Ascorbate Inhibits Edema in Brain Slices

Brahma, Birendra Kumar; Forman, R E; Stewart, Emma E.; Nicholson, Charles; Rice, Margaret E.

doi:10.1046/j.1471-4159.2000.741263.x

Cited by 126 publications

(101 citation statements)

References 73 publications

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“…Oxidative stress has been proposed as an important factor in the development of cell swelling. Free radicals have been shown to cause cell swelling in brain slices (Chan et al, 1982(Chan et al, , 1989Brahma et al, 2000), as well as in cultured astrocytes (Chan et al, 1989;Cubells et al, 1994;Staub et al, 1994;Sharma, 1996; C. J. . In keeping with these findings, our study shows that SOD, catalase, and vitamin E all significantly blocked astrocyte swelling caused by ammonia.…”

Section: Discussionmentioning

confidence: 99%

Oxidative Stress and Mitogen-Activated Protein Kinase Phosphorylation Mediate Ammonia-Induced Cell Swelling and Glutamate Uptake Inhibition in Cultured Astrocytes

Jayakumar¹,

Panickar

Murthy³

et al. 2006

J. Neurosci.

192

158

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Hepatic encephalopathy (HE) is a major neurological complication in patients with severe liver failure. Elevated levels of ammonia have been strongly implicated as a factor in HE, and astrocytes appear to be the primary target of its neurotoxicity. Mechanisms mediating key aspects of ammonia-induced astrocyte dysfunction such as cell swelling and inhibition of glutamate uptake are not clear. We demonstrated previously that cultured astrocytes exposed to ammonia increase free radical production. We now show that treatment with antioxidants significantly prevents ammonia-induced astrocyte swelling as well as glutamate uptake inhibition. Because one consequence of oxidative stress is the phosphorylation of mitogen-activated protein kinases (MAPKs), we investigated whether phosphorylation of MAPKs may mediate astrocyte dysfunction. Primary cultured astrocytes exposed to 5 mM NH 4 Cl for different time periods (1-72 h) significantly increased phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), p38 MAPK , and c-Jun N-terminal kinase (JNK) 1/2/3, which was inhibited by appropriate MAPK inhibitors 1, 4-diamino-2, 3-dicyano-1, 4-bis (2-aminophenylthio) butadiene (UO126; for ERK1/2), trans-1-(4-hydroxyclyclohexyl)-4-(4-fluorophenyl)-5-(2-methoxypyrimidin-4-yl)imidazole (SB 239063; for p38MAPK ), and anthra[1,9-cd]pyrazol-6(2H)-one (SP600125; for JNK1/2/3), as well as by antioxidants. Kinase inhibitors partially or completely prevented astrocyte swelling. Although SB239063 and SP600125 significantly reversed glutamate uptake inhibition and ammonia-induced decline in glutamate-aspartate transporter protein levels, UO126 did not, indicating a differential effect of these kinases in ammonia-induced astrocyte swelling and glutamate transport impairment. These studies strongly suggest the involvement of oxidative stress and phosphorylation of MAPKs in the mechanism of ammonia-induced astrocyte dysfunction associated with ammonia neurotoxicity.

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Section: Discussionmentioning

confidence: 99%

Oxidative Stress and Mitogen-Activated Protein Kinase Phosphorylation Mediate Ammonia-Induced Cell Swelling and Glutamate Uptake Inhibition in Cultured Astrocytes

Jayakumar¹,

Panickar

Murthy³

et al. 2006

J. Neurosci.

192

158

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“…Parenchymal arteriole (PA) function was assessed with a well-established brain slice preparation (4,5,15). After death, the brain was removed and 300-m-thick coronal slices were cut in ice-cold artificial cerebrospinal fluid (aCSF) containing (mM) 3 KCl, 120 NaCl, 1 MgCl 2, 26 NaHCO3, 1.25 NaH2PO4, 2 CaCl 2, 10 glucose, and 0.4 L-ascorbic acid, equilibrated with 95% O 2-5% CO2 (3).…”

Section: Methodsmentioning

confidence: 99%

Early effects of high-fat diet on neurovascular function and focal ischemic brain injury

Prakash

Chawla

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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-Obesity is a risk factor for stroke, but the early effects of high-fat diet (HFD) on neurovascular function and ischemic stroke outcomes remain unclear. The goal of this study was to test the hypotheses that HFD beginning early in life 1) impairs neurovascular coupling, 2) causes cerebrovascular dysfunction, and 3) worsens short-term outcomes after cerebral ischemia. Functional hyperemia and parenchymal arteriole (PA) reactivity were measured in rats after 8 wk of HFD. The effect of HFD on basilar artery function after middle cerebral artery occlusion (MCAO) and associated O-GlcNAcylation were assessed. Neuronal cell death, infarct size, hemorrhagic transformation (HT) frequency/severity, and neurological deficit were evaluated after global ischemia and transient MCAO. HFD caused a 10% increase in body weight and doubled adiposity without a change in lipid profile, blood glucose, and blood pressure. Functional hyperemia and PA relaxation were decreased with HFD. Basilar arteries from stroked HFD rats were more sensitive to contractile factors, and acetylcholine-mediated relaxation was impaired. Vascular O-GlcNAcylated protein content was increased with HFD. This group also showed greater mortality rate, infarct volume, HT occurrence rate, and HT severity and poor functional outcome compared with the control diet group. These results indicate that HFD negatively affects neurovascular coupling and cerebrovascular function even in the absence of dyslipidemia. These early cerebrovascular changes may be the cause of greater cerebral injury and poor outcomes of stroke in these animals. cerebral ischemia; high-fat diet; hemorrhagic transformation; neurovascular coupling; vascular dysfunction OBESITY IS an independent risk factor for acute ischemic stroke (AIS) (19,36). An alarming recent report showed that the prevalence of AIS dramatically increased in children and young adults, which positively correlated with increases in risk factors including obesity, lipid disorders, and diabetes (13). Clinical studies also suggest that obesity is an independent predictor of unfavorable functional outcome and mortality in AIS patients treated with tissue plasminogen activator (tPA), the only therapeutic option these patients have (39,40). Given that stroke is the leading cause of disability and that the obesity epidemic is on the rise these clinical and social problems are expected to get worse, and therefore early interventions are necessary. While experimental studies in genetic or diet-induced obesity models have shown increased cerebral infarct size and poor outcomes of stroke (7,25,32,33,41), the early impact of a high-fat diet (HFD) before the development of obesity on AIS injury and functional outcomes is not known.It is known that the brain relies heavily on constant blood flow for proper function. Two important mechanisms that contribute to the regulation of cerebral blood perfusion are autoregulatory behavior of cerebral vessels and functional hyperemia upon increased neuronal activity (11,16,20). HFD can negatively af...

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“…Following anesthesia with pentobarbital, the brain was rapidly removed, and 300-m-thick coronal slices were cut in ice-cold artificial cerebrospinal fluid (aCSF) containing (in mM) 3 KCl, 120 NaCl, 1 MgCl2, 26 NaHCO3, 1.25 NaH2PO4, 2 CaCl2, 10 glucose, and 0.4 L-ascorbic acid, equilibrated with 95% O2-5% CO2. Ascorbic acid was added to reduce cell swelling associated with oxidative stress (8). An aCSF with identical composition was used for bath perfusion in all experiments, except for those assessing the effects of high external…”

Section: Methodsmentioning

confidence: 99%

Tone-dependent vascular responses to astrocyte-derived signals

Blanco

Stern

Filosa

2008

American Journal of Physiology-Heart and Circulatory Physiology

129

114

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Blanco VM, Stern JE, Filosa JA. Tone-dependent vascular responses to astrocyte-derived signals. Am J Physiol Heart Circ Physiol 294: H2855-H2863, 2008. First published May 2, 2008 doi:10.1152/ajpheart.91451.2007.-A growing number of studies support an important contribution of astrocytes to neurovascular coupling, i.e., the phenomenon by which variations in neuronal activity trigger localized changes in blood flow that serve to match the metabolic demands of neurons. However, since both constriction and dilations have been observed in brain parenchymal arterioles upon astrocyte stimulation, the specific influences of these cells on the vasculature remain unclear. Using acute brain slices, we present evidence showing that the specific degree of constriction of rat cortical arterioles (vascular tone) is a key determinant of the magnitude and polarity of the diameter changes elicited by signals associated with neurovascular coupling. Thus elevation of extracellular K ϩ concentration, stimulation of metabotropic glutamate receptors (mGluR), or 11,12-epoxyeicosatrienoic acid application all elicited vascular responses that were affected by the particular resting arteriolar tone. Interestingly, the data suggest that the extent and/or polarity of the vascular responses are influenced by a delimited set point centered between 30 and 40% tone. In addition, we report that distinct, tone-dependent effects on arteriolar diameter occur upon stimulation of mGluR during inhibition of enzymes of the arachidonic acid pathway [i.e., phospholipase A 2, cytochrome P-450 (CYP) -hydroxylase, CYP epoxygenase, and cycloxygenase-1]. Our findings may reconcile previous evidence in which direct astrocytic stimulation elicited either vasoconstrictions or vasodilations and also suggest the novel concept that, in addition to participating in functional hyperemia, astrocyte-derived signals play a role in adjusting vascular tone to a range where dilator responses are optimal. potassium; glutamate; epoxyeicosatrienoic acid; glia; neurovascular coupling ALTHOUGH MUCH ATTENTION HAS been given to the characterization of the signals that mediate "functional hyperemia," the rapid and localized increase in blood flow that occurs after neuronal activation (41, 53), a prominent gap remains in our understanding of the vascular factors that influence the overall neurovascular response. Because vasoactive stimuli typically affect changes in two interdependent physiological parameters of vascular smooth muscle cells (VSMC), namely membrane potential (V m ) and intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ), it is conceivable that the responsiveness of the vessels when presented to such stimuli is in turn affected by the resting arteriolar tone, defined by the particular status of V m and [Ca 2ϩ ] i in VSMC. Previous work in pial arterioles showed indeed that vascular tone critically influences the type of response evoked by several neurogenic stimuli (3, 52). In contrast, the influence of vascular tone in the responses of brain intracortical arter...

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Ascorbate Inhibits Edema in Brain Slices

Cited by 126 publications

References 73 publications

Oxidative Stress and Mitogen-Activated Protein Kinase Phosphorylation Mediate Ammonia-Induced Cell Swelling and Glutamate Uptake Inhibition in Cultured Astrocytes

Oxidative Stress and Mitogen-Activated Protein Kinase Phosphorylation Mediate Ammonia-Induced Cell Swelling and Glutamate Uptake Inhibition in Cultured Astrocytes

Early effects of high-fat diet on neurovascular function and focal ischemic brain injury

Tone-dependent vascular responses to astrocyte-derived signals

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