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Biomedical subjects

S I Harik

Publications and source records attributed to S I Harik.

At least 19 recordsLinked to original sources
PubMed1992

Transferrin receptors of rat and human brain and cerebral microvessels and their status in Alzheimer's disease.

We studied the regional distribution of specific [125I]transferrin binding to transferrin receptors in the brains and cerebral microvessels of humans and rats. We also assessed transferrin receptors in subjects with Alzheimer's disease. Human diferric [125I]transferrin bound to regional brain and cerebral microvessels with high affinity (dissociation constants of 1-10 nM), and the maximal binding densities ranged from 30 to 90 pmol/mg protein in the brain and were several-fold higher in cerebral microvessels. In Alzheimer's disease, transferrin receptor densities were significantly reduced in the hippocampus and the temporal and occipital cortex but were unchanged in the frontal and parietal cortex and the cerebellum. Although [125I]transferrin binding was higher in cerebral microvessels from subjects with Alzheimer's disease than in those of age-matched controls, this difference did not attain statistical significance. These results suggest that transferrin receptor density was decreased in some cortical areas including the hippocampus in Alzheimer's disease but relatively unchanged in cerebral microvessels.

Alzheimer Disease↗
PubMed1992

Carnitine acetyltransferase activity in the human brain and its microvessels is decreased in Alzheimer's disease.

L-Carnitine and acetyl-L-carnitine facilitate mitochondrial beta-oxidation of fatty acids. In the brain, they may also have a role in acetylcholine synthesis. Carnitine acetyltransferase catalyzes the interchange between L-carnitine and acetyl-L-carnitine. Recently, acetyl-L-carnitine was reported to have a beneficial effect in patients with Alzheimer's disease. We therefore assessed carnitine acetyl-transferase activity in selected brain regions and in isolated cerebral microvessels obtained at autopsy from patients with Alzheimer's disease and from age-matched control subjects. We found a 25 to 40% decrease in carnitine acetyltransferase activity in patients with Alzheimer's disease, which attained statistical significance in most brain regions and in cerebral microvessels. These findings document another neurochemical abnormality in patients with Alzheimer's disease and provide a rationale for the use of acetyl-L-carnitine in the treatment of patients with Alzheimer's disease.

Aged↗
PubMed1992

Monoamine oxidases of the brains and livers of macaque and cercopithecus monkeys.

We assessed the two forms of monoamine oxidase (MAO), MAO-A and MAO-B, in discrete regions of the brain and in cerebral micro- and macrovessels, choroid plexus, and liver of three species of monkeys: African Green, rhesus, and cynomolgus. MAO was determined by specific [3H]pargyline binding which is stoichiometric and irreversible and by measuring the rate of oxidation of several substrates. Cerebral micro- and macrovessels had low MAO content. Regional brain MAO did not vary by more than one-fold in the brains of each of the three species of monkeys and was higher in the basal ganglia than in the cerebral cortex or cerebellum. MAO in the choroid plexus was low, while the liver had higher MAO activity than any of the brain samples. The vast majority of MAO in all the tissues that we examined was of the MAO-B type, and specific [3H]pargyline binding correlated well with the oxidation rate of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. These results show marked similarities in brain MAO distribution between monkey and man. Or the three monkey species, the African Green monkey had the lowest MAO activity in its cerebral microvessels, which constitute the blood-brain barrier, although the small number of observations in each group did not allow statistical analyses of the differences.

Animals↗
PubMed1992

Nicotine enhances 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity.

Epidemiologic evidence of an inverse relationship between cigarette smoking and Parkinson's disease suggests that a component of cigarette smoke protects against nigrostriatal degeneration. Nicotine, a major component of cigarette smoke, is similar in chemical structure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and is metabolized in part by the same enzymes that detoxify MPTP. We investigated the effect of chronic nicotine on MPTP neurotoxicity in two strains of mice and found that nicotine increases rather than decreases MPTP toxicity. These results are not compatible with the hypothesis that nicotine is that component of cigarette smoke that protects against nigrostriatal degeneration, at least in the MPTP experimental model of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1992

Changes in the glucose transporter of brain capillaries.

Brain capillary endothelium has a high density of the GLUT-1 facilitative glucose transporter protein. This is reasonable in view of the brain's high metabolic rate for glucose and its isolation behind unique capillaries with blood-brain barrier properties. Thus, the brain endothelium, which constitutes less than 0.1% of the brain weight, has to transport glucose for the much larger mass of surrounding neurons and glia. I describe here the changes that occur in the density of glucose transporters in brain capillaries of subjects with Alzheimer disease, where there is a decreased cerebral metabolic rate for glucose, and in a novel clinical entity characterized by defective glucose transport at the blood-brain barrier. In subjects with Alzheimer disease, cerebral microvessels showed a marked decrease in the density of the glucose transporter when compared with age-matched controls, but there was no change in the density of glucose transporters in erythrocyte membranes. Thus, I believe that the decreased density of glucose transporters in the brains of subjects with Alzheimer disease is the result rather than the cause of the disease. In contradistinction, the primary defect in glucose transport at the blood-brain barrier in subjects with the recently described entity is associated with decreased density of GLUT-1 in erythrocyte membranes.

Animals↗
PubMed1991

Correlation of MPTP neurotoxicity in vivo with oxidation of MPTP by the brain and blood-brain barrier in vitro in five rat strains.

We studied 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in 5 strains of rats by assessing mortality and brain monoamine changes after MPTP injections into the internal carotid artery. We then attempted to correlate the differences among rat strains in their susceptibility to MPTP neurotoxicity in vivo with MPTP oxidation by monoamine oxidase (MAO) of the cerebral cortex, striatum, and brain microvessels in vitro. Despite the fact that the carotid route delivers much higher amounts of MPTP to the ipsilateral cerebrum than can be achieved by systemic injections, no significant dopamine depletion occurred in ipsilateral striata of Sprague-Dawley rats (the most resistant strain), but significant reductions of about 40% in striatal dopamine were evident in the more sensitive strains. Decreased striatal dopamine levels in these latter rat strains were associated with increased dopamine turnover. Higher doses of MPTP resulted in acute death. MPTP-induced mortality was not affected, but striatal dopamine depletion was prevented, by MAO inhibition. Differences among rat strains in their susceptibility to MPTP neurotoxicity correlated best with MAO activity in their isolated brain microvessels, but not with MAO activity in their striata or cerebral cortices. These results are consistent with the hypothesis that the rats' resistance to MPTP neurotoxicity is to some extent a property of their unique brain endothelium which has high MAO activity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

The erythrocyte-type glucose transporter in blood vessels of primary and metastatic brain tumors.

We previously demonstrated that brain microvessels have a high density of the erythrocyte-type glucose transporter and suggested this could be used as a marker of cells with "occluding" junctions. Now, we have studied by immunocytochemistry the tissue distribution of the glucose transporter in a variety of primary and metastatic human brain tumors with a monoclonal antibody to the glucose transporter of human erythrocytes. Microvessels in normal brain tissue distant from the tumor, and in brain surrounding the tumor, immunostained strongly for the glucose transporter. Microvessels in primary and metastatic tumors, however, lacked glucose transporter immunoreactivity. Only in the relatively benign juvenile cerebellar astrocytomas was glucose transporter immunoreactivity retained in some of the tumor microvessels. Because a high glucose transporter density is a marker of vessels with barrier properties, our results indicate that the vast majority of brain tumor microvessels do nc, have an intact blood-brain barrier.

Astrocytoma↗
PubMed1991

Bradykinin receptors of cerebral microvessels stimulate phosphoinositide turnover.

We examined by ligand binding methods whether bradykinin (BK) receptors exist in rat and pig cerebral microvessels, and in the cerebral cortex from which the microvessels were isolated. We found a high-affinity and saturable BK receptor site in both rat and pig cerebral microvessels, but not in their cerebral cortex. The maximal density of binding and the dissociation constant were 8.0 +/- 4.1 and 6.8 +/- 1.5 fmol/mg of protein and 47 +/- 24 and 150 +/- 8 pM (mean +/- SD) in cerebral microvessels of the pig and rat, respectively. The high-affinity specific binding of BK was effectively displaced by des-Arg0[Hyp3-Thi5-8,D-Phe7]BK, a specific B2 receptor antagonist, but not by des-Arg9[Leu8]BK, a specific B1 antagonist. We also demonstrated that BK increases phosphatidylinositol hydrolysis in cerebral microvessels of the rat and pig. This effect was also blocked by the B2, but not by the B1, antagonist. Increased phosphatidylinositol hydrolysis was manifested by a rapid transient increase in inositol trisphosphate and the later slow accumulation of inositol bisphosphate and inositol monophosphate. Preincubation of microvessels with phorbol ester, stable GTP analogs, pertussis toxin, or in Ca(2+)-free buffer did not influence BK activation of phosphatidylinositol hydrolysis. These results demonstrate the existence of BK receptors of the B2 subtype in brain microvessels, which may play an important role in modulation of the brain microcirculation, probably via increased phosphoinositide turnover.

Animals↗
PubMed1991

Dopaminergic neurotoxicity in vivo and inhibition of mitochondrial respiration in vitro by possible endogenous pyridinium-like substances.

Elucidation of the mechanism(s) by which 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) and its active metabolite 1-methyl-4-phenylpyridinium (MPP+) cause parkinsonism in humans and other primates has prompted consideration of possible endogenous MPTP/MPP(+)-like neurotoxins in the etiology of idiopathic Parkinson's disease. Here we examined inhibition of mitochondrial respiration in vitro and neurotoxicity in rats in vivo produced by beta-carbolinium compounds that are presumed to form following Pictet-Spengler cyclization of serotonin. We also evaluated N-methylisoquinolinium, a putative endogenous neurotoxin, in the same manner. The latter compound exhibited MPP(+)-like mitochondrial respiratory inhibition, whereas the beta-carbolinium compounds, although more potent inhibitors of electron transport, exhibited weak accumulation-dependent enhancement of inhibition in intact mitochondria. It is interesting that the beta-carbolinium compounds inhibited succinate- as well as glutamate-supported respiration, and are best described as inhibitor-uncouplers. The results of partitioning experiments suggest that both the low accumulation potential and the inhibition of succinate respiration may be a consequence of the beta-carboliniums being in equilibrium with neutral "anhydro" bases. Relative to MPP+, all compounds tested had weak dopaminergic uptake activity in vitro and weak dopaminergic toxicity in vivo, consistent with other findings of relatively low neurotoxic potential for presumed endogenous pyridiniums.

1-Methyl-4-phenylpyridinium↗
PubMed1991

Blood-brain barrier abnormalities in Alzheimer's disease.

We studied the cerebral microcirculation and the blood-brain barrier in Alzheimer's disease by assessing the glucose transporter, several functionally important enzymes, and adrenergic receptors in isolated brain microvessels that were obtained at autopsy from subjects with Alzheimer's disease and from age-matched controls. We found a marked decrease of about 50% in the density of the glucose transporter, but increased densities of beta 2- and alpha 2-adrenergic receptors in cerebral microvessels obtained from subjects with Alzheimer's disease. The biologic implications of these findings are discussed.

Alzheimer Disease↗
PubMed1991

Chronic hyperglycemia increases the density of glucose transporters in human erythrocyte membranes.

We investigated the effect of chronic hyperglycemia on glucose transporters in erythrocytes of subjects with and without diabetes mellitus. We found a 22% increase in D-glucose-displaceable cytochalasin-B binding in erythrocyte membranes of diabetic subjects over those of controls (311 +/- 13 vs. 254 +/- 8 pmol/mg protein; P less than 0.001). This increased binding was due to a higher density of binding sites without a significant change in binding affinity. Cytochalasin-B binding to erythrocyte membrane correlated positively with both erythrocyte glycohemoglobin and serum glucose levels, but not with plasma C-peptide levels. The data are compatible with up-regulation of glucose transporters in the erythrocytes of subjects with chronic hyperglycemia. We suspect that this is brought about by increased synthesis and membrane incorporation of the glucose transporter during erythropoiesis.

Adult↗
PubMed1990

Effects of internal carotid administration of MPTP on rat brain and blood-brain barrier.

Unlike primates, rats are resistant to systemic 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) neurotoxicity, but direct infusion of MPTP into rat substantia nigra causes specific destruction of dopaminergic neurons. We now demonstrate that rats are resistant to MPTP neurotoxicity even when MPTP is injected directly into the brain circulation. Injection of 1-3.5 mg of MPTP into the internal carotid artery of Wistar rats causes no behavioral or motor abnormalities and small, but significant, dopamine loss in the ipsilateral striatum. MPTP caused no changes in the levels of norepinephrine or serotonin in the cerebral cortex. Higher doses of intracarotid MPTP were lethal. Pretreatment with pargyline, a monoamine oxidase inhibitor, did not alter the mortality but prevented dopamine depletion. The high uptake and retention of MPTP by rat brain, yet its failure to cause major dopaminergic toxicity suggest that MPTP is rapidly metabolized in brain capillaries to 1-methyl-4-phenylpyridinium (MPP+) and other polar metabolites that have difficulty in traversing the blood-brain barrier. Sequestration of MPTP metabolites in brain capillary endothelial cells could result in their dysfunction. However, we found no defects in the ability of the blood-brain barrier to prevent the entry of vascular aminoisobutyric acid or horseradish peroxidase into brain in spite of morphologic evidence of endothelial changes and astrocytic swelling after intracarotid MPTP injections. Our results provide further evidence that the rat's resistance to systemic MPTP neurotoxicity is probably due to its unique blood-brain barrier properties.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1990

Structure-neurotoxicity trends of analogues of 1-methyl-4-phenylpyridinium (MPP+), the cytotoxic metabolite of the dopaminergic neurotoxin MPTP.

The dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) derives from its metabolism to 1-methyl-4-phenyl-pyridinium cation (MPP+), which is then selectively accumulated in dopaminergic neurons. In an effort to assess the structural requirements governing MPP+ cytotoxicity, we evaluated dopaminergic toxicity of MPP+ analogues 3 weeks after their microinfusion into rat substantia nigra. We also evaluated the substrate suitability of MPP+ analogues for high-affinity dopamine uptake in striatal synaptosomes by measuring their ability to induce specific dopamine release. The intranigral neurotoxicity of MPP+ analogues in vivo correlates mainly with their in vitro inhibitory activity on mitochondrial respiration, consistent with a compromise in cellular energy production as the principal mechanism of MPTP-induced cell death. This study extends the structure-neurotoxicity data base beyond that obtainable using MPTP analogues, since many of these are not metabolized to pyridinium compounds. Such information is crucial to assess which possible endogenous or exogenous compounds may exert MPTP/MPP(+)-like toxicity.

1-Methyl-4-phenylpyridinium↗
PubMed1990

Glucose transporters are abundant in cells with "occluding" junctions at the blood-eye barriers.

We studied the distribution of the "erythroid/brain" glucose transporter protein in the human and rat eye by immunocytochemistry with monoclonal and polyclonal antibodies to the C terminus of the human erythrocyte glucose transporter. We found intense immunocytochemical staining in the endothelium of microvessels of the retina, optic nerve, and iris but not in microvessels of the choroid, ciliary body, sclera, and other retro-orbital tissues. In addition, we found marked immunocytochemical staining of retinal pigment epithelium, ciliary body epithelium, and posterior epithelium of the iris. The common feature of all those endothelial and epithelial cells that stained intensely for the glucose transporter is the presence of "occluding" intercellular junctions, which constitute the anatomical bases of the blood-eye barriers. We propose that a high density of the glucose transporter is a biochemical concomitant of epithelial and endothelial cells with barrier characteristics, at least in tissues that have a high metabolic requirement for glucose.

Animals↗