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PubMed1988

Development of axonal-oligodendroglial relationships and junctions during myelination of the optic nerve.

The early stages of myelination were examined in optic nerves of rats aged 12-15 days. The initial association between oligodendroglial processes and bare axons involves no junctional specialization, as the axoglial extracellular space remains unaltered. Following ensheathment by a collar of glial cytoplasm, at least one full rotation of mesaxon was evident before compact myelin formed. Furthermore, myelin was generally evident before a second rotation was completed. In longitudinal sections, an axoglial junction was always observed beginning on the first paranodal loop, continuing through to the last (or outermost) loop. Thus, the formation of myelin and elaboration of a junctional complex in the paranodal region follow a promyelination phase and appear to be synchronous (and possibly related) events. Although the paranodal plasmalemma and axolemma are in close apposition, there is a material in the extracellular space that precipitates phosphotungstic acid, a characteristic that appears to be featured in a number of different types of cell junctions.

Animals↗
PubMed2001

Degradation of poly(D,L)lactide implants with or without addition of calciumphosphates in vivo.

The study was aimed at examining the in vivo degradation of pure poly(D,L)lactide (PDLLA) or PDLLA with an admixture of calciumphosphates. One rod (20 x 3 x 2 mm) and one cube (3 x 2 x 2 mm) of pure PDLLA, PDLLA with tricalciumphosphate (PDLLA + TCP) or PDLLA with calciumhydrogenphosphate (PDLLA + CHP), respectively, were implanted into the dorsal muscles of 50 male Wistar Albino rats. After definite intervals (from 2nd to 72nd week), pH measurements were performed in the environment of the implants. Afterwards, the cubes with their surrounding tissues were excised for histological examinations, measurements of the outer dimensions and mechanical analyses of the explanted rods were performed. No drop of more than 0.1 pH units was detectable in the tissue surrounding any type of implants. No advantageous effect of the calciumphosphates could be proved. A mild foreign body reaction could be observed around PDLLA implants. After 72 weeks, pure PDLLA had been totally resorbed from the extracellular space, the degradation of calciumphosphate-enriched PDLLA was still in progress. A large amount of inflammations occurred in the tissues surrounding PDLLA with an admixture of slowly degrading TCP or CHP, leading to two abscesses and four fistulas at PDLLA + TCP, and two abscesses and three fistulas at PDLLA + CHP implantation site. Bending strength of pure PDLLA was constant up to the 4th week post-implantation and reduced to 60% of the initial value up to the 12th week. No traces of crystallinity could be observed during the degradation of PDLLA. As a conclusion of the study, complete resorption from the extracellular space and tissue tolerance of pure PDLLA is proved. An admixture of small calciumphosphate particles is not suitable to improve the biocompatibility of PDLLA but leads to a decrease in the mechanical characteristics.

Animals↗
PubMed1994

Permeation of proteins from the blood into peripheral nerves and ganglia.

We have attempted to resolve apparently conflicting observations of previous investigators regarding the penetration of proteins into peripheral ganglia and nerves of the rat. Horseradish peroxidase, which is largely cleared from the blood and extracellular fluids in less than 30 min, entered all the extracellular spaces of ganglia, including the clefts between glial cells and neurons, but it did not enter the endoneurium. Rhodamine B-conjugated bovine albumin quickly entered sensory and sympathetic ganglia, but its penetration into avascular enteric nervous tissue was arrested at the outer margin of each myenteric and submucosal ganglion. If injected daily for a week, this fluorescent protein was seen also in the endoneurium, but it was still absent from enteric ganglia. The failure to enter enteric ganglia may have been due to the entrapment of aggregates of dye-labelled albumin molecules in the basal lamina that encloses the enteric nervous system. Extracellular endogenous albumin immunoreactivity was seen in all parts of peripheral nerves and in all types of ganglion. Some neuronal perikarya contained albumin-immunoreactive material; the strongest staining was in enteric neurons. Albumin may reach these cell bodies by retrograde axonal transport from peripheral terminals. We conclude that all the extracellular spaces of the rat's peripheral nervous system are accessible to plasma proteins, though diffusion occurs more slowly into the endoneurium than into ganglia.

Animals↗
PubMed1993

Effects of calcium antagonists on adrenaline-induced hypokalaemia.

Long term treatment with nifedipine and nitrendipine, but not verapamil and diltiazem, may reduce plasma potassium levels in hypertensive patients. To test the hypothesis that this effect is related to adrenaline-mediated influx of potassium from the extracellular space, the effect of adrenaline infusions (12.5, 25 and 50 ng/kg/min) on plasma potassium levels was assessed in normotensive subjects after administration of placebo for 4 days, and after administration of nitrendipine, verapamil or diltiazem for 4 days. The adrenaline-induced decrease in plasma potassium levels was enhanced in subjects receiving nitrendipine, but was unaffected in those subjects receiving verapamil or diltiazem. The effects of adrenaline on blood glucose levels, heart rate and blood pressure were uninfluenced in subjects receiving nitrendipine or verapamil, and were blunted in subjects receiving diltiazem. These results suggest that enhancement of the adrenaline-induced intracellular transfer of potassium from the extracellular space is relatively specific to dihydropyridine calcium antagonists.

Adult↗
PubMed1988

Morphology of interleukin-2-stimulated human peripheral blood mononuclear effector cells killing glioma-derived tumor cells in vitro.

This is the first morphological study of interleukin-2-stimulated human peripheral blood mononuclear (PBM) cells resulting in lymphokine-activated killer (LAK) cell activity against human glioma-derived tumor cells in vitro, in which high-resolution differential interference video light microscopy, scanning electron microscopy, and transmission electron microscopy were used. A subset of cells within the LAK cell population are the effector cells and have an asymmetric cellular architecture characteristic of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Upon binding to target cells, the LAK effector cell nucleus is positioned away from the target cell, whereas the granules, Golgi apparatus, and microtubules orient toward the target cell. These LAK-glioma cell conjugates form very tight plasma membrane bonds with numerous interdigitations, and vesicles were found in the small extracellular spaces between the cells. This morphology was not observed in unstimulated PBM-glioma cell co-cultures. Glioma-derived cells react to LAK effector cells by blebbing, becoming round, and rapidly detaching from the substrate. The injured glioma-derived cells had a highly condensed cytoplasm and chromatin, lobular nucleus, and severe plasma membrane blebs, which are consistent with an apoptotic rather than an osmotic lysis mechanism of cell death. This study provides morphological evidence that supports a common cytotoxic mechanism for CTLs, NK cells, and LAK effector cells. The cytotoxic mechanism is based on the local exocytosis of vesicles by the effector cell into the small extracellular space between the effector-target cell conjugate. Granules found in CTLs, NK cells, and LAK cells contain a pore-forming protein that inserts holes in the target cell's plasma membrane through which a lethal substance(s) not yet identified is thought to enter the cell.

Cell Line↗
PubMed1999

Metabolism of the complex monofluorophosphate-alpha 2-macroglobulin in the rat.

Sodium monofluorophosphate (MFP) is a drug used in the treatment of primary osteoporosis. Following the intake of MFP, a small fraction of the drug is absorbed intact and forms a complex with alpha 2-macroglobulin (MFP-alpha 2M) inactivating the antiproteasic activity of the globulin. The complex has been shown to occur in the serum of rats and human being. This paper reports data on the metabolism of this complex in the rat. In vitro experiments showed that liver and bone tissue remove MFP-alpha 2M from the incubation medium. When the experiments were pursued beyond the time needed to reduce the complex concentration to very low levels, fluorine (F) reappears in the medium in two forms: bound to low molecular weight macromolecule/s (2,200 +/- 600 Da) and as ionic F. Concentrations of these F fractions increase while that of the complex decreases as a function of time. In vitro, uptake of the complex by liver or bone tissue was not affected by the presence of colchicine or methylamine. These drugs, however, inhibited intracellular metabolism of the complex, as indicated by the impairment of the return of F species to the extracellular space and the increase in F content of the tissue. The cellular receptors responsible for the uptake of the complex in liver and bone are insensitive to low concentration of calcium and inhibited by polyinosinic acid[5']. These features characterize the "scavenger" receptor, one of the two receptor types known to remove inactive alpha 2M from the circulation. Injection of polyinosinic acid [5'] to living rats also hindered the disappearance of the complex from serum. It is concluded that the metabolism of the MFP-alpha 2M complex involves binding to receptors, uptake by cells, lysosomal degradation and return of F bound to low molecular weight macromolecule/s to the extracellular space. It is assumed, however, that inorganic F is the final product of lysosomal hydrolysis of the protein moiety.

Animals↗
PubMed1995

Monte Carlo simulation of the biological effects of boron neutron capture irradiation with d(14)+Be neutrons in vitro.

It was shown that radiation effects in tumor cells treated with fast neutrons may be increased by the neutron capture reaction 10B(n, alpha)7Li. The classic approach for macroscopic dosimetry in fast-neutron therapy cannot be applied to the dose in boron neutron capture therapy (BNCT). The effectiveness of BNCT in killing tumor cells depends on the number of 10B atoms delivered to the tumor, the subcellular distribution of 10B and the thermal neutron fluence at the site of the tumor. Monte Carlo calculations of the energy depositions of short-range particles with high LET coming from 10B disintegrations were performed and compared to the observed biological effects. The simulation allows us to study the influence of the localization of intracellular 10B in the nucleus, cytoplasma, plasma membrane or extracellular space. The biological response function which describes the probability of the lethal effect produced by a single particle track through the cell nucleus was found by comparing the calculated microscopic dose distribution spectra for single events with the survival observed experimentally. Calculations for a human melanoma cell population treated as a monolayer in the presence or absence of boron with d(14)+Be neutrons will be demonstrated. Two different boron compounds enriched in 10B were investigated in this study: boric acid (H3 10BO3) and p-dihydroxyboryl phenylalanine (BPA). The study shows that a high fraction of BPA enters the cytoplasm while boric acid was found only in the extracellular space. The computer simulations indicate that BPA yields a higher potential effectiveness for inactivation of melanoma cells than boric acid.

Boron Neutron Capture Therapy↗
PubMedDate not supplied

Synaptic and nonsynaptic release of neuromediators in the central nervous system.

Different types of release site were studied ultrastructurally with tannic acid and immunohistochemical techniques in the central nervous system (CNS) of the invertebrate pond snail Lymnaea stagnalis and in two neuromediator rich core regions in the CNS of the rat, viz., the median eminence (ME) and the mesencephalic central grey substance (MCG). In the CNS of the snail, release of the contents of the secretory granules could be clearly demonstrated in (1) neurohaemal axonterminals, (2) synapses and (3) in nonsynaptic release sites: neuronal processes without morphological synaptic specializations. In the ME, release of secretory products by exocytosis was found in neurohaemal axonterminals in the external part of the palisade layer and in nonsynaptic release sites in all other layers of the median eminence. It was found that oxytocine and vasopressin were released by exocytosis into the extracellular space from such (preterminal) nonsynaptic release sites. Serial section analysis revealed three types of fibre in the MCG, viz. (1) varicose fibres that made synaptic contacts with MCG dendrites on every varicosity, (2) fibres with two types of varicosity, viz. synapse-bearing varicosities and varicosities without synaptic specializations, and (3) varicose fibres without any synaptic specializations. It has been discussed that the nonsynaptic release sites in the CNS of the snail Lymnaea stagnalis, and the nonsynaptic varicosities in the rat brain are the morphological correlates of nonsynaptic communication in the CNS. The results further indicate that particular peptidergic neuromediators are released from such nonsynaptic varicosities, and may reach via the extracellular space receptors located at some distance.

Animals↗
PubMed2000

A Ca(2+) channel blocker-like effect of dehydrocurdione on rodent intestinal and vascular smooth muscle.

Effects of dehydrocurdione, a zedoary-derived sesquiterpene, on smooth muscle were investigated by recording the mechanical activity of intestines and aorta from guinea pigs and rats. Dehydrocurdione (0.1-3 mM) induced a sustained relaxation of rat duodenum and inhibited spontaneous motility. Dehydrocurdione (0.1-1 mM) inhibited the contractile response of guinea pig ileum induced by acetylcholine (0.01-10 microM), histamine (0.03-10 microM) and substance P (0.1-30 nM) in a non-competitive manner. Acetylcholine (0.5 microM) elicited a transient contraction followed by a sustained contraction of guinea pig ileum, and dehydrocurdione pretreatment inhibited the sustained component, which depends on Ca(2+) entry from the extracellular space. The high K(+)-induced contraction of rat aortic ring is reported to be blocked by Ca(2+) channel blockers, while the norepinephrine-induced contraction includes a Ca(2+) channel blocker-resistant component. Dehydrocurdione (1 mM) blocked the high K(+) (60 mM)-induced contraction of rat aortic ring by 81%, while it inhibited the norepinephrine (1 microM)-induced contraction by only 28%. Dehydrocurdione (1 mM) significantly reduced the high K(+)-stimulated increase in cytosolic Ca(2+) level of Fura-2-loaded mesenteric artery from rats. These results suggest that the inhibitory effects of dehydrocurdione on intestinal and vascular smooth muscle are mediated by blockade of Ca(2+) entry from the extracellular space.

Animals↗
PubMed1992

Neuropathologic findings of bromethalin toxicosis in the cat.

Ten random source male domestic shorthair cats, 2 to 6 years old and 3.0-4.4 kg body weight, were each given a single oral dose (1.5 mg/kg) of bromethalin (cat Nos. 1-5) or bait vehicle carrier (cat Nos. 6-10). Bromethalin-dosed cats developed a toxic syndrome characterized by ataxia, focal motor seizures, vocalization, decerebrate posture, decreased conscious proprioception, recumbency, depression, and semicoma. Bromethalin-dosed cats were euthanatized if seizure activity or hindlimb paralysis developed. Survival times were 48 hours (cat No. 1), 89 hours (cat No. 2), 90 hours (cat No. 3), and 97 hours (cat No. 4). Control cats (cat Nos. 6-10) and one bromethalin-dosed cat (cat No. 5) were euthanatized on day 20 after dosing. Spongy change (edema--characterized by the formation of vacuoles in extracellular spaces and myelin lamellae), hypertrophied fibrous astrocytes, and hypertrophied oligodendrocytes were observed in the white matter of the cerebrum, cerebellum, brain stem, spinal cord, and optic nerve of all bromethalin-dosed cats. Spongy change occasionally extended into contiguous cerebellar Purkinje cell layer and cerebral cortical gray matter. The severity of lesions varied among cats but was most pronounced in cat No. 5 (480 hours after dosing). A leukocytic inflammatory response, gitter cell (macrophage) response, or axonal degeneration was not observed in the vacuolated areas. Ultrastructural findings included separation of myelin lamellae at the interperiod lines with the formation of intramyelinic vacuoles (intramyelinic edema), rupture and coalescence of intramyelinic vacuoles into larger extracellular spaces (spongy change), and pronounced cytosolic edema of astrocytes and oligodendroglial cells.

Aniline Compounds↗
PubMed2006

Calcium signaling in non-excitable cells: Ca2+ release and influx are independent events linked to two plasma membrane Ca2+ entry channels.

The regulatory mechanism of Ca2+ influx into the cytosol from the extracellular space in non-excitable cells is not clear. The "capacitative calcium entry" (CCE) hypothesis suggested that Ca2+ influx is triggered by the IP(3)-mediated emptying of the intracellular Ca2+ stores. However, there is no clear evidence for CCE and its mechanism remains elusive. In the present work, we have provided the reported evidences to show that inhibition of IP(3)-dependent Ca2+ release does not affect Ca2+ influx, and the experimental protocols used to demonstrate CCE can stimulate Ca2+ influx by means other than emptying of the Ca2+ stores. In addition, we have presented the reports showing that IP(3)-mediated Ca2+ release is linked to a Ca2+ entry from the extracellular space, which does not increase cytosolic [Ca2+] prior to Ca2+ release. Based on these and other reports, we have provided a model of Ca2+ signaling in non-excitable cells, in which IP(3)-mediated emptying of the intracellular Ca2+ store triggers entry of Ca2+ directly into the store, through a plasma membrane TRPC channel. Thus, emptying and direct refilling of the Ca2+ stores are repeated in the presence of IP(3), giving rise to the transient phase of oscillatory Ca2+ release. Direct Ca2+ entry into the store is regulated by its filling status in a negative and positive manner through a Ca2+ -binding protein and Stim1/Orai complex, respectively. The sustained phase of Ca2+ influx is triggered by diacylglycerol (DAG) through the activation of another TRPC channel, independent of Ca2+ release. The plasma membrane IP(3) receptor (IP(3)R) plays an essential role in Ca2+ influx, by interacting with the DAG-activated TRPC, without the requirement of binding to IP(3).

Animals↗
PubMed2002

Intrinsic optical signals in the rat optic nerve: role for K(+) uptake via NKCC1 and swelling of astrocytes.

Measurements of extracellular space volume and imaging of intrinsic optical signals (IOSs) have shown that neuronal activity increases light transmittance by causing cellular swelling. However, the cellular mechanisms underlying these volume changes and the contribution of astrocyte swelling to the changes in tissue volume are unclear. In this study, we have investigated IOSs in optic nerves to analyze the mechanisms contributing to these signals in a system consisting of only axons and glial cells. We examined both intact optic nerves and enucleated optic nerves, which contained no axons and consisted primarily of astrocytes. Electrical stimulation of intact optic nerves evoked an increase in light transmittance, which was graded with increasing stimulation frequency and was mimicked by raising extracellular K(+) concentration ([K(+)](o)). The stimulation-induced IOS grew in amplitude and had a time course similar to extracellular space shrinkage. Tetrodotoxin (TTX) blocked the electrically induced but not the high K(+)-induced IOS. In enucleated nerves, light transmittance progressively increased in higher [K(+)](o). The high [K(+)](o)-induced IOSs were reversibly depressed by furosemide and bumetanide, antagonists for Na-K-2Cl cotransport, but were unaltered by TTX. We also used a monoclonal antibody to the NKCC1 form of the Na-K-2Cl cotransporter to show that NKCC1 is expressed in optic nerves as shown in Western blotting and is colocalized in GFAP immunopositive astrocytes. In summary, these results indicated that KCl uptake into astrocytes via an Na-K-2Cl cotransporter during raised [K(+)](o) contributes to the generation of cellular swelling and the intrinsic optical signals.

Action Potentials↗
PubMed1986

An ultrastructural and immunocytochemical analysis of leptomeningeal and meningioma cultures.

Using immunocytochemical methods, we localized several glycoproteins of the extracellular matrix to leptomeningeal cells and meningiomas in vitro. Three cell lines derived from normal human leptomeninges and seven from meningiomas were studied by indirect immunofluorescence to evaluate the cellular production of fibronectin, laminin, collagen type IV, and procollagen type III. All leptomeningeal cell lines stained intensely and uniformly for all matrix proteins; all meningioma cell cultures stained uniformly, but the intensity of staining varied considerably. After removal of the cells in culture adherent to glass with 25 mM ammonium hydroxide, indirect immunofluorescence demonstrated an exuberant residual extracellular residue enriched with fibronectin, laminin, collagen type IV, and procollagen type III. Electron microscopic examination of all leptomeningeal and meningioma cultures revealed desmosomes and dense tonofilament formation; in addition, granular, filamentous basement membrane-like material was abundant in the extracellular spaces of all cultures. Sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis of the cell layer of two leptomeningeal and four meningioma cultures showed production of interstitial collagen types I and III; diethylaminoethyl (DEAE)-cellulose chromatography of the medium demonstrated preferential production of procollagen type I. Our findings show conclusively that normal arachnoid cells in vitro synthesize several of the collagen subtypes and may be responsible for the "fibrous response" of the leptomeninges to trauma, infection, or infiltration by tumor. The similarities between leptomeningeal cells and meningiomas demonstrated by electron microscopy and by indirect immunofluorescence support the notion that meningiomas are derived from arachnoid cells. The localization of various mesenchymal glycoproteins within the intra- and extracellular spaces and the ubiquity of specialized intercellular junctions suggest that leptomeningeal cells in culture have the potential to behave like both stromal and epithelial cells.

Animals↗
PubMed1987

Electrical restitution process in dispersed canine cardiac Purkinje and ventricular cells.

Rate-dependent changes in cardiac action potential duration (APD) have been related to ion accumulation and depletion in restricted extracellular spaces. Isolated cardiac cells lack intercellular clefts and thus are less likely than intact tissue to experience ionic transients immediately outside the plasma membrane. Furthermore, isolated Purkinje cells lack the T tubules found in ventricular tissue and cells, which also can be a site of ion accumulation and depletion. We therefore employed single canine ventricular and Purkinje cells to investigate the contribution of restricted spaces to the electrical restitution process. In both cell types, abrupt changes in cycle length do not alter resting potential, but APD alters with a time constant of approximately 1 min. In addition, both preparations exhibit two components to the electrical restitution process of the APD. The rapid component has a time constant of 66 +/- 17 ms in the ventricle cells and 186 +/- 43 ms in the Purkinje cells. The slower component is both smaller and more variable. These values are similar to those reported in intact canine ventricular and Purkinje tissue. Thus the restitution process of APD, as measured in these isolated cardiac cells, is not markedly dependent on the presence or absence of restricted extracellular spaces.

Action Potentials↗
PubMed2005

Electrical feedback in the cone pedicle: a computational analysis.

One of the fundamental principles of neuroscience is that direct electrical interactions between neurons are not possible without specialized electrical contacts, gap junctions, because the transmembrane resistance of neurons is typically much higher than the resistance of the adjacent extracellular space. However it has been proposed that in the retina direct electrical interactions between cones and second-order neurons occur due to the specific morphology of the cone synaptic terminal. This electrical mechanism could potentially explain the phenomenon of "negative feedback" from horizontal cells to cones and the recent finding that the tips of horizontal cell dendrites contain hemichannels has rekindled interest in the idea. We quantitatively evaluated the possibility that hemichannels and/or glutamate channels mediate electrical feedback from horizontal cells to cones. The calculations show that it is unlikely that an electrical mechanism plays a significant functional role because 1) the necessity of preserving adequate cone-to-horizontal-cell synaptic transmission limits the extracellular space resistance and the horizontal-cell dendritic transmembrane resistances to values at which the effectiveness of electrical feedback is very low and its electrical effect on the cone presynaptic membrane is negligible, 2) electrical feedback is most effective in the dark and weaker during light adaptation, which contradicts the experimental data, and 3) electrical negative feedback is associated with much stronger electrical positive feedback from horizontal cells to cones, a phenomenon that has never been reported. Therefore it is likely that negative feedback from horizontal cells to cones is chemical in nature.

Animals↗
PubMed1999

Status epilepticus-induced neuronal injury and network reorganization.

It is now evident that prolonged febrile seizures in childhood, or an episode of status epilepticus at any age, can produce the highly characteristic pattern of hippocampal cell loss and shrinkage that is seen later in life, when patients develop temporal lobe epilepsy. Seizure-induced and presumably excitotoxic pathology includes neuronal loss, reactive gliosis, aberrant synaptic reorganization of surviving cells, and hippocampal tissue shrinkage that may alter extracellular space and affect ionic homeostasis. Whether any of these pathological effects of prolonged excitation play a causal role in the epileptogenic process that ultimately leads to spontaneous afebrile seizures remains a subject of intense interest. Two hypotheses have been suggested to explain how seizure-induced neuronal loss might initiate the epileptogenic process. One hypothesis suggests that normal inhibition and excitability is maintained by vulnerable non-principal cells, and that their loss deactivates inhibitory neurons, rendering principal cells disinhibited and hyperexcitable. The other hypothesis regards the initial loss as a stimulus for normally unconnected principal cells to form aberrant recurrent excitatory connections. Additional influences undoubtedly include a "kindling" process that gradually overcomes polysynaptic inhibition, and changes in extracellular space that may facilitate synaptic and ephaptic depolarization. Identification of the suspected substrates of epileptogenesis will serve as a stimulus for future progress and provide direction for new experimental designs.

Animals↗
PubMed1978

Potassium contracture of smooth muscle in the presence of dextran.

The apparent diffusion coefficient of Ca ions in the extracellular space of guinea pig taenia coli was estimated from model experiments to be 3.2 x 10(-6) cm2 sec -1, while the relationship between Ca concentration in the medium and tonic tension in 40 mM K-contracture was measured in the same muscle both in the presence and absence of dextran 10. On the basis of these experiments and certain assumptions, the time course of tension decline by Ca withdrawal during K-contracture was calculated. Under all dextran concentrations tested (0--15%) the calculated time course of tension decline was in good agreement with one actually observed except in a short period of time immediately after Ca withdrawal. The results suggested that Ca distribution in the extracellular space during the loss of Ca is in good agreement with the diffusion theory in cylinder, and that each muscle fiber shows its tension without delay in response to the change in Ca concentration in the vicinity of the fiber according to the tonic tension-Ca relationship mentioned above. The discrepancy between calculation and observation was partially explained on an experimental basis.

Animals↗
PubMed2006

Comparison of brain extracellular fluid, brain tissue, cerebrospinal fluid, and serum concentrations of antiepileptic drugs measured intraoperatively in patients with intractable epilepsy.

PURPOSE: The mechanisms of drug resistance in epilepsy are only incompletely understood. According to a current concept, overexpression of drug efflux transporters at the blood-brain barrier may reduce levels of antiepileptic drugs (AEDs) in epileptogenic brain tissue. Increased expression of drug efflux transporters such as P-glycoprotein has been found in brain tissue surgically resected from patients with medically intractable epilepsy, but it is not known whether this leads to decreased extracellular (interstitial) AED concentrations in affected brain regions. This prompted us to measure concentrations of AEDs in the extracellular space of human neocortical tissue by using intraoperative microdialysis (IOMD) in those parts of the brain that had to be removed for therapeutic reasons. For comparison, AED levels were determined in brain tissue, subarachnoid CSF, and serum. METHODS: Concentrations of carbamazepine (CBZ), 10-hydroxy-carbazepine (10-OH-CZ, metabolite of oxcarbazepine), lamotrigine (LTG), levetiracetam (LEV), topiramate, or phenytoin were determined by using one to four catheters during IOMD in the medial temporal gyrus. Furthermore, to calculate the individual recovery of every catheter, an in vitro microdialysis was performed with ultrafiltrate of serum concurrently obtained from the respective patient. In addition, AED levels were determined in the resected brain tissue, CSF, and serum of the same patients. Altogether 22 pharmacoresistant epilepsy patients (nine male, 13 female patients; age 15-54 years) with complex partial seizures or secondarily generalized seizures were involved. In a first series, IOMD samples 40 min after beginning of the microdialysis (flow rate, 1 microl/min), and in a second series, continuous measurements 25, 30, 35, and 40 min from the beginning were evaluated (flow rate, 2 microl/min). With in vitro recovery data of the individual catheters, the concentration in the extracellular space (ECS) was estimated. RESULTS: AED concentrations in the ECS of the cortex measured by catheters located at a distance of 0.6 cm differed markedly in some patients, whereas concentrations in the ultrafiltrate of the serum of the respective patients measured with the same catheters varied only slightly. Furthermore, ECS concentrations related to the ultrafiltrate of serum showed considerable interindividual variations. The high intra- and interindividual variation of ECS concentrations is demonstrated by the low correlation between concentrations in ECS and the ultrafiltrate of serum (CBZ, r= 0.41; 10-OH-CZ, r= 0.42; LTG, r= 0.27) in contrast to the high correlation between brain tissue concentration and the ultrafiltrate of serum (CBZ, r= 0.97; 10-OH-CZ, r= 0.88; LTG, r= 0.98) in the same group of patients. When comparing AED concentrations in the ECS with those in the CSF, ECS concentrations were significantly lower for CBZ, 10-OH-CZ, LTG, and LEV. CONCLUSIONS: The data demonstrate that AED concentrations show a considerable intraindividual and interindividual variation in the ECS of cortical regions. Furthermore, the ECS concentration of several AEDs is significantly lower than their CSF concentration in patients with intractable epilepsy. However, in the absence of data from nonepileptic tissues, it is not possible to judge whether the present findings relate to overexpression of multidrug transporters in the brain. Instead, the present study illustrates the methodologic difficulties involved in performing IOMD studies in patients and may thus be helpful for future approaches aimed at elucidating the role of multidrug transporters in epilepsy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗