Zinc deficiency exacerbates loss in blood-brain barrier integrity induced by hyperoxia measured by dynamic MRI.
ABSTRACT Using dynamic Magnetic Resonance Imaging (dMRI), blood-brain barrier (BBB) permeability (k(PSrho)) and tissue interstitial leakage space (v(e)) were evaluated in zinc-deficient (ZnDF) male weanling Wistar rats following 3 days exposure to hyperoxia (85% O2). Temporal monitoring of T1-weighted MR image changes, following a bolus intravenous injection of gadolinium-DTPA, allowed estimation of BBB integrity. Three-day exposure of hyperoxia caused a marginal loss of BBB integrity, reflected in a slight increase in kPSrho and v(e), observed in both the animals fed adequate zinc (ZnAL) and pair-fed controls (ZnPF). However, zinc deficiency resulted in a significant increase in both kPSrho and v(e), indicating a severely disturbed BBB. In addition MR-visible free water was elevated in ZnDF brains following hyperoxia treatment indicating that a loss of BBB integrity may be associated with neuronal edema. The diminished BBB integrity may be free-radical mediated as the ratio of oxidized to reduced glutathione (GSSG:GSH) was significantly elevated.
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ABSTRACT: Three major models (from Tofts, Larsson, and Brix) for collecting and analyzing dynamic MRI gadolinium-diethylenetriamine penta-acetic acid (Gd-DTPA) data are examined. All models use compartments representing the blood plasma and the abnormal extravascular extracellular space (EES), and they are intercompatible. All measure combinations of three parameters: (1) kpsρ is the influx volume transfer constant (min−1), or permeability surface area product per unit volume of tissue, between plasma and EES; (2) ve is the volume of EES space per unit volume of tissue (0 < ve < 1); and (3) kep, the efflux rate constant (min−1), is the ratio of the first two parameters (kep = kpsρ/ve). The ratio kep is the simplest to measure, requiring only signal linearity with Gd tracer concentration or, alternatively, a measurement of T1 before injection of Gd (T10). To measure the physiologic parameters kpsρ and ve separately requires knowledge of T10 and of the tissue relaxivity R1 (≈ in vitro value).Journal of Magnetic Resonance Imaging 12/1996; 7(1):91 - 101. · 2.57 Impact Factor
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ABSTRACT: Preterm infants are at risk for copper and zinc depletion if sufficient quantities of these nutrients are not provided in a bioavailable form in postnatal life. The purpose of this study was to determine whether the use of a whey-predominant, 50% medium chain triglyceride formula with relatively high concentrations of zinc and copper would promote the achievement of the in utero accretion rate for zinc and copper in the preterm infant. Two groups of five preterm infants were fed a diet containing 12.5 mg/L of zinc and either 0.9 mg/L or 2.1 mg/L of copper. Seventy-two-hour metabolic balance studies were performed at an average postconceptual age of 34 weeks and an average weight of 1,549 g. All infants were in positive zinc balance and nine of ten achieved the in utero accretion rate for zinc for a 34-week gestation fetus (greater than or equal to 0.432 mg/d). Three infants receiving the high copper formula and two receiving the lower copper formula were in positive copper balance. Two infants from each group achieved the in utero accretion rate for copper for a 34-week gestation fetus (0.088 mg/d). A formula that provides 12.5 mg/L of zinc permits positive zinc balance and zinc retention similar to in utero rates. A formula that provides as much as 2.1 mg/L of copper, however, may not always permit positive copper balance.Pediatrics 05/1986; 77(4):513-7. · 5.12 Impact Factor
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ABSTRACT: Periventricular white matter injury, the principal variety of brain injury of the human premature infant, involves differentiating oligodendroglia. Nothing is known of the biochemical mechanism of oligodendroglial death in this disorder. Because an early event in periventricular white matter injury is ischemia-induced axonal disruption and because such axonal destruction could lead to a marked increase in local concentrations of glutamate, we evaluated the vulnerability of differentiating oligodendroglia to glutamate in a culture model. Oligodendroglia were isolated from mixed-glial primary cultures by a selective detachment technique and grown in a primary culture under conditions that lead to differentiation. These oligodendroglia were found to be highly vulnerable to glutamate-induced cell death. The EC50 for glutamate for a 24 hr exposure was approximately 200 microM, comparable to the value reported for neurons in conventional cerebral cortical cultures. Astrocytes, in contrast, were shown to be resistant to as much as 5 mM glutamate. Study of glutamate receptor antagonists and glutamate transport substrates showed that the glutamate-induced oligodendroglial death was not related to a receptor mechanism, as operates in neurons, but rather was secondary to glutamate uptake by the oligodendroglia. Glutamate transport by high-affinity, sodium-dependent and by sodium-independent systems was shown. The central importance of glutamate uptake for the toxic effect of glutamate was shown by total prevention of the oligodendroglial toxicity by the simultaneous inhibition of glutamate uptake by the specific inhibitor D,L-threo-beta-hydroxyaspartate. Subsequent observations showed that the toxicity of glutamate was mediated by free radical attack, the consequence of glutathione depletion, apparently caused by the action of a glutamate-cystine exchange mechanism that results in cystine and thereby glutathione depletion. Thus, addition of cystine or cysteine totally prevented the glutamate toxicity to oligodendroglia. Second, glutamate exposure led to cystine efflux. Third, glutathione levels decreased markedly in cells exposed to glutamate, and this marked decrease preceded the loss of cell viability. Fourth, glutamate toxicity could be prevented totally by exposure to different free radical scavengers, vitamin E and idebenone. The data thus show that glutamate is highly toxic to oligodendroglia. Moreover, the findings raise the possibilities that such glutamate toxicity is operative in the oligodendroglial cell death associated with ischemic processes that disrupt axons, such as periventricular white matter injury of the premature infant, and that novel therapies directed against glutamate transport, glutathione depletion, and free radical attack might be beneficial in prevention of that injury.Journal of Neuroscience 05/1993; 13(4):1441-53. · 6.91 Impact Factor