPSE-1 exposure-augmented invasion depth in brain sections by brain-metastatic melanoma cells. We concluded that applying this brain slice model can be beneficial to investigate HPSE-1- related in vivo modalities in brain-metastatic melanoma and brain invasion in general. These results also further emphasize the potential relevance of using this model to design therapies for controlling this type of cancer by blocking HPSE-1 functionality.

Animals↗
PubMed2003

Relation between brain oxygen metabolism and temperature gradient between brain and bladder.

Brain temperature is slightly higher than systemic core temperature normally. Fluctuations of a temperature gradient between brain and core body have recently been reported after a severe brain insult. The pathophysiological significance of the gradient fluctuations is unclear. This study aims to identify the gradient fluctuations between brain and core temperatures after a brain insult. Temperature gradient (brain temperature minus bladder temperature: degrees C) was measured in 11 patients (125 points) with severe brain injury (4 patients with subarachnoid hemorrhage, 4 with cerebral hemorrhage. and 3 with traumatic brain injury). Cerebral perfusion pressure (CPP; mmHg) and jugular venous blood saturation (SjO2; %) was also measured. The average gradient was 0.29 +/- 0.285 degrees C when CPP was above 50 mmHg. SjO2 was inversely related to the temperature gradient in a significant manner (r = 0.472; P < 0.0001). Temperature gradients tended to increase and then decrease when CPP < 50 mmHg. This study demonstrates that increased temperature gradient has a significant inverse correlation with SjO2 at CPP > 50 mmHg. The current results suggest that the fluctuations in temperature gradient in critical conditions reflect brain ischemia.

Adult↗
PubMed1980

Compositional changes in soluble proteins of cerebral mantle, cerebellum, and brain stem of rat brain during development: a two-dimensional gel electrophoretic analysis.

Soluble proteins from the cerebral mantle, cerebellum, and brain stem of rat brains were analyzed at various developmental stages by a two-dimensional gel electrophoresis technique. The electrophoretic technique resolved the soluble proteins into 100--150 polypeptide spots on two-dimensional gels and gave reproducible and highly resolved profiles of them. Although most of major polypeptides were commonly found in all the three brain regions, some polypeptides were shown to be unique to a specific brain region. Each brain region was different in the electrophoretic profile of soluble proteins at every developmental stage examined, although there was considerable similarity in the profiles of each of the three brain regions in fetal animals (16--17 days), indicating that soluble proteins undergo different compositional changes in each of the three brain regions during postnatal development. In addition, the number of polypeptide spots on the electrophoretic profile increased remarkably during postnatal development in all of the three brain regions, suggesting that soluble proteins become more heterogeneous during postnatal development in each of the three brain regions.

Animals↗
PubMed2001

Theoretical simulation of temperature distribution in the brain during mild hypothermia treatment for brain injury.

Mild or moderate hypothermia (>30 degrees C) has been proposed for clinical use as a therapeutic option for achieving protection from cerebral ischaemia in brain injury patients. In this research, a theoretical model was developed to examine the brain temperature gradients during selective cooling of the brain surface after head injury. The head was modelled as a hemisphere consisting of several layers, representing the scalp, skull and brain tissue, respectively. The dimensions, physical properties and physiological characteristics for each layer, as well as the arterial blood temperature, were used as the input to the Pennes bioheat transfer equation to simulate the steady-state temperature distribution within the brain. Depending on the head surface temperature, a temperature gradient of up to 13 degrees C exists in the brain tissue. The results have shown that the volumetric-averaged brain tissue temperature Tbt,avg for adults and infants can be 1.7 and 4.3 degrees C, respectively, lower than the temperature of the arterial blood supplied to the brain tissue. The location where the probe should be placed to measure Tbt,avg was also determined by the simulation. The calculation suggests that the temperature sensor should be placed 7.5mm and 5.9 mm beneath the brain tissue surface for adults and infants, respectively, to monitor Tbt,avg continuously.

Brain↗
PubMed2002

Brain tumor invasion model system using organotypic brain-slice culture as an alternative to in vivo model.

PURPOSE: The primary cause of local recurrence and therapeutic failure in the treatment of malignant gliomas is the invasion of tumor cells into the surrounding normal brain. While it is known that malignant gliomas infiltrate diffusely into regions of normal brain, it is frequently very difficult to unequivocally identify the solitary invading glioma cell in histopathological preparations, or in experimental glioma models. We have developed an experimental invasion assay system, which allows us to track the solitary invasive glioma cell, using human brain tissue obtained from routine craniotomies for seizures or trauma. METHODS: This tissue is cut into 1-mm thick slices and cultured in the upper chamber of Transwell culture dishes on top of a 0.4- micro m pore size polyester membrane, which is fed on medium provided in the lower chamber. Glioma cells are stably transfected with vectors containing a green fluorescent protein (GFP) cDNA. Stable, high-level expression GFP transfectants were selected by direct visualization under fluorescence microscope. In addition, various tumor spheroids are stained with vital dye, DiI, to track the invading cells. GFP-expressing glioma cells or stained spheroids were then implanted on the center of the brain slice, and the degree of brain tumor invasion into the brain tissue was evaluated at different time points by optical sectioning using a confocal microscope. RESULTS: We observed that GFP-expressing glioma cells or stained spheroids could be readily tracked and followed with this model system. Individual tumor cells that exhibited green or red fluorescence could be identified and their migration path through the brain slices unequivocally followed. CONCLUSION: This experimental invasion system may be of considerable utility in studying the process of brain tumor invasion and in evaluating its invasiveness in individual brain tumor because it not only provides a better representation of extracellular matrix molecules normally encountered by invading glioma cells, but also provides the fluorescent tag applied to the tumor cells.

Astrocytoma↗
PubMed1975

Resuscitation of the monkey brain after one hour's complete ischemia. II. Brain water and electrolytes.

Adult normothermic rhesus monkeys were submitted to one hour's complete cerebral ischemia, followed by periods of blood recirculation varying from 45 min to 24 h. The functional impact of ischemia and the subsequent recovery was monitored by electrophysiological recording and a distinction was made between animals with signs of functional recovery and animals without recovery. Prior to ischemia the water content of the gray matter was 81.1 plus or minus 0.3% (mean plus or minus S.D.) and of the white matter 68.9 plus or minus 0.8%. The sodium-potassium ratio in the gray matter was 0.43 plus or minus 0.02 and in the white matter 0.62 plus or minus 0.06. During one hour's ischemia brain water did not change significantly, but the differences in the sodium-potassium ratio in white and gray matter were reduced. Blood recirculation of the brain after ischemia caused a considerable increase in brain water content and a shift in the sodium-potassium ratio up to 1.0. Calculated brain swelling was maximal after 45 min when it reached 11.1% of the total brain volume in an animal with recovery and 12.2% in another one without recovery. In animals with signs of functional recovery brain swelling rapidly diminished, followed by a more gradual normalization of brain electrolytes within 24 h. In animals without functional recovery electrolyte shifts were irreversible or even progressed further. It is concluded that brain swelling and electrolyte derangements following one hour's cerebral ischemia are fully reversible when signs of functional recovery appear and brain metabolism returns.

Animals↗
PubMed1976

Free amino acids and related substances in human glial tumours and in fetal brain: comparison with normal adult brain.

An ion exchange automatic chromatographic analysis of the free amino acid concentrations of 18 human glial tumours and of 4 human fetal brains was carried out and the concentrations were compared to those of 13 biopsy specimens of normal adult brain. In addition, the concentrations of the amino acids of the glial tumours were compared to those of 7 intracerebral metastases of various origin. The chromatograms of several tumour specimens showed an unidentified peak overlapping proline. As far as the amino acid concentrations are concerned they varied depending upon the origin of the sample. The concentrations of most amino acids were higher in fetal brain than in adult brain with the exception of aspartic acid, glutamic acid, glutamine, cystathionine and GABA. Two peptides: glutathione and homocarnosine were absent in fetal brain and were present in adult brain. In glial tumours, homocarnosine and some amino acids, namely aspartic acid, glutamic acid and GABA, showed lower concentrations than in normal brain. Some amino acids were in the same concentration as in normal brain: taurine, phosphoethanolamine, glutamine and cystathionine. Most of the others were in higher concentrations than in normal brain, mainly proline. The results suggest that the concentrations of 5 compounds: taurine, proline, cystathionine, GABA and homocarnosine, taken as a whole, provide information on the origin of the sample.

Adult↗
PubMed1990

Correlation of blood-brain barrier function and HT7 protein distribution in chick brain circumventricular organs.

The HT7 protein defined by a monoclonal antibody is a specific marker for chick brain endothelial cells (EMBO J., 5 (1986) 3179-3183). In this study, we have investigated the expression of this protein in the brain circumventricular organs which lack a blood-brain barrier. Using immunohistochemical techniques we found that the protein was absent from the vascular system of the pituitary, median eminence, subfornical organ, pineal gland, the organum vasculosum lamina terminalis and the layer of sinusoid blood vessels of the area postrema. In some regions of the median eminence and, more strikingly, in the pineal gland, parenchymal cells expressed the HT7 antigen. Immunoblots of proteins from brain, pituitary, pineal gland and retina showed that the antigen is very abundant in the retina. Lower amounts were present in brain and pineal gland. The glucose transporter was found to be an independent reliable marker for blood-brain barrier endothelium. In the chick brain the distribution of the biochemically distinct proteins was very similar. Using a postembedding technique we have ultrastructurally localized the HT7 protein specifically in blood-brain barrier endothelial cells. Thus, the expression of the HT7 protein and glucose transporter correlated with blood-brain barrier function.

Animals↗
PubMed1988

Developmental changes in brain and serum binding of testosterone and in brain capillary uptake of testosterone-binding serum proteins in the rabbit.

Developmental changes in the brain uptake of circulating testosterone and of testosterone-binding proteins, such as testosterone-binding globulin (TeBG) or albumin, may play a role in the sexually dimorphic changes in brain structure that are mediated by circulating testosterone. The present studies examine developmental changes in binding of testosterone in both the serum and brain compartments in postnatal rabbits in vivo and developmental changes in the uptake of [3H]TeBG or [3H]albumin by capillaries isolated from developing rabbit brain. The results show that between 10 and 15 days postnatally both the brain sequestration of testosterone and rabbit serum binding of the hormone are markedly increased relative to the newborn period. In addition, both [3H]TeBG and [3H]albumin were taken up by microvessels isolated from 28-day-old rabbit brain, and this process for [3H]TeBG was more active in capillaries obtained from neonatal rats as opposed to adult rats. In summary, these studies show that the binding systems for testosterone are modulated in a parallel fashion in both the serum and brain compartments. In addition, uptake mechanisms for serum testosterone-binding proteins such as TeBG and, to a lesser extent, albumin exist in the capillaries of developing rabbits. These brain capillary plasma protein uptake systems may allow for the distribution into brain of circulating serum proteins such as TeBG and, to a lesser extent, albumin, in developing rabbits.

Aging↗
PubMedDate not supplied

Saturable mechanism for delta sleep-inducing peptide (DSIP) at the blood-brain barrier of the vascularly perfused guinea pig brain.

Cellular uptake of [125I] labelled DSIP at the luminal interface of the blood-brain barrier (BBB) was studied in the ipsilateral perfused in situ guinea pig forebrain. Regional unidirectional transfer constants (Kin) calculated from the multiple-time brain uptake analysis were 0.93, 1.33 and 1.66 microliter.min-1 g-1 for the parietal cortex, caudate nucleus and hippocampus, respectively. In the presence of 7 microM unlabelled DSIP the brain uptake of [125I]-DSIP (0.3 nM) was inhibited, the values of Kin being reduced to 0.23-0.38 microliter.min-1 g-1, values that were comparable with the Kin for mannitol. The rapidly equilibrating space of brain, measured from the intercept of the line describing brain uptake versus time on the brain uptake ordinate, Vi, was greater for [125I]-DSIP than for mannitol; in the presence of unlabelled DSIP this was reduced to that of mannitol, and it was suggested that the larger volume for [125I]-DSIP represented binding at specific sites on the brain capillary membrane. L-tryptophan, the N-terminal residue of DSIP, in concentrations of 7 microM and 1 mM, inhibited Kin without affecting Vi. A moderate inhibition of Kin was obtained by vasopressin ([Arg8]-VP), but only at a concentration as high as 0.2 mM. The results suggest the presence of a high affinity saturable mechanism for transport of DSIP across the blood-brain barrier, with subsequent uptake at brain sites that are highly sensitive to L-tryptophan, and may be modulated by [Arg8]-VP.

Animals↗
PubMed2006

Responses of brain and non-brain endothelial cells to meningitis-causing Escherichia coli K1.

Bacterial interaction with specific host tissue may contribute to its propensity to cause an infection in a particular site. In this study, we examined whether meningitis-causing Escherichia coli K1 interaction with human brain microvascular endothelial cells, which constitute the blood-brain barrier, differed from its interaction with non-brain endothelial cells derived from skin and umbilical cord. We showed that E. coli K1 association was significantly greater with human brain microvascular endothelial cells than with non-brain endothelial cells. In addition, human brain microvascular endothelial cells maintained their morphology and intercellular junctional resistance in response to E. coli K1. In contrast, non-brain endothelial cells exhibited decreased transendothelial electrical resistance and detachment from the matrix upon exposure to E. coli K1. These different responses of brain and non-brain endothelial cells to E. coli K1 may form the basis of E. coli K1's propensity to cause meningitis.

Adhesins, Escherichia coli↗
PubMed2005

Preproenkephalin targeted antisenses cross the blood-brain barrier to reduce brain methionine enkephalin levels and increase voluntary ethanol drinking.

Antisense potentially can manipulate target gene expression in the brain if it can cross the blood-brain barrier (BBB). We designed three (10mer, 17mer, and 19mer) phosphorothioated antisenses (PS-ODNs) directed against the precursor molecule of methionine enkephalin (Met-Enk), an opiate peptide which suppresses voluntary ethanol drinking. We measured the ability of the antisenses to cross the BBB, accumulate in the brain and CSF, decrease levels of Met-Enk in brain and blood, and affect voluntary ethanol drinking. Each antisense readily crossed the BBB, with 0.07-0.16% of the i.v. dose accumulating per gram of brain. Capillary depletion and CSF sampling each confirmed that the antisenses entered the CNS. Gel electrophoresis of radioactivity recovered from brain and serum showed intact antisense and a higher molecular weight form likely representing antisense bound to protein, but no degradation products. Each antisense molecule and a cocktail of all three reduced Met-Enk levels in brain and serum. Met-Enk levels in the brain were reduced more rapidly and for a longer duration than Met-Enk levels in the serum, indicating a degree of selective targeting to the CNS. Additionally, administration of the cocktail was more effective in reducing Met-Enk levels than any of the individual antisenses. Each antisense increased voluntary ethanol drinking by about 20% and the cocktail increased it by about 80%. Taken together, these results used pharmacokinetic, immunochemical, and behavioral methods to show that PS-ODN antisenses that readily cross the BBB can decrease brain levels of Met-Enk and increase voluntary ethanol drinking.

Animals↗