Simultaneous Measurement of Salicylate Hydroxylation and Glutamate Release in the Penumbral Cortex following Transient Middle Cerebral Artery Occlusion in Rats

Morimoto, Tokio; Globus, Mordecai Y.‐T.; Busto, Raul; Martinez, Elena; Ginsberg, Myron D.

doi:10.1097/00004647-199601000-00011

Cited by 126 publications

(73 citation statements)

References 54 publications

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“…The general time course observed in the control and tamoxifen groups (ie, an initial peak followed by a gradual reduction), is consistent with the decreases seen previously in the penumbra, 19,20 and is different from the pattern observed in more complete ischemia where EAA levels generally rise throughout the ischemic period, and to a much higher level. 2,21 Although the magnitude and time course of EAA concentrations in the current study are similar to what others have found in penumbra defined by moderate blood flow reductions, 19,22 other investigators in penumbra defined by electrical characteristics found small, transient, or even no changes in EAA levels.…”

Section: Eaa Release Via Glt-1 Transporter Reversalsupporting

confidence: 83%

Volume-Regulated Anion Channels Are the Predominant Contributors to Release of Excitatory Amino Acids in the Ischemic Cortical Penumbra

Feustel

Jin

Kimelberg

2004

Stroke

110

106

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Background and Purpose-Release of excitatory amino acids (EAA) is considered a cause of neuronal damage in ischemia. We investigated the sources and mechanisms of EAA release using microdialysis in regions of incomplete ischemia where perfusion was reduced by 50% to 80%, by applying inhibitors of volume-regulated anion channels (VRACs) and the GLT-1 glutamate transporter. Methods-Reversible middle cerebral artery occlusion (rMCAo) was induced in anesthetized rats using the intraluminal suture technique. Microdialysate concentrations of glutamate, aspartate, and taurine were measured before, during 2 hours of rMCAo, and for 2 hours after rMCAo. Vehicle, dihydrokainate (DHK, 1 mmol/L), a GLT-1 inhibitor, or tamoxifen (50 mol/L), a VRAC inhibitor, were administered continuously via the dialysis probes starting one hour prior to ischemia. Results-During incomplete ischemia, dialysate glutamate levels averaged 1.74Ϯ0.31 mol/L (SEM) in the control group (nϭ8), 2.08Ϯ0.33 mol/L in the DHK group (nϭ7), and were significantly lower at 0.88Ϯ0.30 mol/L in the tamoxifen group (nϭ9; PϽ0.05). As perfusion returned toward baseline levels, EAA levels declined in the vehicle and tamoxifen-treated animals but they remained elevated in the DHK-treated animals. Conclusion-In contrast to previous results in severely ischemic regions, DHK did not reduce EAA release in less severely ischemic brain, suggesting a diminished role for transporter reversal in these areas. These findings also support the hypothesis that in regions of incomplete ischemia, release of EAAs via VRACs may play a larger role than reversal of the GLT-1 transporter. Another potential source is through volume-regulated anion channels (VRACs). Although the molecular identity of the channel is unknown, pharmacologic agents known to block VRACs lead to reduced EAA release in vitro 7 and in vivo. 2,9,10 VRACs are also known as volume-sensitive organic anion channels (VSOACs) and, electrophysiologically, as I cl-swell channels. 11,12 In vivo work has primarily been in severely ischemic brain regions; there have been few studies on the mechanisms of EAA release in the less severely affected brain regions. We hypothesize that transporter reversal may make a decreased contribution to EAA release in less severely affected ischemic brain where energy depletion and ionic disruptions are less severe. The normal operation of these transporters in the penumbra would decrease rather than increase EAA release. We used microdialysis, in an area where cerebral blood flow (CBF) is less affected by reversible middle cerebral artery occlusion (rMCAo) to investigate the relative contributions of reversal of the glutamate transporter (GLT-1) and VRACmediated release to EAA increases by studying the effects of inhibitors of the GLT-1 transporter (dihydrokainate, DHK) and VRACs (tamoxifen) on ischemia-induced EAA increases. MethodsAll animal procedures were in accordance with the guidelines for care and use of laboratory animals and were approved by the institutional animal care and use comm...

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Section: Eaa Release Via Glt-1 Transporter Reversalsupporting

confidence: 83%

Volume-Regulated Anion Channels Are the Predominant Contributors to Release of Excitatory Amino Acids in the Ischemic Cortical Penumbra

Feustel

Jin

Kimelberg

2004

Stroke

110

106

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“…However, these changes are much less severe in the ischemic penumbra (Lipton, 1999). Extracellular glutamate concentrations in penumbral tissue are elevated to a lesser extent than in the core (Wang et al, 2001), estimated at 30-50 µM in different studies (Shimada et al, 1990;Wahl et al, 1994;Morimoto et al, 1996).…”

Section: Stroke: Causes Neuronal Injury and Increased Glutamate And Cmentioning

confidence: 98%

“…However, after daily repetition of stimulations, after discharges increase in duration, eventually progressing to spontaneous seizure activity. Blockade of the NMDA receptor inhibits kindling epileptogenesis, demonstrating the necessity of NMDA receptor activation (Croucher et al, 1988(Croucher et al, , 1992Morimoto et al, 1996).…”

Section: In Vitro Models-in Vitro Models Of Se Have Also Been Developmentioning

confidence: 99%

Cellular mechanisms underlying acquired epilepsy: The calcium hypothesis of the induction and maintainance of epilepsy

DeLorenzo

Sun

Deshpande

2005

Pharmacology & Therapeutics

260

286

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Epilepsy is one of the most common neurological disorders. Although epilepsy can be idiopathic, it is estimated that up to 50% of all epilepsy cases are initiated by neurological insults and are called acquired epilepsy (AE). AE develops in 3 phases: (1) the injury (central nervous system [CNS] insult), (2) epileptogenesis (latency), and (3) the chronic epileptic (spontaneous recurrent seizure) phases. Status epilepticus (SE), stroke, and traumatic brain injury (TBI) are 3 major examples of common brain injuries that can lead to the development of AE. It is especially important to understand the molecular mechanisms that cause AE because it may lead to innovative strategies to prevent or cure this common condition. Recent studies have offered new insights into the cause of AE and indicate that injury-induced alterations in intracellular calcium concentration levels [Ca 2+ ] i and calcium homeostatic mechanisms play a role in the development and maintenance of AE. The injuries that cause AE are different, but they share a common molecular mechanism for producing brain damage -an increase in extracellular glutamate concentration that causes increased intracellular neuronal calcium, leading to neuronal injury and/or death. Neurons that survive the injury induced by glutamate and are exposed to increased [Ca 2+ ] i are the cellular substrates to develop epilepsy because dead cells do not seize. The neurons that survive injury sustain permanent long-term plasticity changes in [Ca 2+ ] i and calcium homeostatic mechanisms that are permanent and are a prominent feature of the epileptic phenotype. In the last several years, evidence has accumulated indicating that the prolonged alteration in neuronal calcium dynamics plays an important role in the induction and maintenance of the prolonged neuroplasticity changes underlying the epileptic phenotype. Understanding the role of calcium as a second messenger in the induction and maintenance of epilepsy may provide novel insights into therapeutic advances that will prevent and even cure AE.

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“…Cerebral cortex contains the major part of ischemic penumbra, in which cells are still only mildly damaged and may undergo apoptosis rather than necrosis (26). Therefore, cerebral cortex could be salvageable after ischemic events (17,28). In experimental models of focal brain ischemia infused with edaravone for 90 min its major oxidation product (2-oxo-3-(phenylbutazono)-butanoic acid, OPB) was found in the penumbra area.…”

Section: H Yoshida Et Almentioning

confidence: 99%

Neuroprotective Effects of Edaravone: a Novel Free Radical Scavenger in Cerebrovascular Injury

Yoshida¹,

Yanai²,

Namiki³

et al. 2006

CNS Drug Reviews

352

191

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Recanalization and neuroprotection have been mainly targeted for the specific treatment of acute ischemic stroke. Free radicals play a crucial role in brain ischemic injury by exacerbating membrane damage through peroxidation of unsaturated fatty acids of cell membrane, leading to neuronal death and brain edema. Free radicals have been implicated in stroke pathophysiology as pivotal contributors to cell injury. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a novel potent free radical scavenger that has been clinically used to reduce the neuronal damage following ischemic stroke. Edaravone exerts neuroprotective effects by inhibiting endothelial injury and by ameliorating neuronal damage in brain ischemia. Edaravone provides the desirable features of NOS: it increases eNOS (beneficial NOS for rescuing ischemic stroke) and decreases nNOS and iNOS (detrimental NOS). Post-reperfusion brain edema and hemorrhagic events induced by thrombolytic therapy may be reduced by edaravone pretreatment. Increased productions of superoxide and NO in the brain after reperfusion and a concomitant surge in oxygen free radicals with increased NO during recirculation lead to formation of peroxynitrite, a superpotent radical. Edaravone, which inhibits oxidation and enhances NO production derived from increased eNOS expression, may improve and conserve cerebral blood flow without peroxynitrite generation during reperfusion. Clinical experience with edaravone suggests that this drug has a wide therapeutic time window. The combination therapy (a thrombolytic plus 9

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Simultaneous Measurement of Salicylate Hydroxylation and Glutamate Release in the Penumbral Cortex following Transient Middle Cerebral Artery Occlusion in Rats

Cited by 126 publications

References 54 publications

Volume-Regulated Anion Channels Are the Predominant Contributors to Release of Excitatory Amino Acids in the Ischemic Cortical Penumbra

Volume-Regulated Anion Channels Are the Predominant Contributors to Release of Excitatory Amino Acids in the Ischemic Cortical Penumbra

Cellular mechanisms underlying acquired epilepsy: The calcium hypothesis of the induction and maintainance of epilepsy

Neuroprotective Effects of Edaravone: a Novel Free Radical Scavenger in Cerebrovascular Injury

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