Dextromethorphan protects male but not female mice with brain ischemia

Comi, Anne M.; Highet, Bridget H.; Mehta, Paulomi; Chong, Tae Hana; Johnston, Michael V.; Wilson, Mary Ann

doi:10.1097/01.wnr.0000220136.98918.41

Cited by 18 publications

(16 citation statements)

References 18 publications

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“…These papers support the hypothesis that gender-specific cell death pathways are conserved across species in the perinatal brain. We have also shown that the glutamate antagonist dextromethorphan is protective against stroke in male but not female mice at 12 days of age 144. This finding also supports the greater influence of the excitotoxic pathway in immature males.…”

Section: Apoptotic Mechanisms Involved In Hypoxia-ischemiasupporting

confidence: 78%

Hypoxic-Ischemic Encephalopathy in the Term Infant

Fatemi

Wilson

Johnston

2009

Clinics in Perinatology

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SynopsisHypoxia-ischemia in the perinatal period is an important cause of cerebral palsy and associated disabilities in children. There has been significant research progress in hypoxic-ischemic encephalopathy over the last two decades and many new molecular mechanisms have been identified. Despite all these advances, therapeutic interventions are still limited. In this review paper, we discuss a number of molecular pathways involved in hypoxia-ischemia, and potential therapeutic targets. KeywordsHypoxia ischemia; neonatal encephalopathy; apoptosis; oxidative stress; hypothermia IntroductionHypoxia-ischemia in the perinatal period is an important cause of cerebral palsy and associated disabilities in children. Cerebral palsy is one of the most costly neurologic disabilities because of its frequency (2/1000 births) and persistence over the life span. 1 In the term infant, the most common mechanism of hypoxic injury is intrauterine asphyxia brought on by circulatory problems, such as clotting of placental arteries, placental abruption, or inflammatory processes. 2 These result in perinatal depression leading to diminished exchange of oxygen and carbon dioxide and severe lactic acidosis. 2 A recent study by Graham et al showed that the incidence of neonatal neurologic morbidity and mortality for term infants born with cord pH < 7.0 is approximately 25%. 3 Reduced cardiac output in the setting of hypoxia is referred to as hypoxiaischemia (HI). 4 If an episode of HI is severe enough to damage the brain, it leads within 12 to 36 hours to a neonatal encephalopathy known as hypoxic-ischemic encephalopathy (HIE). 5 This clinical syndrome includes seizures, epileptic activity on electroencephalogram (EEG), 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. NIH Public Access Author ManuscriptClin Perinatol. Author manuscript; available in PMC 2010 December 1. Published in final edited form as:Clin Perinatol. 2009 December ; 36(4): 835-vii. doi:10.1016/j.clp.2009.011. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript hypotonia, poor feeding, and a depressed level of consciousness that typically lasts from 7-14 days. 6 Pathology studies of term neonates who sustained a profound hypoxic-ischemic event show relative cortical sparing and deep gray matter injury particularly involving hippocampi, lateral geniculate nuclei, putamen, ventrolateral thalami, and dorsal mesencephalon. 7 There is no effective pharmacologic therapy, although hypothermia has shown promise in several clinical trials. 8,9 Magnetic resonance imaging (MRI) has markedly improved the understanding ...

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Section: Apoptotic Mechanisms Involved In Hypoxia-ischemiasupporting

confidence: 78%

Hypoxic-Ischemic Encephalopathy in the Term Infant

Fatemi

Wilson

Johnston

2009

Clinics in Perinatology

Self Cite

226

174

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“…For males, androgens improve developing neuron survival in the hypothalamus (36,37) and visual cortex (38). Male neonatal mice injured by unilateral carotid artery ligation also respond preferentially to the neuroprotective effects of dextromethorphan (39). In contrast, hypoxia triggers IGF-1 expression only in developing females, and estrogen reduces brain injury in adult animal models of stroke (40,41).…”

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confidence: 99%

A Comparison of High-Dose Recombinant Erythropoietin Treatment Regimens in Brain-Injured Neonatal Rats

2007

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Recombinant human erythropoietin (rEpo) is neuroprotective in neonatal models of hypoxic-ischemic brain injury. However, the optimal rEpo dose, dosing interval, and number of doses for reducing brain injury are still undetermined. We compared the neuroprotective efficacy of several subcutaneous rEpo treatment regimens. Seven-day-old rats underwent unilateral carotid ligation plus 90 min 8% hypoxia. Treatment began immediately after injury. Treatment regimens examined included 1, 3, or 7 daily subcutaneous injections of either 0 (vehicle), 2,500, 5,000, or 30,000 U/kg rEpo. Gross brain injury, neuronal apoptosis (TUNEL), and gliosis (glial fibrillary acidic protein) were assessed at 48 h or 1 wk post injury. Immunoreactive cells and brain injury were quantified for statistical comparison to vehicle controls. rEpo treatment reduced brain injury, apoptosis, and gliosis, in a dose-dependent U-shaped manner at both 48 h and 1 wk. Neither one injection of 2,500, seven injections of 5,000, or three injections of 30,000 U/kg rEpo were protective. Three doses of 5,000 and one dose of 30,000 U/kg rEpo were most protective at both time intervals. rEpo provides dose-dependent neuroprotection. Of the regimens tested, three doses of 5,000 U/kg was optimal because it provided maximal benefit with limited total exposure. (Pediatr Res 61: [451][452][453][454][455] 2007) N eonatal brain injury continues to affect the lives of thousands of infants in the United States and worldwide. In fact, perinatal asphyxia accounts for 23% of deaths globally (1). Hypothermia following hypoxia-ischemia offers promise of improved neurodevelopmental outcomes, however, thus far, the therapeutic benefit has been modest (2). When strict entry criteria are defined, up to 60% of untreated infants exposed to moderate to severe perinatal hypoxia-ischemia die or have significant neurodevelopmental sequelae (3,4). Erythropoietin (Epo), a hematopoietic cytokine known best for its erythropoietic effects, has neuroprotective effects in many animal models of brain injury, including hypoxia-ischemia, trauma, and excitotoxic injury (5-12). Although many neuroprotective strategies appeared promising in animal models, most have failed clinically (often due to toxicity). In contrast, rEpo is a safe treatment for anemia (13) and, more importantly, the neuroprotective effects of rEpo have translated well from bench to clinical trials for both amyotrophic lateral sclerosis (ALS) (14) and middle cerebral artery stroke (15).Initial studies provided no evidence that the 37 kD charged glycoprotein rEpo could cross the blood-brain barrier (BBB) (16 -18). Therefore, early rEpo neuroprotection experiments used either in vitro application (19,20) or direct intracerebral injection (21). More recently, robust neuroprotection was produced after systemic injection of high-dose rEpo (5,000 U/kg i.p.) (5). Although the neuroprotective rEpo dose is clearly above the anemia treatment range, there is no consensus as to the optimal neuroprotective dose, dose number, or in...

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“…On the morning of P12, equal numbers of male and female animals (Table 1) were subjected to modified Levine procedure (unilateral carotid ligation only) for producing ischemic brain injury as previously described under isoflurane anesthesia [6,7]. Previous studies have demonstrated that early cortical reperfusion occurs in the carotid ligation model [8], thereby mimicking the clinical situation in patients.…”

Section: Surgical Procedures For Ischemic Modelmentioning

confidence: 99%

Systemic Injection of CD34⁺-Enriched Human Cord Blood Cells Modulates Poststroke Neural and Glial Response in a Sex-Dependent Manner in CD1 Mice

Kadam

Chen

Markowitz

et al. 2015

Stem Cells and Development

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Stroke in the developing brain is an important cause of neurological morbidity. We determined the impact of human cord blood-derived CD34+ -enriched mononuclear cells (CBSC) intraperitoneally injected 48 h after an ischemic stroke at postnatal day 12 by evaluating poststroke neurogenic niche proliferation, glial response, and recovery in CD1 mice. Percent brain atrophy was quantified from Nissl-stained sections. Density of BrdU, Iba-1, and GFAP staining were quantified in the dentate gyrus and the subventricular zone (SVZ). Immunohistochemistry for human nuclear antibody, human mitochondrial antibody, and human CD34+ cells was done on injured and uninjured brains from CBSC-and vehicle-treated mice. Developmental neurobehavioral milestones were evaluated pre-and post-treatment. No significant differences in stroke severity were noted between CBSC and vehicle-treated injured animals. With a 1 · 10 5 CBSC dose, there was a significant increase in subgranular zone (SGZ) proliferation in the CBSC-versus vehicle-treated stroke-injured male mice. SVZ glial fibrillary acidic protein (GFAP) expression was increased contralaterally in injured females treated with CBSC but suppressed in injured males. Significant negative correlations between severity of the stroke-injury and spleen weights, and between spleen weights and SGZ proliferation, and a positive correlation between GFAP expression and severity of brain injury were noted in the vehicle-treated injured mice but not in the CBSC-treated mice. GFAP expression and SVZ proliferation were positively correlated. In conclusion, neurogenic niche proliferation and glial brain responses to CBSC after neonatal stroke may involve interactions with the spleen and are sex dependent.

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Dextromethorphan protects male but not female mice with brain ischemia

Cited by 18 publications

References 18 publications

Hypoxic-Ischemic Encephalopathy in the Term Infant

Hypoxic-Ischemic Encephalopathy in the Term Infant

A Comparison of High-Dose Recombinant Erythropoietin Treatment Regimens in Brain-Injured Neonatal Rats

Systemic Injection of CD34⁺-Enriched Human Cord Blood Cells Modulates Poststroke Neural and Glial Response in a Sex-Dependent Manner in CD1 Mice

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Dextromethorphan protects male but not female mice with brain ischemia

Cited by 18 publications

References 18 publications

Hypoxic-Ischemic Encephalopathy in the Term Infant

Hypoxic-Ischemic Encephalopathy in the Term Infant

A Comparison of High-Dose Recombinant Erythropoietin Treatment Regimens in Brain-Injured Neonatal Rats

Systemic Injection of CD34+-Enriched Human Cord Blood Cells Modulates Poststroke Neural and Glial Response in a Sex-Dependent Manner in CD1 Mice

Contact Info

Product

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About

Systemic Injection of CD34⁺-Enriched Human Cord Blood Cells Modulates Poststroke Neural and Glial Response in a Sex-Dependent Manner in CD1 Mice