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Biomedical subjects

M Diksic

Publications and source records attributed to M Diksic.

At least 19 recordsLinked to original sources
PubMed1992

Autoradiographic study of peripheral benzodiazepine receptors in animal brain tumor models and human gliomas.

In vitro binding of [3H]PK-11195 (1-(2-chlorophenyl)-N-methyl-(1- methylpropyl)-3-isoquinoline carboxamide) in rodent AA ascites and C6 glioma as well as in human gliomas was investigated. The Bmax (mean +/- S.D.) of AA ascites tumor and C6 glioma is 1.39 +/- 0.15 pmol/mg tissue and 4.50 +/- 0.76 pmol/mg tissue, respectively. This Bmax is 9 and 30 times, respectively, higher than the one found in the rat cortex (0.15 +/- 0.03 pmol/mg tissue). A Bmax of 1.26 +/- 0.24 pmol/mg tissue and 0.64 +/- 0.08 pmol/mg tissue was found in human malignant and low grade gliomas respectively. This Bmax value should be compared to 0.35 +/- 0.04 pmol/mg tissue found in the normal human cortex. There are significant (P less than 0.05) differences between Bmax in tumors and normal cortex. There was no significant difference in KD between the malignant and low grade gliomas. C6 glioma has a KD significantly greater than rat cortex. In some cases of human low grade gliomas, kinetic measurements suggested the presence of two affinity receptor sites. However, at this time, heterogeneity of the tissue cannot be excluded as being at least in part a source of this.

Animals↗
PubMed1992

3-O-methyldopa administration does not alter fluorodopa transport into the brain.

To determine if 3-O-methyldopa (3OMD) significantly inhibits the transport of 6-[18F]fluorodopa (6-FD) into the brain at the concentration normally encountered during L-dopa administration, we performed 6-FD studies with positron emission tomography in cynomolgus monkeys in the presence and absence of 3OMD. Infusion of 3OMD was designed to produce plasma concentrations equivalent to those seen in patients on chronic L-dopa therapy. Plasma 3OMD levels of 39 +/- 4 microM did not alter the blood-brain transfer rate of 6-FD. 6-FD positron emission tomographic studies in parkinsonian patients will therefore not be altered by 3OMD present in the blood in those patients taking L-dopa preparations. These results do not support the hypothesis that transport of L-dopa into the brain is inhibited by 3OMD to cause the declining response seen in patients with advanced Parkinson's disease.

Amino Acid Transport Systems↗
PubMed1992

Influence of the tumor mass on the valine rate constants and on valine incorporation into proteins in an experimental brain tumor model.

Quantitative autoradiography was used to estimate regional transfer coefficients for valine incorporation and the rate of valine (exogenous and total) incorporation into proteins in an implanted brain-tumor model (AA ascites tumor). Special attention was paid to the evaluation of the tumor mass influence on the transfer coefficients and the rate of incorporation. The size of the tumors used in this study ranged from 2 to 5 mm in diameter. Nine groups of two to three animals each were used to determine the transfer coefficient. The transfer coefficients for movement of the label between different compartments were significantly greater in the tumor than in the normal brain. There is no tumor mass effect on the transfer coefficients or the rate of valine incorporation into proteins in surrounding or remote brain structures. The ratio between specific radioactivities of the free value in tissue and plasma was also measured. Results indicate that approximately the same fraction of the total valine is recycled in cortex as in the tumor tissue. The mean rates of exogenous valine incorporation into proteins (nmol g-1 min-1) is about one order of magnitude greater in the tumor than in the contralateral parietal cortex.

Animals↗
PubMed1992

Blood-brain barrier transfer of L-Trp and alpha-MTrp in Li-treated rats.

Blood-brain barrier (BBB) transport for L-Trp and alpha-methyl-L-tryptophan was evaluated in Li-treated rats. Five different brain areas as well as left to right differences were examined. No left to right difference in the PS product was observed. Lithium treatment had a significant effect on the plasma concentration of Val, Leu and Ile but no effect on plasma total or free Trp. The ratio of plasma Trp to the sum of Leu, Val, Ile, Phe, Met and Tyr is increased in the Li-treated rats but not significantly. However, the ratio of Trp/(Val+Leu+Ile) is significantly increased in the Li-treated rats. The Km apparent (Kmapp) for the BBB Trp transport is significantly decreased (affinity of the carrier for Trp is increased) in the Li-treated rats. A decrease in the Kmapp is one of the possible factors responsible for an increase in the brain Trp concentration and subsequent increase in the brain serotonin synthesis in Li-treated rats.

Animals↗
PubMed1992

Synthesis, receptor binding and target-tissue uptake of carbon-11-labeled carbamate derivatives of estradiol and hexestrol.

Carbon-11-labeled estradiol and hexestrol derivatives were prepared via the reaction of [11C]ethylchloroformate with the 2- and 4-amino derivatives of estradiol, the 3'-amino derivatives of hexestrol, and the 1-aminophenoxy derivatives of hexestrol and 1-norhexestrol. The corresponding nonradioactive carbamates were prepared for chemical characterization and in vitro receptor binding assays. The positions of the substituents on the parent molecules were selected with a view to minimize interference with the receptor binding process. In spite of this, affinity for the estrogen receptor was strongly impaired for all carbamate derivatives. Likewise, in vivo, the [11C]carbamate analogs failed to localize in receptor rich tissue via an estrogen receptor mediated process.

Amines↗
PubMed1991

Dopa decarboxylase activity of the living human brain.

Monoaminergic neurons use dopa decarboxylase (DDC; aromatic-L-amino-acid carboxy-lyase, EC 4.1.1.28) to form dopamine from L-3,4-dihydroxyphenylalanine (L-dopa). We measured regional dopa decarboxylase activity in brains of six healthy volunteers with 6-[18F]fluoro-L-dopa and positron emission tomography. We calculated the enzyme activity, relative to its Km, with a kinetic model that yielded the relative rate of conversion of 6-[18F]fluoro-L-dopa to [18F]fluorodopamine. Regional values of relative dopa decarboxylase activity ranged from nil in occipital cortex to 1.9 h-1 in caudate nucleus and putamen, in agreement with values obtained in vitro.

Brain↗
PubMed1991

Pharmacokinetics of 11C-labelled BCNU and SarCNU in gliomas studied by PET.

This paper describes the study of the pharmacodynamics of two 11C-labelled nitrosoureas, 1,3-bis-(2-chloroethyl) nitrosourea (BNCU) and sarcosinamide chloroethylnitrosourea (SarCNU), both labelled in the carbonyl position. Distribution of the radioactivity as measured by positron emission tomography was compared to the distribution of radioactivity observed after injection of 68Ga-EDTA, this being used as an indicator of the blood-brain barrier integrity around the brain tumor. Data suggest that the new nitrosourea, SarCNU, most likely enters brain tissue by different mechanism(s) than BCNU, which enters by diffusion. Data also indicate that use of SarCNU may result in a better tumor to brain ratio than BCNU.

Antineoplastic Agents↗
PubMed1991

PET studies of potential chemotherapeutic agents--X. Synthesis of "no-carrier-added" (11C)-HECNU: the hydroxyethyl analog of the chemotherapeutic agent BCNU.

Carbon-11-labeled HECNU [1-(2-chloroethyl)-1-nitroso-3-(2-hydroxyethyl) urea] a potential chemotherapeutic agent, has been prepared by the nitrosation of the corresponding carbon-11-labeled urea, HECU, [1-(2-chloroethyl)-3-(2-hydroxyethyl) urea]. The isometric byproduct of nitrosation, 1-(2-chloroethyl)-3-nitroso-3-(2-hydroxyethyl) urea can be efficiently removed by preparative scale HPLC on a Partisil column. (11C)-HECU was prepared by reacting ethanolamine with (11C)-2-chloroethyl-isocyanate which was itself prepared by reacting [11C)-phosgene with 2-chloroethylamine hydrochloride suspended in dioxane at 60-65 degrees C. This synthesis yielded (11C)-HECNU with an average radiochemical purity of 98% in an average radiochemical yield of 18% relative to the radioactivity measured at the end of the 11C-phosgene introduction.

Carbon Radioisotopes↗
PubMed1991

Neurotoxicity after intracarotid 1,3-bis(2-chloroethyl)-1-nitrosourea administration in the rat: hemodynamic changes studied by double-tracer autoradiography.

Changes in blood-brain (BBB) permeability and local cerebral blood flow after intracarotid administration of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) were examined quantitatively in rats with double-tracer autoradiography using [14C]alpha-amino-isobutyric acid and [18F]fluoroantipyrine. Forty-eight female Wistar rats were divided into four groups. The control group (Group 1) received 1 ml of 5% dextrose. The other three groups received three different doses of BCNU dissolved in 5% dextrose: Group II rats received 1 mg, Group III 3 mg, and Group IV 10 mg. The tracer study was performed on Day 1 or Days 4 to 12 after intracarotid administration of BCNU. In 11 rats in Group II, there were no changes of BBB permeability. Transient BBB permeability changes were seen in the striatum or hippocampus in 3 of the 5 rats (60%) in Group III within 24 hours. In 8 of 9 rats (89%) in the same group, late BBB permeability changes were observed in the hypothalamus with or without histological changes. BBB permeability changes were seen in all rats of Group IV. Focal increase of local cerebral blood flow on the infused side compared with the non-infused side of the brain was observed, although not at a significant level, in 5 of 25 rats examined with [18F]fluoroantipyrine. The results of BBB permeability and histological examinations and study of heterogenous distribution by [18F]fluorodeoxyglucose indicated that the ipsilateral subcortical structures such as the hypothalamus, amygdala, internal capsule, and caudate putamen have the highest incidence of neurotoxicity, which are closely related to histopathological damage seen in human BCNU leucoencephalopathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminobutyrates↗
PubMed1991

Efficacy of bypass between extracerebral artery and cerebral vein with retrograde verapamil infusion into focal cerebral ischemic tissue in rats.

We examined the efficacy of a bypass from an extracerebral artery to a cerebral vein (EA-CV) with retrograde verapamil infusion on acute focal cerebral ischemia in 35 rats. In 12 rats, within 1 hour after occlusion of the middle cerebral artery (MCAO), changes in blood-brain barrier permeability were examined by [14C]alpha-aminoisobutyric acid autoradiography after EA-CV bypass surgery; there were no significant changes during a period of 2 hours after EA-CV bypass. The other 18 rats having MCAO were divided into three groups of six each. Group A rats (control) underwent only cannulation of the cerebral vein. Group B rats had an EA-CV bypass. Group C rats received verapamil (0.1 mg/kg every 2 h) by transvenous perfusion of the brain (TVPOB) through the EA-CV bypass. In all rats in Groups A and C, local cerebral blood flow (LCBF) and quantitative measurement of early cerebral infarct volume were performed by autoradiography using [14C]iodoantipyrine and histochemical staining methods. Group B rats were examined only with the LCBF measurement. Group B (EA-CV bypass only) showed a nonsignificant improvement (18-40%) of LCBF in the ischemic cerebral cortical areas as compared with control Group A. Group C (EA-CV bypass with TVPOB with verapamil) showed an extensive and significant improvement in LCBF in the ischemic cortical areas (115-140%; P less than 0.05) and a slight increase in LCBF in the subcortical areas (17-29%), with a significant reduction (greater than 35%; P less than 0.05) in a total cerebral infarct volume in the ischemic cerebral hemisphere as compared with the control Group A.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Serotonin synthesis rate measured in living dog brain by positron emission tomography.

In vivo measurements by positron emission tomography of the brain serotonin synthesis rates in the normal dog, in the dog with increased plasma tryptophan concentration, and in the dog under different arterial oxygen tensions are described. The method described here permits repeated measurements in the same brain for the first time. An increase in the plasma tryptophan concentration from 16.6 to 191.5 and then to 381 microM resulted in close to a linear increase in the brain serotonin synthesis rate. When PaO2 was raised from 76 +/- 2 to 106 +/- 1 mm Hg, the rate of serotonin synthesis in the dog brain increased from 39 +/- 8 to 54 +/- 10 pmol g-1 min-1. The estimates of the Michaelis-Menten constants, Kappm and Vmax, for the transport of tryptophan through the blood-brain barrier are 303 +/- 54 microM and 63 +/- 10 nmol g-1 min-1, respectively.

Animals↗
PubMed1991

Stereospecificity of high- and low-affinity transport of choline analogues into rat cortical synaptosomes.

The present experiments used methylcholines to examine the stereoselectivity of choline transport into rat synaptosomes. R(+)-alpha-methylcholine and S(+)-beta-methylcholine were significantly better inhibitors of the high-affinity choline transport system than were their enantiomers. Although both enantiomers of alpha- and of beta-methylcholine inhibited [3H]choline transport, only R(+)-alpha-methylcholine and S(+)-beta-methylcholine could be transported by the high-affinity choline uptake mechanism. Therefore, we conclude that the chiral requirements for recognition of and for transport by the high-affinity transporter are clearly different. In addition to high-affinity choline transport, Na(+)-independent low-affinity transport was measured. This process transported R(+)-alpha-methylcholine, but not S(-)-alpha-methylcholine; however, it showed no stereoselectivity for the enantiomers of beta-methylcholine. Thus, high- and low-affinity choline transport mechanisms exhibit distinct differences in their substrate selectivities. We suggest that the stereoselective properties of choline transport might present a unique opportunity to study choline uptake and metabolism.

Animals↗
PubMed1991

Efficacy of retrograde perfusion of the cerebral vein with verapamil after focal ischemia in rat brain.

BACKGROUND AND PURPOSE: For treatment of acute stroke, drug therapy administered systemically has been unreliable due to inadequate delivery of drug into ischemic tissue. We have developed a new method to deliver drugs into the ischemic tissue by retrograde perfusion of the cerebral vein. METHODS: We examined in rats the effectiveness of administering verapamil into ischemic tissue by retrograde perfusion through the cerebral vein, starting 3 hours after occlusion of the middle cerebral artery. Twenty-four Fischer-344 rats with occlusion of the middle cerebral artery were divided into four groups of six rats each. Group A rats had no treatment, group B rats received verapamil intravenously, and groups C and D rats received verapamil by transvenous perfusion of the brain with blood and with saline, respectively. We studied local cerebral blood flow using the autoradiographic method with carbon-14-labeled iodoantipyrine and examined cerebral infarct volume with cresyl violet and Luxol fast blue staining. RESULTS: As compared with group A rats, in groups C and D rats we found a significant and extensive increase of cerebral blood flow in the ischemic cortical and subcortical areas (55-119%, p less than 0.05) and a significant reduction of cerebral infarct volume (31-39%, p less than 0.05). We found no significant changes in group B rats. CONCLUSIONS: This study shows that transvenous perfusion of the brain with verapamil starting 3 hours after occlusion of the middle cerebral artery produces a significantly beneficial effect in rats.

Animals↗
PubMed1990

Non-invasive in-vivo autoradiographic method to measure axonal transport in serotoninergic neurons in the rat brain.

We studied axonal transport of serotoninergic neurons by autoradiography following intravenous administration of alpha-[14C]methyl-L-tryptophan (alpha-[14C]MTrp). Autoradiograms obtained 24 h after intravenous injection of the tracer demonstrated clearly all raphe nuclei and the major ascending pathway, the medial forebrain bundle (MFB). From these autoradiograms it was clear that radioactivity traveling along the MFB had already reached the substantia nigra and ventrolateral geniculate body nuclei, terminal field. The whole route of the MFB was well visualized from an axial cross-section of a three-dimensional display of data. Autoradiograms obtained at 6 h after injection revealed only the caudal part of the MFB but all raphe nuclei were labelled, indicating that the tracer was in the process of being transported, probably as an alpha-methyl-5-hydroxytryptamine, via the MFB. The axonal transport rate was estimated from the brain autoradiograms of 4 rats killed 6 h after injection of the tracer. The mean distance of the tracer transported via the medial forebrain bundle in 4 rats was 3.8 +/- 0.4 (S.D.) mm, which corresponded to the level of the posterior to mid-hypothalamus. The axonal transport rate calculated from this distance from the medial raphe was 0.63 +/- 0.07 mm/h (14 mm/day). There was no significant difference in the axonal transport rate between the right and left side of the MFB.

Animals↗
PubMed1990

Biological model for the in vivo measurement of rate of serotonin synthesis in the brain.

A biological model for the measurement of the rate of serotonin synthesis in rat brain with alpha-[14C]methyl-L-tryptophan is described. The rate of serotonin synthesis in several grossly dissected brain structures is reported. The half-life of the precursor pool, estimated from kinetic data, is between 20 and 25 min. The method allows, for the first time, measurement of the brain serotonin synthesis rate without any pharmacological manipulation and does not require separation of metabolites. Autoradiographic data are also presented to demonstrate anatomical resolution of this method. The synthesis rate can be estimated in a large number of discrete structures when autoradiography is applied. Long retention of the tracer in brain is also demonstrated.

Animals↗
PubMed1990

A new method to measure brain serotonin synthesis in vivo. I. Theory and basic data for a biological model.

We describe here an autoradiographic method to measure the in vivo rate of serotonin synthesis in rat brain. The method is based on the use of the L-tryptophan analogue alpha-methyl-L-tryptophan (alpha-MTrp), which is converted in vivo into alpha-methylserotonin (alpha-M5HT). Since alpha-M5HT is not a substrate for monoamine oxidase, it is accumulated in the brain tissue. Data are presented to confirm time-dependent conversion of alpha-MTrp into alpha-M5HT in the dorsal raphe nucleus and also in the pineal body, an organ outside the blood-brain barrier. It has also been shown that washing brain slices in 10% trichloroacetic acid results in less than 3% incorporation of alpha-MTrp into brain proteins. The rates of synthesis are calculated in several grossly dissected brain structures by using tracer kinetics and a three-compartment biological model. The half-life of the precursor pool is estimated to be approximately 20 min. The rate of serotonin synthesis is highest in the pineal body.

Animals↗
PubMed1990

Blood-brain transfer and metabolism of 6-[18F]fluoro-L-dopa in rat.

In a study designed to reveal the rates of blood-brain transfer and decarboxylation of fluoro-L-3,4-dihydroxyphenylalanine (FDOPA), we discovered a major discrepancy between the DOPA decarboxylase activity reported in the literature and the rate of FDOPA decarboxylation measured in the study. "Donor" rats received intravenous injections of 6 mCi fluorine-18-labeled FDOPA. The donor rats synthesized methyl-FDOPA. Arterial plasma, containing both FDOPA and methyl-FDOPA, was sampled from the donor rats at different times and reinjected into "recipient" rats in which it circulated for 20 s. The blood-brain clearance of the mixture of labeled tracers in the plasma was determined by an integral method. The individual permeabilities were determined by linear regression analysis, according to which the average methyl-FDOPA permeability in the blood-brain barrier was twice that of FDOPA, which averaged 0.037 ml g-1 min-1. The permeability ratio was used to determine the fractional clearance from the brain of FDOPA (and hence of methyl-FDOPA), which averaged 0.081 min-1. In the striatum, the measured average FDOPA decarboxylation rate constant (kD3) was 0.010 min-1, or no more than 1% of the rate of striatal decarboxylation of DOPA measured in vitro and in vivo. We interpreted this finding as further evidence in favor of the hypothesis that striatum has two dopamine (DA) pools, of which only DA in the large pool is protected from metabolism. Hence, no more than 1% of the quantity of fluoro-DA theoretically synthesized was actually retained in striatum.

Animals↗