Effect of Hypoxia on Nitric Oxide Free Radical Generation in the Cerebral Cortex of Newborn Guinea Pigs

Mishra, Om P.; Zanelli, Santina; Ohnishi, S. Tsuyoshi; Anday, Endla K.; Delivoria‐Papadopoulos, Maria

doi:10.1203/00006450-199904020-00262

Cited by 25 publications

(33 citation statements)

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“…Data are expressed as mean±SD, n08-9 *P<0.05, vs. control group; **P<0.05, vs. senescent group reported the increase of lipid peroxidation and decrease of anti-oxidative enzyme activity in the brain injected with Dgal in mice (Cui et al 2000. NaNO 2 -induced hypoxia also increased the free radical production (Klimmek et al 1998;Mishra et al 2000). Therefore, this animal model has been widely used for brain aging and antiaging pharmacology studies.…”

Section: Discussionmentioning

confidence: 97%

FLZ, synthetic squamosamide cyclic derivative, attenuates memory deficit and pathological changes in mice with experimentally induced aging

Fang

Wang

Liu

2012

Naunyn-Schmiedeberg's Arch Pharmacol

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The aim of this study was to investigate the protective effects of N-[2-(4-hydroxy-phenyl)-ethyl]-2-(2,5-dimethoxy-phenyl)-3-(3-methoxy-4-hydroxy-phenyl)-acrylamide (FLZ), a synthetic squamosamide cyclic derivative, on senescent mice induced by D: -galactose/NaNO(2) (120/90 mg/kg, i.p.) once daily for 60 days. FLZ (75 and 150 mg/kg) was orally administered once daily for 30 days after D: -galactose/NaNO(2) treatment for 30 days. The cognitive function of mice was evaluated with step-down task. The brain biomarkers including monoamine oxidase B (MAO-B), glutathione peroxidase (GSH-px), and malondialdehyde (MDA) were determined according to the manufacturer's instructions. The expression of acetylcholinesterase (ACh-E) and choline acetyltransferase (ChAT) protein in the CA1 region of hippocampus were counted by immunohistochemical staining. The results showed that the cognitive function, GSH-px activity in the brain, and the expression of ACh-E and ChAT in the CA1 region of hippocampus were significantly decreased, while MAO-B activity and MDA level in the brain were increased in senescent mice compared with the control mice. FLZ treatment prolonged the step-down latency and decreased the number of step-down errors in the senescent mice. In addition, FLZ treatment increased the GSH-px activity and the expression of ACh-E and ChAT in the hippocampus and decreased the MDA level and MAO-B activity compared with the senescent mice without drug administration. These findings suggested that FLZ improves the performance in the step-down task and the pathological alternations in senescent mice.

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Section: Discussionmentioning

confidence: 97%

FLZ, synthetic squamosamide cyclic derivative, attenuates memory deficit and pathological changes in mice with experimentally induced aging

Fang

Wang

Liu

2012

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Hypoxia resulted in increased phosphorylation of cyclic AMP response element binding (CREB) protein and increased expression of proapototic protein Bax [29,30]. Furthermore, we have demonstrated that hypoxia results in increased generation of NO [23]. The present study specifically investigated the effect of hypoxia on tyrosine phosphorylation of calmodulinion at Tyr 99 in the cerebral cortex of newborn piglets and tested the hypothesis that cerebral hypoxia results in increased tyrosine phosphorylation of calmodulin at Tyr 99 and the hypoxia-induced tyrosine phosphorylation of calmodulin is mediated by nitric oxide derived from nNOS.…”

Section: Discussionmentioning

confidence: 92%

“…concentration in hypoxic synaptosomes [22] may activate several pathways of oxygen free radical generation including the NOS pathway. We demonstrated that cerebral hypoxia results in increased generation of NO free radicals [23]. Peroxynitrite mediated nitration of the NMDA receptor resulted in modification of the NMDA receptorion-channel and the glutamate recognition site similar to hypoxia [24].…”

Section: Introductionmentioning

confidence: 98%

Mechanism of Increased Tyrosine (Tyr99) Phosphorylation of Calmodulin During Hypoxia in the Cerebral Cortex of Newborn Piglets: The Role of nNOS-Derived Nitric Oxide

Mishra

Ashraf

Delivoria‐Papadopoulos

2009

Neurochem Res

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The present study aims to investigate the mechanism of calmodulin modification during hypoxia and tests the hypothesis that hypoxia-induced increase in Tyr(99) phosphorylation of calmodulin in the cerebral cortex of newborn piglets is mediated by NO derived from nNOS. Fifteen piglets were divided into normoxic (Nx, n = 5), hypoxic (Hx, F(i)O(2) of 0.07 for 1 h, n = 5) and hypoxic-pretreated with nNOSi (Hx-nNOSi, n = 5) groups. nNOS inhibitor I (selectivity >2,500 vs. eNOS and >500 vs. iNOS) was administered (0.4 mg/kg, I.V.) 30 min prior to hypoxia. Cortical membranes were isolated and tyrosine phosphorylation (Tyr(99) and total) of calmodulin determined by Western blot using anti-phospho-(pTyr(99))-calmodulin and anti-pTyr antibodies. Protein bands were detected by enhanced chemiluminescence, analyzed by densitometry and expressed as absorbance. The pTyr(99) calmodulin (ODxmm(2)) was 78.55 +/- 10.76 in Nx, 165.05 +/- 12.26 in Hx (P < 0.05 vs. Nx) and 96.97 +/- 13.18 in Hx-nNOSi (P < 0.05 vs. Hx, P = NS vs. Nx). Expression of total tyrosine phosphorylated calmodulin was 69.24 +/- 13.69 in Nx, 156.17 +/- 16.34 in Hx (P < 0.05 vs. Nx) and 74.18 +/- 3.9 in Hx-nNOSi (P < 0.05 vs. Hx, P = NS vs. Nx). The data show that administration of nNOS inhibitor prevented the hypoxia-induced increased Tyr(99) phosphorylation of calmodulin. Total tyrosine phosphorylation of calmodulin was similar to Tyr(99) phosphorylation. We conclude that the mechanism of hypoxia-induced modification (Tyr(99) phosphorylation) of calmodulin is mediated by NO derived from nNOS. We speculate that Tyr(99) phosphorylated calmodulin, as compared to non-phosphorylated, binds with a higher affinity at the calmodulin binding site of nNOS leading to increased activation of nNOS and increased generation of NO.

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“…This hypothesis was further strengthened by the demonstration that inhibition of NO synthesis attenuates NMDA-dependent neurotoxicity in neuronal culture and reduces brain damage produced by middle cerebral artery occlusion in mice [Dawson et al, 1994;Huang et al, 1994;Yun et al, 1997]. In a recent study we have shown that cerebral hypoxia results in generation of nitric oxide free radicals [Mishra et al, 2000], as demonstrated by electron spin resonance spectroscopy of NO. In addition, we have observed that administration of the NOS inhibitor, N-nitro-L-arginine (NNLA), prevented the hypoxia-induced (1) generation of oxygen free radicals, (2) lipid peroxidation of cell membranes, (3) modification of NMDA receptor, and (4) expression of apoptotic protein Bax.…”

Section: Role Of Nitric Oxide In Hypoxic Brain Injurymentioning

confidence: 95%

NMDA receptor and neonatal hypoxic brain injury

Mishra

Fritz

Delivoria‐Papadopoulos

2001

Ment. Retard. Dev. Disabil. Res. Rev.

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The NMDA-type glutamate receptor is a predominant mediator of excitotoxicity in the immature brain due to overexpression of the receptor in the developing brain. Within the development period however, the extent of NMDA receptor mediated processes including hypoxia-induced excitotoxicity may depend on the ontogeny of the NMDA receptor recognition and modulation sites, and subunits leading to altered function of the ion-channel comples. The function of the receptor may be modified by intracellular mechanisms such as phosphorylation/dephosphorylation, nitration, and generation of free radicals including nitric oxide. The susceptibility of the developing brain to hypoxia depends on several factors: the lipid composition of the brain cell membrane; the rate of membrane lipid peroxidation and the status of anti-oxidant defenses; the development and modulation of the NMDA receptor sites; the intracellular Ca(2+) influx mechanisms; expression of apoptotic and antiapoptotic genes such as Bax and Bcl-2; and the activation of initiator caspases and caspase-3, the "executioner" of cell death. The developmental status of these cellular mechanisms and their response to hypoxia determine the fate of the hypoxic cell in the developing brain in the fetus and the newborn.

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Effect of Hypoxia on Nitric Oxide Free Radical Generation in the Cerebral Cortex of Newborn Guinea Pigs

Cited by 25 publications

References 0 publications

FLZ, synthetic squamosamide cyclic derivative, attenuates memory deficit and pathological changes in mice with experimentally induced aging

FLZ, synthetic squamosamide cyclic derivative, attenuates memory deficit and pathological changes in mice with experimentally induced aging

Mechanism of Increased Tyrosine (Tyr99) Phosphorylation of Calmodulin During Hypoxia in the Cerebral Cortex of Newborn Piglets: The Role of nNOS-Derived Nitric Oxide

NMDA receptor and neonatal hypoxic brain injury

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