Peri-Infarct Depolarizations Reveal Penumbra-Like Conditions in Striatum

Umegaki, Masao; Sanada, Yasuhiro; Waerzeggers, Yannic; Rösner, Gerhard; Yoshimine, Toshiki; Heiss, Wolf‐Dieter; Graf, Rudolf

doi:10.1523/jneurosci.4182-04.2005

Cited by 29 publications

(20 citation statements)

References 43 publications

(60 reference statements)

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“…We have previously reported that the striatum is dramatically protected by estradiol in female mice following MCAO (Dubal, et al, 2006, Dubal, et al, 2001, Suzuki, et al, 2007), but the exact mechanism is unclear. The dramatic level of neuroprotection we observe in the striatum may be due to estradiol-mediated suppression of spreading depression from the cortex (Umegaki, et al, 2005, Witte, et al, 2000. In addition, a direct effect of estradiol in the striatum has been attributed to the activation of non-classical, membrane-bound estrogen receptors (Xiao, et al, 2003).…”

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confidence: 77%

Inducible nitric oxide synthase and estradiol exhibit complementary neuroprotective roles after ischemic brain injury

Brown

Cruz

Yang

et al. 2008

Experimental Neurology

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Estradiol-17β exerts profound neuroprotective actions following cerebral ischemia through multiple molecular mechanisms. To examine the putative anti-inflammatory mechanisms employed by estradiol during stroke, we explored the interactions between estradiol and inducible nitric oxide synthase (iNOS) in both wildtype and iNOS knockout (iNOSKO) female mice following permanent middle cerebral artery occlusion (MCAO). Female mice were ovariectomized and treated with estradiol. One week later, they were subjected to MCAO, and then killed 24 hours later. Analysis of total, cortical and striatal infarct volumes confirmed that estradiol is neuroprotective in wildtype mice. Infarct volumes were also significantly smaller in female iNOSKO female mice, but estradiol did not further decrease injury. We found that one mechanism by which estradiol may act is by decreasing nitric oxide synthase 2 gene expression in the cortex and in the striatum of wildtype mice. These results show that the pro-inflammatory actions of iNOS exacerbate stroke-induced injury within the cortex and striatum, and that iNOS deletion is neuroprotective in ovariectomized and estrogen-replaced female mice. Keywords estradiol; estrogen; iNOS; stroke; inflammation; nitric oxide synthase; ischemia; middle cerebral artery occlusion Stroke is a complex neurological disorder characterized by loss of cerebral blood flow, significant cell death, both necrotic and apoptotic in nature, and an enhanced inflammatory response (Dirnagl, et al., 1999). Women appear to be protected against stroke compared to men since studies show that premenopausal women have a lower incidence of stroke compared to age-matched males, but this protection is lost after the menopause (American Heart Association, 2004, Bushnell, et al., 2006. The biological basis of this protection has been thought to result from the neuroprotective properties of 17β-estradiol. However, the results of the Women's Health Initiative (WHI), which concluded that estrogen treatment afforded no Please address correspondence and reprint requests to: Candice M. Brown, Ph.D., Department of Physiology and Biophysics, University of Washington, 1959 NE Pacific St., Health Sciences Building BB-604, Box 356460, Seattle, WA 98195, Telephone: (206) Fax: (206) 543-5480, Email: canbrown@u.washington.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. benefit or could increase risk for stroke in certain age groups, have encouraged reexamination of the actions of this hormone and its mechanisms of action (Anderson, et al., 2004, Rossouw, et al., 2007, Turgeon, et al., 2...

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confidence: 77%

Inducible nitric oxide synthase and estradiol exhibit complementary neuroprotective roles after ischemic brain injury

Brown

Cruz

Yang

et al. 2008

Experimental Neurology

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“…Despite these changes, CSDs do not cause any longlasting structural damage to otherwise healthy brain tissue (Nedergaard and Hansen, 1988). In ischemic brain, however, repetitive waves of depolarization result in stepwise depletion of energy stores and functional as well as structural deterioration of the penumbra leading to an increase of infarcted tissue volume (Ohta et al, 2001;Selman et al, 2004;Hopwood et al, 2005;Umegaki et al, 2005). The deleterious effects of CSDs are believed to be mainly mediated by a lack of compensatory hyperperfusion usually occurring to match the metabolic strain caused by repolarization (Back et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Role of Cortical Spreading Depressions for Secondary Brain Damage after Traumatic Brain Injury in Mice

Baumgarten¹,

Trabold²,

Thal³

et al. 2008

J Cereb Blood Flow Metab

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In recent years, several studies have unequivocally shown the occurrence of cortical spreading depressions (CSDs) after stroke and traumatic brain injury (TBI) in humans. The fundamental question, however, is whether CSDs cause or result from secondary brain damage. The aim of the current study was, therefore, to investigate the role of CSDs for secondary brain damage in an experimental model of TBI. C57/BL6 mice were traumatized by controlled cortical impact. Immediately after trauma, each animal showed one heterogeneous direct current (DC) potential shift accompanied by a profound depression of electroencephalogram (EEG) amplitude, and a temporary decrease of ipsi-and contralateral regional cerebral blood flow (rCBF) suggesting bilateral CSDs. Within the next 3 h after TBI, CSDs occurred at a low frequency (0.38 CSD/h per animal, n = 7) and were accompanied by rCBF changes confined to the ipsilateral hemisphere. No significant relationship between the number of SDs and lesion size or intracranial pressure (ICP) could be detected. Even increasing the number of posttraumatic CSDs by application of KCl by more than six times did not increase ICP or contusion volume. We therefore conclude that CSDs may not contribute to posttraumatic secondary brain damage in the normally perfused and oxygenated brain.

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“…Murphy et al (2008) demonstrated that ischemic depolarizations and increases in intracellular calcium were glutamate receptor independent and suggested that these depolarizations were the major ionic event associated with the degeneration of synaptic structure early after ischemic onset. Notably, persistent depolarizations resembling anoxic depolarization and transient depolarizations resembling recurrent peri-infarct depolarizations emerge not only in cortex, but also occur in striatal gray matter, suggesting that infarct expansion due to peri-infarct depolarization extends beyond the cortex (Umegaki et al, 2005).…”

Section: Peri-infarct Depolarizationsmentioning

confidence: 99%