Effects of glutamate, quisqualate, and N-methyl-d-aspartate in neonatal brain

Young, Richard S.; Petroff, Ognen A. C.; Aquila, William J.; Yates, Johnnie

doi:10.1016/0014-4886(91)90104-k

Cited by 36 publications

(11 citation statements)

References 21 publications

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“…These findings are in good agreement with those of previous studies that have used NMDA injection (Dijkhuizen et al, 1999;Young et al, 1991). A reduction in the mitochondrial membrane potential (⌬) and impaired mitochondrial function can be expected to occur given the suspected increase in [Ca 2+ ] i (Nicholls and Ward, 2000).…”

Section: W B Veldhuis Et Al 70supporting

confidence: 91%

In Vivo Excitotoxicity Induced by Ouabain, a Na+/K+-ATPase Inhibitor

Veldhuis¹,

Stelt²,

Delmas³

et al. 2003

Journal of Cerebral Blood Flow & Metabolism

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Section: W B Veldhuis Et Al 70supporting

confidence: 91%

In Vivo Excitotoxicity Induced by Ouabain, a Na+/K+-ATPase Inhibitor

Veldhuis¹,

Stelt²,

Delmas³

et al. 2003

Journal of Cerebral Blood Flow & Metabolism

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“…Thus, as compared with adult brain, the larger lesion volumes obtained after ouabain application to neonatal brain are likely due to both the higher sensitivity of neonatal brain to NMDAreceptor overstimulation, and to the less hindered extra- The initial ADC decrease after ouabain injection was not accompanied by a major disturbance in metabolite levels or intracellular pH as detected by 1 H-and 31 P-MRS, respectively. These findings are in good agreement with those of previous studies that have used NMDA injection (Dijkhuizen et al, 1999;Young et al, 1991). A reduction in the mitochondrial membrane potential (⌬) and impaired mitochondrial function can be expected to occur given the suspected increase in [Ca 2+ ] i (Nicholls and Ward, 2000).…”

Section: Ouabain-induced In Vivo Excitotoxicitysupporting

confidence: 82%

In Vivo Excitotoxicity Induced by Ouabain, a Na⁺/K⁺-ATPase Inhibitor

Veldhuis

Stelt

Delmas

et al. 2003

J Cereb Blood Flow Metab

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Summary:The susceptibility of immature rat brain to neurotoxicity of N-methyl-D-aspartate (NMDA) has provided a widely used in vivo paradigm to study excitotoxicity relevant to acute neurodegenerative diseases such as cerebral ischemia. In this study, in vivo excitotoxicity was induced via injection of ouabain (1 mM/0.5 L), a Na + /K + -ATPase-inhibitor, into neonatal rat brain and compared with NMDA injection. The aim of the study was to induce excitotoxicity secondary to cellular membrane depolarization, thereby more closely mimicking the pathophysiologic processes of ischemia-induced brain injury where NMDA-receptor overstimulation by glutamate follows, not precedes, membrane depolarization. Na + /K + -ATPaseinhibition caused an acute, 40% ± 8% decrease of the apparent diffusion coefficient (ADC) of water, as measured using diffusion-weighted magnetic resonance imaging (MRI), and resulted in infarctlike lesions as measured using T 2 -weighted MRI and histology up to 2 weeks later. Localized one-and twodimensional 1 H-magnetic resonance spectroscopy (MRS) demonstrated that the early excitotoxic diffusion changes were not accompanied by an overall metabolic disturbance. Furthermore, 31 P-MRS demonstrated that energy depletion is not a prerequisite for ADC decrease or excitotoxic cell death. Treatment with the NMDA-antagonist MK-801 (1 mg/kg) attenuated the volume of tissue exhibiting a decreased ADC (P < 0.005), demonstrating that the ouabain-induced injury is indeed excitotoxic in nature. The authors argue that, compared with NMDA-injection, ouabain-induced excitotoxicity elicits more appropriate glutamate-receptor overstimulation and is better suited to detect relevant neuroprotection in that it is more sensitive to attenuation of synaptic glutamate levels.

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“…Several source s of data support this hypothesis: (i) glutamate produces neurona l injury similar to that observed after cerebra l hypoxia-ischemia; (ii) elevated extracellu lar levels of glutamate and aspartate are present during cerebral ischemia; (iii) excitatory deafferentation results in improved neuronal survival; and (iv) NMDA receptor an-tagonists exhibit neurop rotective effects under a varie ty of experim ental conditions (1)(2)(3)(4). Although NMDA antagonists may be of therapeutic value in severa l forms of acute brain injury , the pharmacology of these compo unds is complex, and their effects on the developing anima l are not always pred ictable.…”

mentioning

confidence: 91%

Experimental Neuronal Injury in the Newborn Lamb: A Comparison of N-Methyl-D-Aspartic Acid Receptor Blockade and Nitric Oxide Synthesis Inhibition on Lesion Size and Cerebral Hyperemia

Taylor¹,

Trescher

Johnston³

et al. 1995

Pediatr Res

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Vol. 38, No. 5, 1995 Printed in U.S.A.The purpose of this study was to compa re the effects of dizocilipine maleate (MK-801) and W -nitro-L-arginine methyl ester (L-NAME) on focal excitotoxic brain injury and associated hemod ynamic response in the newborn lamb. A 27 gauge needle was placed into the right striatum in 28 anesthetized newborn lambs. Seven animals were placed in each group. A negative control group received 0.2 mL of buffered saline, a positive control group received 5 /Lmol of N-methyl-D-aspartic acid (NMDA) alone, and two groups received NMDA and pretreatment with L-NAME. Ultrasound images and cerebral blood flow determinations (microspheres) were obtained before, and at 20, 40, and 60 min after, intrastrial injection. Three animals in each group underwent histopathologic evaluation. Sonographic lesions were visible immediatel y after intracerebral injection . Saline injection resulted in small lesions (mean volume; 13.6 :t 5 mrrr') without hyperemia. NMDA alone resulted in larger lesions (92.9 :t 24 mrrr') and hyperemia to both hemispheres, whereas pretreatment with MK-801 reduced lesion size (11.7 :t 6 mm") and completely ablated cerebral hyperemia . Pretreatment with L-NAME showed no effect on lesion size (69.9 :t 20 mm") and hyperemia only in the ipsilateral hemisphere. Sonogr aphic lesions correlated well with gross and histopathologic appearance. We concluded that NMDA-induced focal brain injury and associated hyperemia in the newborn lamb appear to be specific NMDA receptor-mediated events. NO production probab ly does not play a major part in NMDA-indu ced neonatal neuronal injury, and may be only partly responsible for regional hyperemia during NMDA injection. (Pediatr Res 38: 644-651 , 1995) Abbr eviations NM DA, N-methyl-D-aspartic acid L-NAME, AP-nitro-L-arginine methyl ester MK-801, dizoci lipine maleate NO, nitric oxide CVR, cerebrovascula r resistance CBF, cerebral blood flow ANOVA, analysis of variance There is considerable evidence now suggesting that glutamate may mediate the neurotoxicity observe d in hypoxicischemic brain injury. Several source s of data support this hypothesis: (i) glutamate produces neurona l injury similar to that observed after cerebra l hypoxia-ischemia; (ii) elevated extracellu lar levels of glutamate and aspartate are present during cerebral ischemia; (iii) excitatory deafferentation results in improved neuronal survival; and (iv) NMDA receptor an-

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Effects of glutamate, quisqualate, and N-methyl-d-aspartate in neonatal brain

Cited by 36 publications

References 21 publications

In Vivo Excitotoxicity Induced by Ouabain, a Na+/K+-ATPase Inhibitor

In Vivo Excitotoxicity Induced by Ouabain, a Na+/K+-ATPase Inhibitor

In Vivo Excitotoxicity Induced by Ouabain, a Na⁺/K⁺-ATPase Inhibitor

Experimental Neuronal Injury in the Newborn Lamb: A Comparison of N-Methyl-D-Aspartic Acid Receptor Blockade and Nitric Oxide Synthesis Inhibition on Lesion Size and Cerebral Hyperemia

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