[Electrophysiologic brain stem diagnosis. Acoustic evoked brain stem potentials--pattern recognition and significance for the function of the brain stem].
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Acoustic Stimulation↗
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Brain-endocrine interaction V. The Schmitt brain symposium. "Neuropeptides: central and peripheral". Proceedings of the Fifth Brain-Endocrine Interaction Symposium. Wurzburg, Federal Republic of Germany, July 27-29, 1983.
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Animals↗
Ventricle-brain ratio, computed tomographic density, and brain area in 50 schizophrenics.
A sample of 50 DSM-III-diagnosed schizophrenics (mean age, 34 years) intentionally biased to contain a relatively high proportion of persistently unemployed persons was compared with a sample of 87 normal volunteers on three computed tomographic measures. These were lateral ventricle-brain ratio, regional brain computed tomographic density values, and brain slice area. Images were made with the same computed tomographic scanner and identical scan parameters. Computed tomographic data were assessed blindly using a computer-linked image array processor and electronic planimeter. Ventricle-brain ratios were significantly higher in schizophrenics, with 28% of the patient sample exceeding 2 SDs of the control mean. Brain area measures were not associated with an enlarged ventricle-brain ratio. Contrary to our prediction, ventricular enlargement was unassociated with most negative symptom ratings, but was correlated with the absence of positive symptoms. A history of abnormal delivery and the presence of left-handedness were significant predictors of an enlarged ventricle-brain ratio on multiple regression analysis. Schizophrenics had a significantly smaller brain slice area compared with normal controls, a finding not attributable to height differences between groups. Brain slice area was inversely correlated with computed tomographic brain density across all subjects. After correction of computed tomographic density values for area using a linear regression model, no significant regional density differences were detectable between normal controls and schizophrenics. Within normal controls there was a significant relationship between social class and brain slice area, but not ventricle-brain ratio.
Adult↗
Morphology and histology of chimpanzee primary visual striate cortex indicate that brain reorganization predated brain expansion in early hominid evolution.
Human brain evolution is characterized by an overall increase in brain size, cerebral reorganization, and cerebral lateralization. It is generally understood when brain enlargement occurred during human evolution. However, issues concerning cerebral reorganization and hemispheric lateralization are more difficult to determine from brain endocasts, and they are topics of considerable debate. One region of the cerebral cortex that may represent the earliest evidence for brain reorganization is the primary visual cortex (PVC), or area 17 of Brodmann. In nonhuman primates, this region is larger in volume (demarcated anteriorly by the lunate sulcus), and extends further rostrally than it does in modern humans. In early hominid fossil (Australopithecus) endocasts, this region appears to occupy a smaller area compared to that in nonhuman primates. Some have argued that the brain first underwent size expansion prior to reorganization, while others maintain that reorganization predated brain expansion. To help resolve this question, we provide a description of two male, common chimpanzee (Pan troglodytes) brains, YN77-111 and YN92-115, which clearly display a more posterior lunate sulcal morphology than seen in other chimpanzees. These data show that neurogenetic variability exists in chimpanzees, and that significant differences in organization (e.g., a reduced PVC) can predate brain enlargement. While the human brain has experienced numerous expansion and reorganization events throughout evolution, the data from these two chimpanzees offer significant support for the hypothesis that the neurogenetic basis for brain reorganization was present in our early fossil ancestors (i.e., the australopithecines) prior to brain enlargement.
Animals↗
Determination of regional brain temperature using proton magnetic resonance spectroscopy to assess brain-body temperature differences in healthy human subjects.
Proton magnetic resonance spectroscopy ((1)H MRS) was used to determine brain temperature in healthy volunteers. Partially water-suppressed (1)H MRS data sets were acquired at 3T from four different gray matter (GM)/white matter (WM) volumes. Brain temperatures were determined from the chemical-shift difference between the CH(3) of N-acetyl aspartate (NAA) at 2.01 ppm and water. Brain temperatures in (1)H MRS voxels of 2 x 2 x 2 cm(3) showed no substantial heterogeneity. The volume-averaged temperature from single-voxel spectroscopy was compared with body temperatures obtained from the oral cavity, tympanum, and temporal artery regions. The mean brain parenchyma temperature was 0.5 degrees C cooler than readings obtained from three extra-brain sites (P < 0.01). (1)H MRS imaging (MRSI) data were acquired from a slice encompassing the single-voxel volumes to assess the ability of spectroscopic imaging to determine regional brain temperature within the imaging slice. Brain temperature away from the center of the brain determined by MRSI differed from that obtained by single-voxel MRS in the same brain region, possibly due to a poor line width (LW) in MRSI. The data are discussed in the light of proposed brain-body temperature gradients and the use of (1)H MRSI to monitor brain temperature in pathologies, such as brain trauma.
Adult↗
The brain link protein-1 (BRAL1): cDNA cloning, genomic structure, and characterization as a novel link protein expressed in adult brain.
We report here molecular cloning and expression analysis of the gene for a novel human brain link protein-1 (BRAL1) which is predominantly expressed in brain. The predicted open reading frame of human brain link protein-1 encoded a polypeptide of 340 amino acids containing three protein modules, the immunoglobulin-like fold and proteoglycan tandem repeat 1 and 2 domains, with an estimated mass of 38 kDa. The brain link protein-1 mRNA was exclusively present in brain. When analyzed during mouse development, it was detected solely in the adult brain. Concomitant expression pattern of mRNAs for brain link protein-1 and various lectican proteoglycans in brain suggests a possibility that brain link protein-1 functions to stabilize the binding between hyaluronan and brevican. The human BRAL1 gene contained 7 exons and spanned approximately 6 kb. The entire immunoglobulin-like fold was encoded by a single exon and the proteoglycan tandem repeat 1 and 2 domains were encoded by a single and two exons, respectively. The deduced amino acid sequence of human brain link protein-1 exhibited 45% identity with human cartilage link protein-1 (CRTL1), previously reported as link protein to stabilize aggregates of aggrecan and hyaluronan in cartilage. These results suggest that brain link protein-1 may have distinct function from cartilage link protein-1 and play specific roles, especially in the adult brain.
Adult↗
Assessment of the relationship between ischemic damage and brain swelling in frozen brain slices.
The purpose of the study was to verify a method for the measurement of both cerebral infarction and brain swelling in frozen brain slices for histology. The animals were divided into two groups sham-operated control (n = 10) and focal cerebral ischemia group (n = 10). Focal cerebral ischemia was produced by permanent occlusion of the left middle cerebral artery. The rats were sacrificed 24 hours postocclusion. The brain was divided into two through the corpus callosum. Each hemisphere was weighted and frozen. Cerebral infarction and brain swelling were each assessed at 8 predetermined coronal planes. The volume of brain swelling was obtained by subtracting the total volume of nonischemic hemisphere from the total volume of the ischemic one. In the MCA occlusion group, brain infarction and the differences of hemispheric volume and weight between the right and left hemispheres were consistently observed, whereas sham-operated rats demonstrated no brain infarction or significant differences between two hemispheres. There were good corelationships not only between the volumes of brain edema and infarction (p < 0.05) but between the volume of brain edema and the difference in weight (p < 0.01) also. The results indicate that the measurement of the volume of ischemic brain edema in frozen brain slices may be useful in elusidating relationship with ischemic brain damage.
Animals↗
Lithium-induced decrease of brain inositol and increase of brain inositol-1-phosphate is transient.
The effects of a single dose of LiCl (2.5 or 10 mEq/kg) on brain inositol and inositol-1-phosphate (Ins1P), intermediates of brain phosphoinositide (PI) turnover, were determined in male Han: Wistar rats. There was a remarkable, 36-58 fold elevation of brain Li+ as the single dose of LiCl was increased 4-fold. Moreover, the accumulation of brain lithium was slow during repeated administration of LiCl. Brain lithium did not correlate with changes in brain PI turnover either after a single or repeated doses. Thus, after a single dose of LiCl the increases in brain Ins1P were much less than the decreases in brain inositol. Also, brain inositol was significantly decreased only with the high dose of LiCl whereas brain Ins1P accumulation was more prominent with the lower dose. Moreover, repeated daily doses of LiCl only transiently increased brain Ins1P at 1 and 7 d whereas inositol remained at control levels throughout the 14 d observation period. Lithium probably caused the transient decrease in brain inositol by inhibiting several enzymes, in addition to the inhibition of myo-inositol mono-phosphates, in the PI cycle. Moreover, a slow dampening down of PI turnover by lithium, possible via an inhibitory action on G-protein-coupling, may also explain the present findings.
Analysis of Variance↗
Quantifying mRNA in postmortem human brain: influence of gender, age at death, postmortem interval, brain pH, agonal state and inter-lobe mRNA variance.
The quantification of mRNA in postmortem human brain is often made complicated by confounding factors. To assess the importance of potential confounders TaqMan real-time RT-PCR was used to measure seven mRNAs (beta-actin, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), cyclophilin, microtubule-associated protein (MAP) 2, neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), amyloid precursor protein (APP) isoform 770) in cortical samples taken from 90 Alzheimer's disease (AD) and 81 control brains. Demographic data for the brain samples were assessed for interaction between factors and amounts of mRNA. Gender was found to play a role in that females had lower levels of mRNA relative to males; this was consistent in both the AD and control brains. Age at death had inconsistent but significant correlations to amounts of mRNA; male and female controls both had negative correlations, female AD a positive correlation and male AD no correlation. Positive correlations were found between brain pH and amount of mRNA in all genes except glial fibrillary acidic protein (GFAP); correlations were consistent across all groupings of pathology and gender. Mean brain pH was significantly lower in AD (6.4) than in control subjects (6.5, ANOVA, p<0.01), though there was no difference between male and females of either group. No correlation was found between brain pH and age at death. Postmortem interval was correlated with brain pH in Alzheimer's disease brains but not controls. Agonal state was generally a poor predictor of mRNA levels whilst inter-lobe variance of mRNA was found to be non-significant in control brains. Given that gender, age at death and brain pH all have significant effects upon mRNA levels it is recommended that these factors be taken into account when quantifying gene expression in postmortem human brain.
Adult↗
Identification of two splice variant forms of type-IVB cyclic AMP phosphodiesterase, DPD (rPDE-IVB1) and PDE-4 (rPDE-IVB2) in brain: selective localization in membrane and cytosolic compartments and differential expression in various brain regions.
In order to detect the two splice variant forms of type-IVB cyclic AMP phosphodiesterase (PDE) activity, DPD (type-IVB1) and PDE-4 (type-IVB2), anti-peptide antisera were generated. One set ('DPD/PDE-4-common'), generated against a peptide sequence found at the common C-terminus of these two PDEs, detected both PDEs. A second set was PDE-4 specific, being directed against a peptide sequence found within the unique N-terminal region of PDE-4. In brain, DPD was found exclusively in the cytosol and PDE-4 exclusively associated with membranes. Both brain DPD and PDE-4 activities, isolated by immunoprecipitation, were cyclic AMP-specific (KmcyclicAMP: approximately 5 microM for DPD; approximately 4 microM for PDE-4) and were inhibited by low rolipram concentrations (K1rolipram approximately 1 microM for both). Transient expression of DPD in COS-1 cells allowed identification of an approx. 64 kDa species which co-migrated on SDS/PAGE with the immunoreactive species identified in both brain cytosol and membrane fractions using the DPD/PDE-4-common antisera. The subunit size observed for PDE-4 (approx. 64 kDa) in brain membranes was similar to that predicted from the cDNA sequence, but that observed for DPD was approx. 4 kDa greater. Type-IV, rolipram-inhibited PDE activity was found in all brain regions except the pituitary, where it formed between 30 and 70% of the PDE activity in membrane and cytosolic fractions when assayed with 1 microM cyclic AMP, PDE-4 formed 40-50% of the membrane type-IV activity in all brain regions save the midbrain (approx. 20%). DPD distribution was highly restricted to certain regions, providing approx. 35% of the type-IV cytosolic activity in hippocampus and 13-21% in cortex, hypothalamus and striatum with no presence in brain stem, cerebellum, midbrain and pituitary. The combined type-IVB PDE activities of DPD and PDE-4 contributed approx. 10% of the total PDE activity in most brain regions except for the pituitary (zero) and the mid-brain (approx. 3%. The isolated cDNAs for DPD and PDE-4 appear to reflect transcription products which are expressed in vivo in brain. The unique N-terminal domain of PDE-4 is suggested to target this PDE to membranes in brain. Type-IVB PDEs are differentially expressed in various brain regions, indicating that there are tissue-specific controls on both the expression of the gene and the splicing of its products.
3',5'-Cyclic-AMP Phosphodiesterases↗
Effect of aminophylline on tryptophan and other aromatic amino acids in plasma, brain and other tissues and on brain 5-hydroxytryptamine metabolism.
1 Aminophylline and other methylxanthines increase brain tryptophan and hence 5-hydroxytryptamine turnover. The mechanism of this effect of aminophylline was investigated. 2 At lower doses (greater than 100 mg/kg i.p.) the brain tryptophan increase could be explained by the lipolytic action of the drug, i.e. increased plasma unesterified fatty acid freeing plasma tryptophan from protein binding so that it became available to the brain. 3 Plasma unesterified fatty acid did not increase when aminophylline (109 mg/kg i.p.) was given to nicotinamide-treated rats but as both plasma total and free tryptophan rose, a tryptophan increase in the brain still occurred. 4 The rise in brain tryptophan concentration following the injection of a higher dose of the drug (150 mg/kg i.p.) could no longer be explained by a rise of plasma free tryptophan as the ratio of brain tryptophan to plasma free tryptophan rose considerably. Plasma total tryptophan fell and the plasma insulin concentration rose. 5 The increase of brain tryptophan concentration after injection of 150 mg/kg aminophylline appeared specific for this amino acid as brain tyrosine and phenyllanine did not increase. However as their plasma concentrations fell the brain/plasma ratio for all three amino acids rose. 6 The higher dose of aminophylline increased the muscle concentration of tryptophan but that of tyrosine fell and that of phenylalanine remained unaltered. The liver concentrations were not affected. 7 The aminophylline-induced increase of the ratio of brain tryptophan of plasma free tryptophan no longer occurred when the drug was given to animals injected with the beta-adrenoreceptor blocking agent propranolol or the diabetogenic agent streptozotocin. 8 The changes in brain tryptophan upon aminophylline injection may be explained by (a) increased availability of plasma tryptophan to the brain due to increased lipolysis and (b) increased effectiveness of uptake of tryptophan by the brain due to increased insulin secretion.
Amino Acids↗
Genetic differences between blood- and brain-derived viral sequences from human immunodeficiency virus type 1-infected patients: evidence of conserved elements in the V3 region of the envelope protein of brain-derived sequences.
Human immunodeficiency virus type 1 (HIV-1) sequences were generated from blood and from brain tissue obtained by stereotactic biopsy from six patients undergoing a diagnostic neurosurgical procedure. Proviral DNA was directly amplified by nested PCR, and 8 to 36 clones from each sample were sequenced. Phylogenetic analysis of intrapatient envelope V3-V5 region HIV-1 DNA sequence sets revealed that brain viral sequences were clustered relative to the blood viral sequences, suggestive of tissue-specific compartmentalization of the virus in four of the six cases. In the other two cases, the blood and brain virus sequences were intermingled in the phylogenetic analyses, suggesting trafficking of virus between the two tissues. Slide-based PCR-driven in situ hybridization of two of the patients' brain biopsy samples confirmed our interpretation of the intrapatient phylogenetic analyses. Interpatient V3 region brain-derived sequence distances were significantly less than blood-derived sequence distances. Relative to the tip of the loop, the set of brain-derived viral sequences had a tendency towards negative or neutral charge compared with the set of blood-derived viral sequences. Entropy calculations were used as a measure of the variability at each position in alignments of blood and brain viral sequences. A relatively conserved set of positions were found, with a significantly lower entropy in the brain-than in the blood-derived viral sequences. These sites constitute a brain "signature pattern," or a noncontiguous set of amino acids in the V3 region conserved in viral sequences derived from brain tissue. This brain-derived signature pattern was also well preserved among isolates previously characterized in vitro as macrophage tropic. Macrophage-monocyte tropism may be the biological constraint that results in the conservation of the viral brain signature pattern.
Acquired Immunodeficiency Syndrome↗
Intraventricular brain injection of adeno-associated virus type 1 (AAV1) in neonatal mice results in complementary patterns of neuronal transduction to AAV2 and total long-term correction of storage lesions in the brains of beta-glucuronidase-deficient mice.
Inherited metabolic disorders that affect the central nervous system typically result in pathology throughout the brain; thus, gene therapy strategies need to achieve widespread delivery. We previously found that although intraventricular injection of the neonatal mouse brain with adeno-associated virus serotype 2 (AAV2) results in dispersed gene delivery, many brain structures were poorly transduced. This limitation may be overcome by using different AAV serotypes because the capsid proteins use different cellular receptors for entry, which may allow enhanced global targeting of the brain. We tested this with AAV1 and AAV5 vectors. AAV5 showed very limited brain transduction after neonatal injection, even though it has different transduction patterns than AAV2 in adult brain injections. In contrast, AAV1 vectors, which have not been tested in the brain, showed robust widespread transduction. Complementary patterns of transduction between AAV1 and AAV2 were established and maintained in the adult brain after neonatal injection. In the majority of structures, AAV1 transduced many more cells than AAV2. Both vectors transduced mostly neurons, indicating that differential expression of receptors on the surfaces of neurons occurs in the developing brain. The number of cells positive for a vector-encoded secreted enzyme (beta-glucuronidase) was notably greater and more widespread in AAV1-injected brains. A comprehensive analysis of AAV1-treated brains from beta-glucuronidase-deficient mice (mucopolysaccharidosis type VII) showed complete reversal of pathology in all areas of the brain for at least 1 year, demonstrating that the combination of this serotype and experimental strategy is therapeutically effective for treating global neurometabolic disorders.
Animals↗
The brain reserve hypothesis, brain atrophy and aging.
BACKGROUND: Researchers have used the concept of brain reserve to explain the dissociation between pathological brain damage and cognitive and functional performance. A variety of brain reserve hypotheses exist, and different empirical strategies have been employed to investigate these variants. OBJECTIVE: The study investigates (i) the relationship between measures of brain burden (atrophy, white matter hyperintensities (WMH)) and measures of reserve (education, creativity, and intelligence); (ii) the relationship between cognitive decline and reserve; (iii) whether measures of reserve mediate the effect of atrophy on estimated cognitive change, and (iv) the association between brain risk factors, education and atrophy. METHODS: A cross-sectional study of a sample of 446 individuals 60-64 years of age who underwent MRI scans as part of a large epidemiological study. Measures were taken of education, intelligence, creativity, cognitive speed, brain volume, WMH, estimated cognitive decline from earlier in life and brain atrophy. RESULTS: No association was found between estimated cognitive decline and brain burden (atrophy, WMH). Risk factors for brain insult were not associated with greater brain atrophy in the less well educated. Neither education, nor any other measure including intelligence or creativity, provided a buffer for cognitive decline in individuals with high levels of brain atrophy. CONCLUSION: Little support was found for the brain reserve hypothesis.
Aging↗
Associations among right minus left brain weight, right- and left-brain weight and the degree of paw preference in right- and left-preferent male and female cats.
The relation of right and left brain weight to right minus left (R-L) brain weight and the relation of R-L paw use to brain weight were studied in adults cats. The R-L brain weight was significantly larger than zero in right-pawed (RH) male and left-pawed (LH) females. The R-L brain weight was significantly smaller than zero in LH males, not significantly different from zero in RH females. The R-L brain weight was negatively linearly correlated with the left-brain weight in RH and LH males (no significant correlations in females). The R-L paw use showed a significant positive linear correlation with the R-L brain weight in RH male and females. There was a significant negative linear correlation between R-L paw use and R-L brain weight especially in LH males. Total brain weight showed a significant negative linear correlation with R-L paw use in RH males, and a positive linear correlation in LH males (no correlations in female cats). These results indicated that intermanual difference in paw use is associated with interhemispheric weight difference and total brain weight, especially in male cats; the left brain seems to be of importance in cerebral lateralization.
Animals↗
Immunocytochemical expression of the blood-brain barrier glucose transporter (GLUT-1) in neural transplants and brain wounds.
The present study examined the immunocytochemical expression of the blood-brain barrier glucose transporter (GLUT-1) in a series of fetal neocortical transplants, autonomic tissue transplants, and stab wounds to the rat brain. GLUT-1 is one of a family of different glucose transporters and is found exclusively on barrier-type endothelial cells. In the brain it is responsible for the regulated facilitative diffusion of glucose across the blood-brain barrier. This investigation is the first to determine if this important molecule is altered during the process of angiogenesis that occurs following neural transplantation procedures or direct brain injury. Beginning in late fetal brain, e.g., E18 and continuing into maturity, GLUT-1 was strongly and exclusively expressed on normal cerebral vessels. In solid fetal central nervous system (CNS) transplants up to around 3 weeks postoperative, GLUT-1 was only weakly expressed, particularly as exemplified by colloidal gold immunostaining when compared with the host. At later times examined, up to 15 months postoperative, GLUT-1 immunoexpression was comparable with the normal adjacent brain. In autonomic tissue transplants, where the vessels do not have a blood-brain barrier, as expected, GLUT-1 was not expressed. In stab wounds, at 1 week there was extensive gliosis, and the injured vessels appeared fragmented and collapsed but still expressed GLUT-1, although to a somewhat lesser extent than normal brain. Between 3 and 6 weeks, GLUT-1 was expressed on tortuous vessels and in apparently fibrillar processes in the wound vicinity with a similar pattern to astrocyte (GFAP) reactivity. These results suggest the occurrence of a down-regulation of GLUT-1 in early transplants, perhaps related to reduced glycolytic activity or transient ischemia, or possibly due to the utilization of alternative energy sources. That GLUT-1 expression was not entirely lost in stab wounds to the mature brain suggests that the protein may be more labile in fetal or perinatal brain than in the adult and may not be affected by direct injury. Coupled with previous transplantation studies that have shown reduced neuronal glycolysis and potential barrier alterations, the reduction of GLUT-1 activity within nearly the identical time frame could indicate a relatively early critical period in cellular metabolism following transplantation of CNS tissue.
Animals↗
Cocaethylene exposure during the brain growth spurt period: brain growth restrictions and neurochemistry studies.
The concurrent use of alcohol and cocaine has recently attracted attention in the medical research field due to the prevalence of this drug abuse pattern and the exclusive formation of a pharmacologically active substance, cocaethylene (CE). This is the first study to examine the neuroteratogenic effects of cocaethylene exposure during the brain growth spurt (part of the third trimester equivalent) on brain growth restrictions and neurochemical profiles. For the brain growth restrictions study, three groups of artificially reared rat pups were given daily injections of 0, 10 or 20 mg/kg cocaethylene (s.c.) from postnatal days (PDs) 4 through 9. One group of normally reared pups (suckle control) also was used. These pups were perfused on PD 10 and the brains were removed and weighed (forebrain, cerebellum and brainstem). For the neurochemistry study, five groups of artificially reared pups were used and were treated identically to those in the brain growth restrictions study, with the exceptions that animals assigned to acute cocaethylene treatment groups did not receive cocaethylene from PDs 4 through 8 and all animals in this study were sacrificed on PD 9 by decapitation. One suckle control group was included to control the possible artificial rearing effects on the neurochemical measures. Blood and fresh brain tissues (cortex, subcortical structures, cerebellum and brainstem) were collected for blood cocaethylene concentration and neurochemical analyses using GC/MS and HPLC techniques, respectively. The statistical analyses indicated that daily administration of 10 or 20 mg/kg cocaethylene, but not 0 mg/kg cocaethylene, significantly restricted the brain growth (brain weights) in all three brain regions assessed. Furthermore, cocaethylene administration from PDs 4 through 9 produced region-specific alterations in various neurotransmitter concentrations. The changes in neurotransmitter levels were not a function of the responses to the last cocaethylene injection on PD 9, since the outcomes between six days of cocaethylene treatment (PDs 4 to 9) and one day acute treatment (PD 9) were notably different. Furthermore, the artificial rearing procedure appeared to produce significant alterations in various neurotransmitter levels when compared with normally reared (suckle) controls. Collectively, these results suggest that cocaethylene is neuroteratogenic to the developing brain during the third trimester equivalent and the unique formation of cocaethylene resulting from the concurrent use of alcohol and cocaine may represent an increased risk to the developing brain beyond the intrinsic neuroteratogenic effects of cocaine and alcohol individually.
Animals↗
Distribution of domperidone into the rat brain is increased by brain ischaemia or treatment with the P-glycoprotein inhibitor verapamil.
Domperidone (DOM), a peripheral dopamine D2 receptor antagonist, is a substrate of P-glycoprotein (P-gp). Therefore, the transport of DOM into the brain may be restricted by P-gp function at the blood-brain barrier, and when the function of P-gp is impaired by ATP depletion under conditions of brain ischaemia (e.g. cerebral thrombosis), side-effects may be induced as a result of increased distribution of DOM into the brain. In this study, we investigated the effects of brain ischaemia and verapamil, a P-gp inhibitor, on the permeability coefficient-surface area product (PS values) of DOM across the blood-brain barrier by using an in-situ rat brain perfusion technique. The PS values of DOM were increased 3.4- and 3.6-fold after brain ischaemia for 10 and 20 min, respectively. Furthermore, co-administration of verapamil significantly increased the PS values of DOM by 42.6- and 43.3-fold in the normal and ischaemia groups, respectively. Brain vascular volume was not affected by ischaemia or verapamil. These results show that the transport of DOM into the brain is restricted by P-gp and that the brain distribution of DOM can be increased by cerebral ischaemia or co-administration of a P-gp inhibitor.
ATP Binding Cassette Transporter, Subfamily B, Mem↗