Estrogen and Selective Estrogen Receptor Modulators: Neuroprotection in the Women's Health Initiative Era

Endocrine. Jun, 2003  |  Pubmed ID: 12777699

Estrogen has been comprehensively studied as a neuroprotective agent in women, animals, and a variety of in vitro models of neural injury and degeneration. Most data suggest that estrogen can benefit the ischemic brain and reduce cell death. However, recent data from the Women's Health Initiative have raised concerns about the utility and safety of chronic estrogen use in women. While estrogen is a potent and reproducible neuroprotectant in animals and in vitro, its current administration in women has had unanticipated and paradoxical effects. Nonetheless, estrogen's diverse actions make it an ideal prototype for developing new neuroprotectants such as selective estrogen receptor modulators (SERMs). SERMs represent a class of drugs with mixed estrogen agonistic and antagonistic activity. Experimental and clinical data suggest a neuroprotective role for SERMs in normal and injured brain. The discrepancy among observational studies, preclinical data, and clinical trials emphasizes the need for further study of the mechanisms leading to the increased incidence of stroke observed in postmenopausal women. Research is still needed to optimize combined or estrogen alone hormone replacement therapy options as well as the prevention/management of cerebrovascular/ central nervous system disorders. This review critiques estrogen and SERMs' neuroprotective potential in experimental and clinical studies of stroke and cerebrovascular disease.

Estrogen and Ischemic Neuroprotection: an Integrated View

Trends in Endocrinology and Metabolism: TEM. Jul, 2003  |  Pubmed ID: 12826329

Women are protected from stroke in their early years relative to men. This native neuroprotection is lost within ten years of the menopause, an observation commonly attributed to loss of estrogen with age. Data are now available from large, randomized, clinical trials that question the use of hormone replacement therapy (HRT) for either the primary or secondary prevention of vascular disease and stroke. In contrast to these studies of disease prevention, evidence from the bench suggests that estrogen is a potent neuroprotectant, demonstrating cell salvage from ischemic death pathways. This apparent dichotomy between the limitation of HRT in ameliorating complex disease development vs the excellent performance of estradiol in containing experimental brain damage remains to be understood.

Aromatase Cytochrome P450 and Extragonadal Estrogen Play a Role in Ischemic Neuroprotection

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Sep, 2003  |  Pubmed ID: 14507969

Female animals are protected from many forms of neurological injury and degeneration relative to their male counterparts, in part attributable to their native estrogens. We hypothesized that estradiol aromatized from precursor androgens via the cytochrome P450 aromatase contributes to ischemic neuroprotection in the female. Female homozygous aromatase knock-out (ArKO) mice and randomly cycling, wild-type (WT) female littermates were treated with reversible middle cerebral artery occlusion (90 min; 22 hr reperfusion). Total and regional ischemic damage was greater in female ArKOs (total, 33.5 +/- 4.8%; cortical, 47.4 +/- 5.7%; striatal, 44.8 +/- 7.8%) compared with WT (total, 14.2 +/- 5%; cortical, 14.2 +/- 4.5%; striatal, 17.5 +/- 8%). Baseline blood pressure and intra-ischemic cortical perfusion were comparable in knock-outs and WT, suggesting that vascular factors do not explain ArKO ischemic sensitivity. Injury was smaller in ovariectomized WT than in ArKO, emphasizing that extragonadal local estradiol plays a critical role in females. Similar increases in cortical and striatal damage were observed in female WT mice chronically treated with the aromatase inhibitor fadrozole compared with vehicle-treated control mice. Restoration of plasma 17beta-estradiol to physiological levels completely reversed the ArKO female's susceptibility to injury. These findings indicate that the biosynthetic enzyme P450 aromatase is key to endogenous neuroprotection in females and suggest that enhancing local, nongonadal estrogen formation could have therapeutic implications is ischemic neuropathology.

Neuroprotective Function of the PGE2 EP2 Receptor in Cerebral Ischemia

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Jan, 2004  |  Pubmed ID: 14715958

The cyclooxygenases COX-1 and COX-2 catalyze the first committed step of prostaglandin synthesis from arachidonic acid. Previous studies in rodent stroke models have shown that the inducible COX-2 isoform promotes neuronal injury, and the administration of COX-2 inhibitors reduces infarct volume. We investigated the function of PGE2, a principal prostaglandin product of COX-2 enzymatic activity, in neuronal survival in cerebral ischemia. PGE2 exerts its downstream effects by signaling through a class of four distinct G-protein-coupled EP receptors (for E-prostanoid: EP1, EP2, EP3, and EP4) that have divergent effects on cAMP and phosphoinositol turnover and different anatomical distributions in brain. The EP2 receptor subtype is abundantly expressed in cerebral cortex, striatum, and hippocampus, and is positively coupled to cAMP production. In vitro studies of dispersed neurons and organotypic hippocampal cultures demonstrated that activation of the EP2 receptor was neuroprotective in paradigms of NMDA toxicity and oxygen glucose deprivation. Pharmacologic blockade of EP2 signaling by inhibition of protein kinase A activation reversed this protective effect, suggesting that EP2-mediated neuroprotection is dependent on cAMP signaling. In the middle cerebral artery occlusion-reperfusion model of transient forebrain ischemia, genetic deletion of the EP2 receptor significantly increased cerebral infarction in cerebral cortex and subcortical structures. These studies indicate that activation of the PGE2 EP2 receptor can protect against excitotoxic and anoxic injury in a cAMP-dependent manner. Taken together, these data suggest a novel mechanism of neuroprotection mediated by a dominant PGE2 receptor subtype in brain that may provide a target for therapeutic intervention.

Chronic Behavioral Testing After Focal Ischemia in the Mouse: Functional Recovery and the Effects of Gender

Experimental Neurology. May, 2004  |  Pubmed ID: 15081592

Several useful behavioral tests exist for measuring behavioral recovery after ischemia in higher-order animals and rats. With the increasing use of mice in focal stroke research, simple, reliable, and reproducible behavioral testing has become a priority. As neuroprotective agents are tested, long-term outcome must be assessed, especially in studies focused on neuronal plasticity and regeneration after ischemia. Our laboratory and others have previously shown that estrogen (E2) is neuroprotective in rodent stroke paradigms. We examined a battery of behavioral tests in male and female mice subjected to 90 min of middle cerebral artery occlusion (MCAO) to determine the most sensitive tests for detecting sensorimotor dysfunction after stroke, and to determine the functional significance of E2-mediated neuroprotection. Only two tests, the corner test and the cylinder test, were able to differentiate between groups (sham and stroke) after several days of repeated testing. The cylinder test was sensitive to the neuroprotective/neurorestorative effects of E2, but 2 weeks after stroke, the cylinder test was unable to distinguish between sham and stroke animals treated with E2. In contrast, the corner test was able to differentiate stroke and sham animals even 6 weeks after stroke, but did not distinguish animals treated with E2 vs. vehicle. These tests provide a simple, rapid, reliable assessment of sensorimotor dysfunction in the mouse after focal ischemia. Hormonal status influences speed of recovery on cylinder testing in animals of both genders. This suggests that a short battery of tests including the neurological score, cylinder, and corner test may be adequate to rapidly and repeatedly assess sensorimotor dysfunction in mice of both genders.

Stroke in the Female: Role of Biological Sex and Estrogen

ILAR Journal / National Research Council, Institute of Laboratory Animal Resources. 2004  |  Pubmed ID: 15111734

Women are protected from stroke relative to men until the years of menopause. Because stroke is the leading cause of serious, long-term disability in the United States, modeling sex-specific mechanisms and outcomes in animals is vital to research. Important research questions are focused on the effects of hormone replacement therapy, age, reproductive status, and identification of sex-specific risk factors. Available research relevant to stroke in the female has almost exclusively utilized rodent models. Gender-linked stroke outcomes are more detectable in experimental studies than in clinical trials and observational studies. Various estrogens have been extensively studied as neuroprotective agents in women, animals, and a variety of in vitro models of neural injury and degeneration. Most data in animal and cell models are based on 17 beta estradiol and suggest that this steroid is neuroprotective in injury from ischemia/reperfusion. However, current evidence for the clinical benefits of hormone replacement therapy is unclear. Future research in this area will need to expand into stroke models utilizing higher order, gyrencephalic animals such as nonhuman primates if we are to improve extrapolation to the human scenario and to direct and enhance the design of ongoing and future clinical studies and trials.

Animal Models of Ischemic Stroke: Balancing Experimental Aims and Animal Care

Comparative Medicine. Oct, 2004  |  Pubmed ID: 15575362

Animal models of ischemic stroke are examples of an induced model that can present challenges from the perspectives of protocol review and animal management. The review presented here will include a brief summary of the current state of knowledge about clinical stroke; a general synopsis of important unanswered research questions that justify use of animal stroke models; an overview of various animal models of ischemic stroke, including strengths and limitations; and a discussion of animal care issues relative to ischemic stroke models. Good communication and interactive education among primary investigators, laboratory animal veterinarians and caretakers, and institutional animal care and use committee members are critical in achieving a balance between research objectives and animal care issues when using animal stroke models.

Estradiol Regulates Angiopoietin-1 MRNA Expression Through Estrogen Receptor-alpha in a Rodent Experimental Stroke Model

Stroke; a Journal of Cerebral Circulation. Feb, 2005  |  Pubmed ID: 15637314

Female, compared with male, animals are protected from cerebral ischemic injury. Physiological concentrations of 17beta-estradiol (E2) reduce damage in experimental stroke. E2 augments angiogenesis in reproductive organs and noncerebral vascular beds. We hypothesized that E2 protects brain in stroke through modulation of angiogenesis. We quantified molecular markers of angiogenesis and capillary density before and after unilateral middle cerebral artery occlusion (MCAO).

Ischemic Nitric Oxide and Poly (ADP-ribose) Polymerase-1 in Cerebral Ischemia: Male Toxicity, Female Protection

Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism. Apr, 2005  |  Pubmed ID: 15689952

It is well established that tissue damage and functional outcome after experimental or clinical stroke are shaped by biologic sex. We investigated the novel hypothesis that ischemic cell death from neuronally derived nitric oxide (NO) or poly-ADP ribose polymerase (PARP-1) activation is sexually dimorphic and that interruption of these molecular death pathways benefits only the male brain. Female neuronal nitric oxide synthase (nNOS) knockout (nNOS-/-) mice exhibited exacerbated histological injury after middle cerebral artery occlusion (MCAO) relative to wild-type (WT) females, unlike the protection observed in male nNOS-/- littermates. Similarly, treatment with the nNOS inhibitor (7-nitroindozole, 25 mg/kg) increased infarction in female C57Bl6 WT mice, but protected male mice. The mechanism for this sexually specific response is not mediated through changes in protein expression of endothelial NOS or inducible NOS, or differences in intraischemic cerebral blood flow. Unlike male PARP-1 knockouts (PARP1-/-), female PARP1-/- littermates sustained grossly increased ischemic damage relative to sex-matched WT mice. Treatment with a PARP inhibitor (PJ-34, 10 mg/kg) resulted in identical results. Loss of PARP-1 resulted in reversal of the neuroprotective activity by the female sex steroid, 17beta estradiol. These data suggest that the previously described cell death pathways involving NO and PARP ischemic neurotoxicity may be operant solely in male brain and that the integrity of nNO/PARP-1 signaling is paradoxically protective in the female.

Pharmacological Inhibition of AMP-activated Protein Kinase Provides Neuroprotection in Stroke

The Journal of Biological Chemistry. May, 2005  |  Pubmed ID: 15772080

The restoration of energy balance during ischemia is critical to cellular survival; however, relatively little is known concerning the regulation of neuronal metabolic pathways in response to central nervous system ischemia. AMP-activated protein kinase (AMPK), a master sensor of energy balance in peripheral tissues, is phosphorylated and activated when energy balance is low. We investigated whether AMPK might also modulate neuronal energy homeostasis during ischemia. We utilized two model systems of ischemia, middle cerebral artery occlusion in vivo and oxygen-glucose deprivation in vitro, to delineate changes in AMPK activity incurred from a metabolic stress. AMPK is highly expressed in cortical and hippocampal neurons under both normal and ischemic conditions. AMPK activity, as assessed by phosphorylation status, is increased following both middle cerebral artery occlusion and oxygen-glucose deprivation. Pharmacological inhibition of AMPK by either C75, a known modulator of neuronal ATP levels, or compound C reduced stroke damage. In contrast, activation of AMPK by 5-aminoimidazole-4-carboxamide ribonucleoside exacerbated damage. Mice deficient in neuronal nitric-oxide synthase demonstrated a decrease in both stroke damage and AMPK activation compared with wild type, suggesting a possible interaction between NO and AMPK activation in stroke. These data demonstrate a role for AMPK in the response of neurons during metabolic stress and suggest that in ischemia the activation of AMPK is deleterious. The ability to manipulate pharmacologically neuronal energy balance during ischemia represents an innovative approach to neuroprotection.

Sex Differences in Cell Death

Annals of Neurology. Aug, 2005  |  Pubmed ID: 15988750

Female patients experience substantial neuroprotection after experimental stroke compared with male patients, a finding attributed to the protective effects of gonadal hormones. This study examined the response of male- and female-derived organotypic hippocampal slices to oxidative and excitotoxic injury. Both oxygen and glucose deprivation and N-methyl-D-aspartic acid exposure led to neuronal death; however, female-derived cultures sustained less injury than male-derived cultures. Cell death after oxygen and glucose deprivation was ameliorated in male cultures, but not female cultures, by the addition of 7-nitroindazole, a neuronal nitric oxide synthase inhibitor. These studies have relevance to researchers investigating neuroprotective agents in mixed sex experiments.

Social Interaction Improves Experimental Stroke Outcome

Stroke; a Journal of Cerebral Circulation. Sep, 2005  |  Pubmed ID: 16100018

Social interaction can have a profound effect on health. The purpose of the present study was to determine whether affiliative social interactions before and after stroke improve ischemic outcomes as assessed through histological analysis and behavioral assays.

The "drip-and-ship" Approach: Starting IV T-PA for Acute Ischemic Stroke at Outside Hospitals Prior to Transfer to a Regional Stroke Center

Connecticut Medicine. Nov-Dec, 2005  |  Pubmed ID: 16381108

Acute stroke therapy with intravenous (IV) tissue plasminogen activator (t-PA) is vastly underutilized. Increasingly, patients are being started on IV t-PA and being transferred to regional Stroke Center programs, where additional therapies can be offered in a multimodal format. We describe our experience at the Stroke Center at Hartford Hospital with interhospital patient transfers who received IV t-PA prior to transfer to our medical center.

Acute Stroke Management in the Elderly

Cerebrovascular Diseases (Basel, Switzerland). 2007  |  Pubmed ID: 17199089

Though the proportion of elderly stroke patients is increasing, patients >80 years are often excluded from clinical stroke trials. We reviewed the management of older patients presenting with acute ischemic stroke (AIS) and assessed the safety and efficacy of recombinant tissue plasminogen activator (rtPA) administration in a community-based setting.

System X(c)- Activity and Astrocytes Are Necessary for Interleukin-1 Beta-mediated Hypoxic Neuronal Injury

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Sep, 2007  |  Pubmed ID: 17881516

The purpose of this study was to elucidate the cellular/biochemical pathway(s) by which interleukin-1beta (IL-1beta) contributes to the pathogenesis of hypoxic-ischemic brain damage. In vivo, IL-1 receptor type I (IL-1RI)-deficient mice showed smaller infarcts and less neurological deficits than wild-type animals after a 90 min reversible middle cerebral artery occlusion. In vitro, IL-1beta mediated an enhancement of hypoxic neuronal injury in murine cortical cultures that was lacking in cultures derived from IL-1RI null mutant animals and was blocked by the IL-1 receptor antagonist or an IL-1RI blocking antibody. This IL-1beta-mediated potentiation of hypoxic neuronal injury was associated with an increase in both cellular cystine uptake ([cystine]i) and extracellular glutamate levels ([glutamate]e) and was prevented by either ionotropic glutamate receptor antagonism or removal of L-cystine, suggesting a role for the cystine/glutamate antiporter (System x(c)-). Indeed, dual System x(c)-/metabotropic glutamate receptor subunit 1 (mGluR1) antagonism but not selective mGluR1 antagonism prevented neuronal injury. Additionally, cultures derived from mGluR1-deficient mice exhibited the same potentiation in injury after treatment with IL-1beta as wild-type cultures, an effect prevented by System x(c)-/mGluR1 antagonism. Finally, assessment of System x(c)- function and kinetics in IL-1beta-treated cultures revealed an increase in velocity of cystine transport (Vmax), in the absence of a change in affinity (Km). Neither the enhancement in [cystine]i, [glutamate]e, or neuronal injury were observed in chimeric cultures consisting of IL-1RI(+/+) neurons plated on top of IL-1RI(-/-) astrocytes, highlighting the importance of astrocyte-mediated alterations in System x(c)- as a novel contributor to the development and progression of hypoxic neuronal injury.

Neuroprotective Effects of Adenosine Monophosphate-activated Protein Kinase Inhibition and Gene Deletion in Stroke

Stroke; a Journal of Cerebral Circulation. Nov, 2007  |  Pubmed ID: 17901380

5' adenosine monophosphate-dependent protein kinase (AMPK) acts as a metabolic sensor. AMPK is elevated under ischemic conditions, but the role of AMPK in ischemic brain remains controversial. In this study, we examined the effects of AMPK inhibition using both pharmacological and genetic approaches in an in vivo stroke model.

Akt1 Gene Deletion and Stroke

Journal of the Neurological Sciences. Jun, 2008  |  Pubmed ID: 18258266

Activation of Akt has been implicated as a major contributor to neuronal survival after an ischemic insult. Numerous neuroprotective agents have been shown to augment Akt activity, suggesting that this protein represents a major mechanism of cellular salvage after injury. Estrogen is known to augment Akt, but the possibility that Akt plays a differential role in the male and female brain has yet to be evaluated. In this study, we employed both pharmacological and genetic approaches to investigate the role of Akt in stroke. Utilizing a focal stroke model we show that deletion of the Akt1 isoform does not affect stroke outcome in either male or female mice. Akt1 deficient mice had equivalent levels of phosphorylated Akt (p-Akt) when compared to their WT controls following stroke suggesting that alternative isoforms can compensate for Akt1 loss. Secondly, estrogen's neuroprotective effect is maintained in Akt1(-/-) mice and estrogen exposure did not enhance p-Akt levels in WT female mice. Thirdly, we show that inhibiting Akt using the direct pan-Akt inhibitor triciribine has no effect on stroke outcome despite dramatic reductions in p-Akt. Our study demonstrates the limitations of genetic mouse models and suggests that the importance of Akt to ischemic outcome remains unclear.

Misoprostol, an Anti-ulcer Agent and PGE2 Receptor Agonist, Protects Against Cerebral Ischemia

Neuroscience Letters. Jun, 2008  |  Pubmed ID: 18472336

Induction of COX-2 activity in cerebral ischemia results in increased neuronal injury and infarct size. Recent studies investigating neurotoxic mechanisms of COX-2 demonstrate both toxic and paradoxically protective effects of downstream prostaglandin receptor signaling pathways. We tested whether misoprostol, a PGE(2) receptor agonist that is utilized clinically as an anti-ulcer agent and signals through the protective PGE(2) EP2, EP3, and EP4 receptors, would reduce brain injury in the murine middle cerebral artery occlusion-reperfusion (MCAO-RP) model. Administration of misoprostol, at the time of MCAO or 2h after MCAO, resulted in significant rescue of infarct volume at 24 and 72h. Immunocytochemistry demonstrated dynamic regulation of the EP2 and EP4 receptors during reperfusion in neurons and endothelial cells of cerebral cortex and striatum, with limited expression of EP3 receptor. EP3-/- mice had no significant changes in infarct volume compared to control littermates. Moreover, administration of misoprostol to EP3+/+ and EP3-/- mice showed similar levels of infarct rescue, indicating that misoprostol protection was not mediated through the EP3 receptor. Taken together, these findings suggest a novel function for misoprostol as a protective agent in cerebral ischemia acting via the PGE(2) EP2 and/or EP4 receptors.

Pathways to Ischemic Neuronal Cell Death: Are Sex Differences Relevant?

Journal of Translational Medicine. 2008  |  Pubmed ID: 18573200

We have known for some time that the epidemiology of human stroke is sexually dimorphic until late in life, well beyond the years of reproductive senescence and menopause. Now, a new concept is emerging: the mechanisms and outcome of cerebral ischemic injury are influenced strongly by biological sex as well as the availability of sex steroids to the brain. The principal mammalian estrogen (17 beta estradiol or E2) is neuroprotective in many types of brain injury and has been the major focus of investigation over the past several decades. However, it is becoming increasingly clear that although hormones are a major contributor to sex-specific outcomes, they do not fully account for sex-specific responses to cerebral ischemia. The purpose of this review is to highlight recent studies in cell culture and animal models that suggest that genetic sex determines experimental stroke outcome and that divergent cell death pathways are activated after an ischemic insult. These sex differences need to be identified if we are to develop efficacious neuroprotective agents for use in stroke patients.

Sex Differences in Stroke

Cerebrovascular Diseases (Basel, Switzerland). 2008  |  Pubmed ID: 18810232

Increasing evidence suggests that sex differences exist in the etiology, presentation, treatment, and outcome from stroke. The reasons for these sex disparities are becoming increasingly explored, but large gaps still exist in our knowledge. Experimental studies over the past several years have demonstrated intrinsic sex differences both in vivo and in animal models which may have relevance to our understanding of stroke in clinical populations. A greater understanding of the differences and similarities between males and females with respect to the risk factors, pathophysiology, and response to stroke will facilitate the design of future clinical trials and enhance the development of treatment strategies to improve stroke care in both sexes. This article reviews the current literature on sex differences in stroke with an emphasis on the clinical data, incorporating an analysis of bench research as it pertains to the bedside.

TTC, Fluoro-Jade B and NeuN Staining Confirm Evolving Phases of Infarction Induced by Middle Cerebral Artery Occlusion

Journal of Neuroscience Methods. Apr, 2009  |  Pubmed ID: 19167427

Considerable debate exists in the literature on how best to measure infarct damage and at what point after middle cerebral artery occlusion (MCAO) infarct is histologically complete. As many researchers are focusing on more chronic endpoints in neuroprotection studies it is important to evaluate histological damage at later time points to ensure that standard methods of tissue injury measurement are accurate. To compare tissue viability at both acute and sub-acute time points, we used 2,3,5-triphenyltetrazolium chloride (TTC), Fluoro-Jade B, and NeuN staining to examine the evolving phases of infarction induced by a 90-min MCAO in mice. Stroke outcomes were examined at 1.5h, 6h, 12h, 24h, 3d, and 7d after MCAO. There was a time-dependent increase in infarct volume from 1.5h to 24h in the cortex, followed by a plateau from 24h to 7d after stroke. Striatal infarcts were complete by 12h. Fluoro-Jade B staining peaked at 24h and was minimal by 7d. Our results indicated that histological damage as measured by TTC and Fluoro-Jade B reaches its peak by 24h after stroke in a reperfusion model of MCAO in mice. TTC staining can be accurately performed as late as 7d after stroke. Neurological deficits do not correlate with the structural lesion but rather transient impairment of function. As the infarct is complete by 24h and even earlier in the striatum, even the most efficacious neuroprotective therapies are unlikely to show any efficacy if given after this point.

Sex Differences in Minocycline-induced Neuroprotection After Experimental Stroke

Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism. Apr, 2009  |  Pubmed ID: 19190654

Minocycline is neuroprotective in clinical and experimental stroke studies, due in part to its ability to inhibit poly (ADP-ribose) polymerase. Previous preclinical data have shown that interference with poly (ADP-ribose) polymerase signaling leads to sex-specific neuroprotection, reducing stroke injury only in males. In this study, we show that minocycline is ineffective at reducing ischemic damage in females after middle cerebral artery occlusion, likely due to effects on poly (ADP-ribose) polymerase signaling. Clinical trials must consider possible sex differences in the response to neuroprotective agents, if we hope to translate promising therapies to stroke patients of both sexes.

Perception of Risk and Knowledge of Risk Factors in Women at High Risk for Stroke

Stroke; a Journal of Cerebral Circulation. Apr, 2009  |  Pubmed ID: 19211481

Women face a higher mortality after stroke and have different risk factors than men. Despite educational campaigns, women continue to underestimate their own risk for stroke. We present a theoretical model to understand risk perception in high-risk women.

Changes in Experimental Stroke Outcome Across the Life Span

Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism. Apr, 2009  |  Pubmed ID: 19223913

Acute ischemic stroke is a leading cause of mortality and disability in the elderly. Age is the most important nonmodifiable risk factor for stroke, yet many preclinical models continue to examine only young male animals. It remains unclear how experimental stroke outcomes change with aging and with biologic sex. If sex differences are present, it is not known whether these reflect an intrinsic differing sensitivity to stroke or are secondary to the loss of estrogen with aging. We subjected both young and aging mice of both sexes to middle cerebral artery occlusion (MCAO). Young female mice had smaller strokes compared with age-matched males, an effect that was reversed by ovariectomy. Stroke damage increased with aging in female mice, whereas male mice had decreased damage after MCAO. Blood-brain barrier (BBB) permeability changes are correlated with infarct size. However, aging mice had significantly less edema formation, an effect that was independent of sex and histologic damage. Differences in the cellular response to stroke occur across the life span in both male and female mice. These differences need to be considered when developing relevant therapies for stroke patients, the majority of whom are elderly.

Sex Differences in Caspase Activation After Stroke

Stroke; a Journal of Cerebral Circulation. May, 2009  |  Pubmed ID: 19265047

Over the past 5 years, experimental data have emerged that ischemia-induced cell death pathways may differ in males and females. Cell death in males is triggered by poly(ADP-ribose) polymerase activation and nuclear translocation of apoptosis-inducing factor. We have previously shown that interference with this pathway benefits males but not females after an experimental stroke. In contrast, caspase activation may be the major pathway activated after ischemic injury in females. The aim of this study is to examine whether sex differences exist in caspase activation in adult mice after stroke and to determine if interference with stroke-induced caspase activation preferentially protects females.

Sex Differences in the Response to Activation of the Poly (ADP-ribose) Polymerase Pathway After Experimental Stroke

Experimental Neurology. May, 2009  |  Pubmed ID: 19268668

It is increasingly recognized that histological and functional outcomes after stroke are shaped by biologic sex. Emerging data suggests that ischemic cell death pathways are sexually dimorphic (Hurn, P., Vannucci, S., Hagberg, H. (2005) Adult or perinatal brain injury: does sex matter?. Stroke 36, 193-195 ; Lang, J.T., McCullough, L.D. (2008) Pathways to ischemic neuronal cell death: are sex differences relevant?. J. Transl. Med. 6). Reducing neuronal nitric oxide (NO) or poly-ADP-ribose polymerase (PARP1) activation protects only the male brain (Hagberg, H., et al. PARP-1 gene disruption in mice preferentially protects males from perinatal brain injury. J. Neurochem. 90, 1068-1075 (2004)), and paradoxically enhances ischemic injury in females (McCullough, L.D., et al. Ischemic nitric oxide and poly (ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection. J. Cereb. Blood Flow Metab. 25, 502-512 (2005)). In this study, we examined downstream mediators of NO/PARP activation to investigate possible mediators of ischemic sexual dimorphism. Nuclear translocation of Apoptosis Inducing Factor (AIF) was equivalent in wild type males and females after stroke and was unaffected by estrogen exposure. Deletion of PARP1 led to a dramatic reduction in stroke-induced poly (ADP-ribose) polymerase (PAR) formation and AIF translocation in both sexes, yet ischemic damage was reduced only in males. Subsequent examination of AIF-deficient Harlequin mice demonstrated that male Harlequin mice had less PAR formation, reduced AIF translocation and less ischemic damage than male wild type mice. In contrast, female Harlequin mice had no neuroprotective effect of gene deletion despite robust reductions in PAR formation and AIF translocation. Although equivalent activation of this cell death pathway occurs in both sexes after ischemia, detrimental effects are only present in males. AIF translocation and PAR formation do not mediate ischemic injury in the female brain, therefore agents designed to reduce PARP1 activation are unlikely to benefit females.

Stroke-risk Perception in Women: Getting the Message Out

Women's Health (London, England). May, 2009  |  Pubmed ID: 19392606

Disruption of the Axon Initial Segment Cytoskeleton is a New Mechanism for Neuronal Injury

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Oct, 2009  |  Pubmed ID: 19846712

Many factors contribute to nervous system dysfunction and failure to regenerate after injury or disease. Here, we describe a previously unrecognized mechanism for nervous system injury. We show that neuronal injury causes rapid, irreversible, and preferential proteolysis of the axon initial segment (AIS) cytoskeleton independently of cell death or axon degeneration, leading to loss of both ion channel clusters and neuronal polarity. Furthermore, we show this is caused by proteolysis of the AIS cytoskeletal proteins ankyrinG and betaIV spectrin by the calcium-dependent cysteine protease calpain. Importantly, calpain inhibition is sufficient to preserve the molecular organization of the AIS both in vitro and in vivo. We conclude that loss of AIS ion channel clusters and neuronal polarity are important contributors to neuronal dysfunction after injury, and that strategies to facilitate recovery must preserve or repair the AIS cytoskeleton.

Effects of Gender and Sex Steroids on Ischemic Injury

Handbook of Clinical Neurology / Edited by P.J. Vinken and G.W. Bruyn. 2009  |  Pubmed ID: 18790274

Effects of AMP-activated Protein Kinase in Cerebral Ischemia

Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism. Mar, 2010  |  Pubmed ID: 20010958

AMP-activated protein kinase (AMPK) is a serine threonine kinase that is highly conserved through evolution. AMPK is found in most mammalian tissues including the brain. As a key metabolic and stress sensor/effector, AMPK is activated under conditions of nutrient deprivation, vigorous exercise, or heat shock. However, it is becoming increasingly recognized that changes in AMPK activation not only signal unmet metabolic needs, but also are involved in sensing and responding to 'cell stress', including ischemia. The downstream effect of AMPK activation is dependent on many factors, including the severity of the stressor as well as the tissue examined. This review discusses recent in vitro and in vivo studies performed in the brain/neuronal cells and vasculature that have contributed to our understanding of AMPK in stroke. Recent data on the potential role of AMPK in angiogenesis and neurogenesis and the interaction of AMPK with 3-hydroxy-3-methy-glutaryl-CoA reductase inhibitors (statins) agents are highlighted. The interaction between AMPK and nitric oxide signaling is also discussed.

Emergency Department Arrival Times, Treatment, and Functional Recovery in Women with Acute Ischemic Stroke

Journal of Women's Health (2002). Apr, 2010  |  Pubmed ID: 20187750

Sex disparities have been well documented in patients with ischemic stroke. Previous studies have suggested that female sex is a risk factor for delay in arrival time to the emergency department (ED) and may contribute to ineligibility for thrombolytic therapy. With the increase in education efforts targeting women, we investigated whether ED arrival times, rates of thrombolytic use, and functional outcomes continue to differ in men and women with acute ischemic stroke (AIS).

Sex-specific Responses to Stroke

Future Neurology. Jan, 2010  |  Pubmed ID: 20190872

Stroke is a sexually dimorphic disease, with differences between males and females observed both clinically and in the laboratory. While males have a higher incidence of stroke throughout much of the lifespan, aged females have a higher burden of stroke. Sex differences in stroke result from a combination of factors, including elements intrinsic to the sex chromosomes as well as the effects of sex hormone exposure throughout the lifespan. Research investigating the sexual dimorphism of stroke is only in the beginning stages, but early findings suggest that different cell death pathways are activated in males and females after ischemic stroke. A greater understanding of the mechanisms underlying sex differences in stroke will lead to more appropriate treatment strategies for patients of both sexes.

Expression of Na-K-Cl Cotransporter and Edema Formation Are Age Dependent After Ischemic Stroke

Experimental Neurology. Aug, 2010  |  Pubmed ID: 20406636

Age is the most important independent risk factor for stroke; however aging animals are rarely used in stroke studies. Previous work demonstrated that young male mice had more edema formation after an induced stroke than aging animals. An important contributor to cerebral edema formation is the Na-K-Cl cotransporter (NKCC). We examined the expression of NKCC in young (10-12 weeks) and aging (15-16 months) C57BL6 male mice after middle cerebral artery occlusion (MCAO) and investigated the effect of pharmacological inhibition of NKCC with Bumetanide on cerebral edema formation. Both immunofluorescent staining and Western blotting analysis showed that NKCC expression was significantly higher in the ischemic penumbra of young compared to aging mice after stroke. Edema formation was significantly more robust in young mice and was reduced with Bumetanide. Bumetanide had no effect on cerebral edema in aging mice after MCAO. This suggests that NKCC expression and edema formation are age dependent after ischemic stroke.

Stroke in Women: Disparities and Outcomes

Current Cardiology Reports. Jan, 2010  |  Pubmed ID: 20425178

Stroke is the leading cause of disability in the United States and affects 15 million people worldwide. Studies performed in various parts of the world have found differences between sexes in stroke incidence, prevalence, mortality, and outcomes. Although men are at higher risk of stroke for most age groups below age 85 years, after this age the incidence reverses dramatically, with women being much more at risk. Furthermore, recent studies suggest that women have worse recovery than men post-stroke. Many aspects of recovery may influence this outcome, including sex-specific comorbidities, aggressiveness of acute treatment, prevention therapies, and varying degrees of social support and rates of depression. It is important to further define and investigate sex differences in stroke incidence, care, treatment, and outcomes to improve functional recovery in women.

Thrombolysis in Right Versus Left Hemispheric Stroke

Journal of Stroke and Cerebrovascular Diseases : the Official Journal of National Stroke Association. Jul-Aug, 2010  |  Pubmed ID: 20471856

Recent evidence has suggested that patients with right hemispheric stroke (RHS) present later to an emergency department, have a lower chance to receive intravenous (IV) recombinant tissue plasminogen activator (t-PA), and have poorer clinical outcomes than do patients with left hemispheric stroke (LHS).

Attitudes of US Medical Trainees Towards Neurology Education: "Neurophobia" - a Global Issue

BMC Medical Education. 2010  |  Pubmed ID: 20573257

Several studies in the United Kingdom and Asia have suggested that medical students and residents have particular difficulty in diagnosing and managing patients with neurological problems. Little recent information is available for US trainees. We examined whether students and residents at a US university have difficulty in dealing with patients with neurological problems, identified the perceived sources of these difficulties and provide suggestions for the development of an effective educational experience in neurology.

Adenosine Monophosphate Activated Protein Kinase Inhibition is Protective in Both Sexes After Experimental Stroke

Neuroscience Letters. Sep, 2010  |  Pubmed ID: 20621158

Sex differences in clinical and experimental stroke are now well recognized. Adenosine monophosphate activated protein kinase (AMPK) is an important energy sensor that is activated in times of energy demand. Increasing AMPK is deleterious in experimental cerebral ischemia, at least in males. Interestingly, studies in peripheral tissues have suggested that there are sex differences in the regulation of AMPK in muscle after exercise. PolyADP ribose polymerase (PARP), a key mediator of ischemic cell death, stimulates AMPK activation, yet activation of PARP appears to be selectively detrimental in male brain. As interference with sex specific cell death pathways can determine the efficacy of experimental neuroprotective agents, and AMPK inhibition is a novel neuroprotective target, we examined the effect of AMPK inhibition in male and female mice. In this study, AMPK alpha2 gene expression (mRNA) and pAMPK protein levels were examined and found to be comparable between both sexes after transient middle cerebral artery occlusion (MCAO). Treatment with the AMPK inhibitor Compound C at stroke onset significantly reduced infarct size and neurological deficits 24h after stroke in ovariectomized female mice. Finally, genetic deletion of AMPK alpha2 in ovariectomized females was neuroprotective as assessed by smaller infarct volumes and improved neurological deficits when compared to wild type littermates. This work demonstrates that AMPK activation is deleterious in experimental stroke, and this effect is independent of sex.

Sex Differences in Cerebral Ischemia: Possible Molecular Mechanisms

Journal of Neuroscience Research. Oct, 2010  |  Pubmed ID: 20698025

Sex is emerging as an important factor in the etiology and expression of many different pathological conditions, including stroke. Initially, the levels of sex hormones were thought to be the major contributor to these sex differences, especially after puberty, when gonadal steroid levels sharply diverge between the sexes. More recently, it is recognized that sex differences also result from the organizational effects of sex hormone exposure early in development, even in the absence of hormone exposure later in life, as well as effects mediated by the sex chromosomes themselves. Epigenetic modifications of developmental genes important in sexual differentiation and the response to sex steroid hormones are also emerging as another important contributor to sex differences in disease expression. This review describes recent research on the relationship between hormones, organizational-activational effects of gonadal steroids, and epigenetic modifications in brain pathology, focusing specifically on cerebral ischemia.

Effects of Metformin in Experimental Stroke

Stroke; a Journal of Cerebral Circulation. Nov, 2010  |  Pubmed ID: 20847317

Adenosine 5'-monophosphate-activated protein kinase (AMPK) is an important sensor of energy balance. Stroke-induced AMPK activation is deleterious because both pharmacological inhibition and genetic deletion of AMPK are neuroprotective. Metformin is a known AMPK activator but reduces stroke incidence in clinical populations. We investigated the effect of acute and chronic metformin treatment on infarct volume and AMPK activation in experimental stroke.

The Blood-brain Barrier: Geriatric Relevance of a Critical Brain-body Interface

Journal of the American Geriatrics Society. Sep, 2010  |  Pubmed ID: 20863334

The blood-brain barrier (BBB) represents the interface between the brain and other body tissues. Its ability to protect the brain from harmful compounds has attracted the attention of clinicians and investigators, but far from being a simple physical barrier, the BBB is a complex, heterogeneous, and dynamic tissue. The integrated function of the cerebral microvasculature, tight junction proteins, brain microvascular endothelial cells (BMECs), cellular transport pathways, and enzymatic machinery jointly contribute to normal BBB integrity. Aging, systemic diseases, and ischemic injury can disrupt these processes, resulting in a decline in overall BBB function and integrity. Based on the published literature, this study proposes that age- and disease-related BBB alterations play a key role in diminishing the ability of older patients to recover from acute ischemic stroke. Evidence linking deficits in the cerebral microvasculature and BBB integrity to dementia, medication-related cognitive decline, white matter disease (WMD or leukoaraiosis), and related geriatric syndromes including delirium, gait disorders, and urinary incontinence is also reviewed. Priority areas for a future research agenda include strategies to improve clinicians' ability to diagnose, prevent, and manage BBB abnormalities. In future years, in vivo measures such as functional and contrast-enhanced neuroimaging will be used to evaluate BBB integrity in older adults while also assessing the effectiveness of interventions, some targeting inflammatory pathways known to disrupt the BBB, for their ability to prevent or slow the progression of these complex multifactorial geriatric syndromes.

Estrogen Enhances Neurogenesis and Behavioral Recovery After Stroke

Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism. Feb, 2011  |  Pubmed ID: 20940729

Stroke is a leading cause of permanent disability and death. It is well accepted that the principal mammalian estrogen (E2), 17-β estradiol, provides robust neuroprotection in a variety of brain injury models in animals of both sexes. E2 enhances neurogenesis after stroke in the subventricular zone; however, it is unknown if these cells survive long-term or enhance functional recovery. In this study, we examined stroke-induced neurogenesis in male, gonadally intact female, and ovariectomized female mice 2 and 6 weeks after stroke. Treatment with 17-β estradiol increased 5-bromo-2'-deoxyuridine-labeled cells at both time points in both the dentate gyrus and subventricular zone; the majority were colabeled with doublecortin at 2 weeks and with NeuN at 6 weeks. Stroke-induced neurogenesis was reduced in estrogen receptor knockout mice, as well as in mice lacking the gene for aromatase, which converts testosterone into E2. Improved behavioral deficits were seen in E2-treated mice, suggesting that E2-induced increases in poststroke neurogenesis contribute to poststroke recovery.

Sex Differences in the Response to Poly(ADP-ribose) Polymerase-1 Deletion and Caspase Inhibition After Stroke

Stroke; a Journal of Cerebral Circulation. Apr, 2011  |  Pubmed ID: 21311064

Emerging data suggest that the molecular cell death pathways triggered by ischemic insults differ in the male and female brain. Cell death in males is initiated by poly(ADP-ribose) polymerase-1 (PARP-1) activation; however, manipulation of this pathway paradoxically increases ischemic damage in females. In contrast, females are exquisitely sensitive to caspase-mediated cell death. The effect of caspase inhibition in PARP-1 knockout mice was evaluated to determine if the detrimental effects of PARP deletion in females were secondary to increased caspase activation.

Middle Cerebral Artery Occlusion Model in Rodents: Methods and Potential Pitfalls

Journal of Biomedicine & Biotechnology. 2011  |  Pubmed ID: 21331357

A variety of animal models have been developed for modeling ischemic stroke. The middle cerebral artery occlusion (MCAO) model has been utilized extensively, especially in rodents. While the MCAO model provides stroke researchers with an excellent platform to investigate the disease, controversial or even paradoxical results are occasionally seen in the literature utilizing this model. Various factors exert important effects on the outcome in this stroke model, including the age and sex of the animal examined. This paper discusses emerging information on the effects of age and sex on ischemic outcomes after MCAO, with an emphasis on mouse models of stroke.

Clinical Reasoning: a Case of Progressive Cognitive Decline Reversed by Middle Cerebral Artery Stent Placement

Neurology. Mar, 2011  |  Pubmed ID: 21422450

Post-stroke Hypothermia Provides Neuroprotection Through Inhibition of AMP-activated Protein Kinase

Journal of Neurotrauma. Jul, 2011  |  Pubmed ID: 21446786

Hypothermia is robustly protective in pre-clinical models of both global and focal ischemia, as well as in patients after cardiac arrest. Although the mechanism for hypothermic neuroprotection remains unknown, reducing metabolic drive may play a role. Capitalizing on the beneficial effects of hypothermia while avoiding detrimental effects such as infection will be the key to moving this therapy forward as a treatment for stroke. AMPK is a master energy sensor that monitors levels of key energy metabolites. AMPK is activated via phosphorylation (pAMPK) when cellular energy levels are low, such as that seen during ischemia. AMPK activation appears to be detrimental in experimental stroke, likely via exacerbating ischemia-induced metabolic failure. We tested the hypothesis that hypothermia reduces AMPK activation. First, it was found that hypothermia reduced infarct after middle cerebral artery occlusion. Second, induced hypothermia reduced brain pAMPK in both sham control and stroke mice. Third, hypothermic neuroprotection was ameliorated after administration of compound C, an AMPK inhibitor. Finally, deletion of one of the catalytic isoforms of AMPK completely reversed the effect of hypothermia on stroke outcome after both acute and chronic survival. These effects were mediated by a reduction in AMPK activation rather than a reduction in LKB1, an upstream AMPK kinase. In summary, these studies provide evidence that hypothermia exerts its protective effect in part by inhibiting AMPK activation in experimental focal stroke. This suggests that AMPK represents a potentially important biological target for stroke treatment.

Sexual Dimorphism in Ischemic Stroke: Lessons from the Laboratory

Women's Health (London, England). May, 2011  |  Pubmed ID: 21612353

Ischemic stroke is emerging as a major health problem for elderly women. Women have lower stroke incidence than men until an advanced age, when the epidemiology of ischemic stroke shifts and incidence rises dramatically in women. Experimental models of rodent stroke have replicated this clinical epidemiology, with exacerbated injury in older compared with young female rodents. Many of the detrimental effects of aging on ischemic stroke outcome in females can be replicated by ovariectomy, suggesting that hormones such as estrogen play a neuroprotective role. However, emerging data suggest that the molecular mechanisms leading to ischemic cell death differ in the two sexes, and these effects may be independent of circulating hormone levels. This article highlights recent clinical and experimental literature on sex differences in stroke outcomes and mechanisms.

MiR-23a Regulation of X-linked Inhibitor of Apoptosis (XIAP) Contributes to Sex Differences in the Response to Cerebral Ischemia

Proceedings of the National Academy of Sciences of the United States of America. Jul, 2011  |  Pubmed ID: 21709246

It is increasingly recognized that the mechanisms underlying ischemic cell death are sexually dimorphic. Stroke-induced cell death in males is initiated by the mitochondrial release of apoptosis-inducing factor, resulting in caspase-independent cell death. In contrast, ischemic cell death in females is primarily triggered by mitochondrial cytochrome c release with subsequent caspase activation. Because X-linked inhibitor of apoptosis (XIAP) is the primary endogenous inhibitor of caspases, its regulation may play a unique role in the response to injury in females. XIAP mRNA levels were higher in females at baseline. Stroke induced a significant decrease in XIAP mRNA in females, whereas no changes were seen in the male brain. However, XIAP protein levels were decreased in both sexes after stroke. MicroRNAs (miRNAs) predominantly induce translational repression and are emerging as a major regulators of mRNA and subsequent protein expression after ischemia. The miRNA miR-23a was predicted to bind XIAP mRNA. miR-23a directly bound the 3' UTR of XIAP, and miR-23a inhibition led to an increase in XIAP mRNA in vitro, demonstrating that XIAP is a previously uncharacterized target for miR-23a. miR-23a levels differed in male and female ischemic brains, providing evidence for sex-specific miRNA expression in stroke. Embelin, a small-molecule inhibitor of XIAP, decreased the interaction between XIAP and caspase-3 and led to enhanced caspase activity. Embelin treatment significantly exacerbated stroke-induced injury in females but had no effect in males, demonstrating that XIAP is an important mediator of sex-specific responses after stroke.

Functional Recovery in Aging Mice After Experimental Stroke

Brain, Behavior, and Immunity. Nov, 2011  |  Pubmed ID: 21756996

Aging is a non-modifiable risk factor for stroke. Since not all strokes can be prevented, a major emerging area of research is the development of effective strategies to enhance functional recovery after stroke. However, in the vast majority of pre-clinical stroke studies, the behavioral tests used to assess functional recovery have only been validated for use in young animals, or are designed for rats. Mice are increasingly utilized in stroke models but well validated behavioral tests designed for rats are not necessarily reproducible in mice. We examined a battery of behavioral tests to evaluate functional recovery in an aging murine model of stroke. We found that the vertical pole, hanging wire and open field can accurately assess acute behavioral impairments after stroke in both young and aging male mice, but animals recover rapidly on these tasks. The corner test can accurately and repeatedly differentiate stroke from sham animals up to 30 days post stroke and can be performed reliably in aging mice. Aging male mice had significantly worse behavioral impairment compared to young male mice in the first two weeks after stroke but eventually recovered to the same degree as young mice. In contrast, chronic infarct size, as measured by ipsilateral cerebral atrophy, was significantly lower in aging male mice compared to young male mice. Reactive gliosis, formation of glial scar, and an enhanced innate immune response was seen in the aging brain and may contribute to the delayed behavioral recovery seen in the aging animals.

X Chromosome Dosage and the Response to Cerebral Ischemia

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Sep, 2011  |  Pubmed ID: 21917808

Gonadal hormones contribute to ischemic neuroprotection, but cannot fully explain the observed sexual dimorphism in stroke outcomes seen during life stages with low sex steroid hormones. Sex chromosomal complement (XX in females; XY in males) may also contribute to ischemic sexual dimorphism. A transient middle cerebral artery occlusion model was used to investigate the role of X chromosome dosage in female XX and XO littermates of two mouse strains (Paf and Eda(Ta)). Cohorts of XX and XO gonadally intact, ovariectomized, and ovariectomized females supplemented with estrogen were examined. Infarct sizes were equivalent between ovariectomized XX and XO mice, between intact XX and XO mice, and between estrogen-supplemented ovariectomized XX and XO mice. This is the first study to investigate the role of sex chromosome dosage in the response to cerebral ischemia. Neither the number of X chromosomes nor the parent of origin of the remaining X chromosome had a significant effect on the degree of cerebral infarction after experimental stroke in adult female mice. Estrogen was protective against cerebral ischemia in both XX and XO mice.

"Won't You Be My Neighbor?": Deciphering the Mechanisms of Neuroprotection Induced by Social Interaction

Stroke; a Journal of Cerebral Circulation. Dec, 2011  |  Pubmed ID: 21960565

Peripheral Leukocyte Counts and Outcomes After Intracerebral Hemorrhage

Journal of Neuroinflammation. 2011  |  Pubmed ID: 22087759

Intracerebral hemorrhage (ICH) is a devastating disease that carries a 30 day mortality of approximately 45%. Only 20% of survivors return to independent function at 6 months. The role of inflammation in the pathophysiology of ICH is increasingly recognized. Several clinical studies have demonstrated an association between inflammatory markers and outcomes after ICH; however the relationship between serum biomarkers and functional outcomes amongst survivors has not been previously evaluated. Activation of the inflammatory response as measured by change in peripheral leukocyte count was examined and assessment of mortality and functional outcomes after ICH was determined.

Early Experience with Community Implementation of Thrombolysis Three to 4.5 Hours After Acute Ischemic Stroke

Connecticut Medicine. Oct, 2011  |  Pubmed ID: 22308640

The therapeutic time window for IV thrombolytic treatment was recently extended at Hartford Hospital to 4.5-hours. We assessed the safety and efficacy of delayed thrombolysis.

Mismatch: when the Imaging Studies Conflict with the Neurologic Exam

Journal of Stroke and Cerebrovascular Diseases : the Official Journal of National Stroke Association. Jan-Feb, 2011  |  Pubmed ID: 20580258

As neurologists, we increasingly rely on imaging studies to help us diagnose acute stroke. This unusual case is a reminder that even sophisticated imaging techniques can have false negatives and emphasizes the importance of the clinical exam.

Impact of Emergency Department Transitions of Care on Thrombolytic Use in Acute Ischemic Stroke

Stroke; a Journal of Cerebral Circulation. Jan, 2012  |  Pubmed ID: 22282889

BACKGROUND AND PURPOSE: In-hospital mortality is higher for certain medical conditions based on the time of presentation to the emergency department. The primary goal of this study was to determine whether patients with acute ischemic stroke who arrived to the emergency department during a nursing shift change had similar rates of thrombolytic use and functional outcomes compared with patients presenting during nonshift change hours. METHODS: A retrospective review of patients with acute ischemic stroke presenting to the emergency department of a primary stroke center from 2005 through 2010. The time to notify the stroke team, perform a head CT scan, and to start intravenous or intra-arterial thrombolysis was assessed. Thrombolysis rates, mortality rate, discharge disposition, change in the National Institutes of Health Stroke Scale, and change in modified Barthel Index at 3 and 12 months were assessed. RESULTS: Of 3133 patients with acute ischemic stroke, 917 met criteria for inclusion. Arrival during nursing shift change, weekends, and July through September had no impact on process times, thrombolysis rates, and functional outcomes. Arrival at night did result in longer time to intra-arterial but not to intravenous thrombolysis, higher mortality rate, and smaller gain in functional status as measured by the modified Barthel Index at 3 months. The degree of emergency department "busyness" also did not influence tissue-type plasminogen activator treatment times. CONCLUSIONS: Presentation during a nursing shift change, a time of transition of care, did not delay thrombolytic use in eligible patients with acute ischemic stroke. Presentation with acute ischemic stroke at night did result in delays of care for patients undergoing interventional therapies.

Upregulation of Fibronectin and the α5β1 and αvβ3 Integrins on Blood Vessels Within the Cerebral Ischemic Penumbra

Experimental Neurology. Jan, 2012  |  Pubmed ID: 22056225

Following focal cerebral ischemia, blood vessels in the ischemic border, or penumbra, launch an angiogenic response. In light of the critical role for fibronectin in angiogenesis, and the observation that fibronectin and its integrin receptors are strongly upregulated on angiogenic vessels in the hypoxic CNS, the aim of this study was to establish whether angiogenic vessels in the ischemic CNS also show this response. Focal cerebral ischemia was established in C57/Bl6 mice by middle cerebral artery occlusion (MCA:O), and brain tissue analyzed 7days following re-perfusion, a time at which angiogenesis is ongoing. Within the ischemic core, immunofluorescent (IF) studies demonstrated vascular expression of MECA-32, a marker of leaky cerebral vessels, and vascular breakdown, defined by loss of staining for the endothelial marker, CD31, and the vascular adhesion molecules, laminin, dystroglycan and α6 integrin. Within the ischemic penumbra, dual-IF with CD31 and Ki67 revealed the presence of proliferating endothelial cells, indicating ongoing angiogenesis. Significantly, vessels in the ischemic penumbra showed strong upregulation of fibronectin and the fibronectin receptors, α5β1 and αvβ3 integrins. Taken together with our recent finding that the α5β1 integrin plays an important role in promoting cerebral angiogenesis in response to hypoxia, these results suggest that stimulation of the fibronectin-α5β1 integrin signaling pathway may provide a novel approach to amplifying the intrinsic angiogenic response to cerebral ischemia.

Impact of a Neurointensivist on Outcomes in Critically Ill Stroke Patients

Neurocritical Care. Feb, 2012  |  Pubmed ID: 21847702

Current guidelines for management of critically ill stroke patients suggest that treatment in a neurocritical care unit (NCCU) and/or by a neurointensivist (NI) may be beneficial, but the contribution of each to outcome is unknown. The relative impact of a NCCU versus NI on short- and long-term outcomes in patients with acute ischemic stroke (AIS), intracerebral hemorrhage (ICH), and aneurysmal subarachnoid hemorrhage (SAH) was assessed.

Age-related Changes in AMP-activated Protein Kinase After Stroke

Age (Dordrecht, Netherlands). Feb, 2012  |  Pubmed ID: 21360073

Adenosine monophosphate-activated protein kinase (AMPK) is an evolutionary conserved energy sensor sensitive to changes in cellular AMP/ATP ratio which is activated by phosphorylation (pAMPK). pAMPK levels decrease in peripheral tissues with age, but whether this also occurs in the aged brain, and how this contributes to the ability of the aged brain to cope with ischemic stress is unknown. This study investigated the activation of AMPK and the response to AMPK inhibition after induced stroke in both young and aged male mice. Baseline levels of phosphorylated AMPK were higher in aged brains compared to young mice. Stroke-induced a robust activation of AMPK in young mice, yet this response was muted in the aged brain. Young mice had larger infarct volumes compared with aged animals; however, more severe behavioral deficits and higher mortality were seen in aged mice after stroke. Inhibition of AMPK with Compound C decreased infarct size in young animals, but had no effect in aged mice. Compound C administration led to a reduction in brain ATP levels and induced hypothermia, which led to enhanced neuroprotection in young but not aged mice. This work demonstrates that aging increases baseline brain pAMPK levels; aged mice have a muted stroke-induced pAMPK response; and that AMPK inhibition and hypothermia are less efficacious neuroprotective agents in the aged brain. This has important translational relevance for the development of neuroprotective agents in preclinical models and our understanding of the enhanced metabolic stress experienced by the aged brain.