Women undergoing cardiovascular procedures have a greater perioperative stroke risk than men. Anesthesia for such cardiovascular procedures is an important consideration since anesthetic agents affect ischemic outcome in experimental stroke and may attenuate perioperative stroke incidence. Such anesthetic preconditioning (ARC) may therefore prevent or even delay neurological complications from perioperative stroke. Our preliminary data suggests that the ARC neuroprotection observed in male animals does not occur in females and that ARC in females actually enhances ischemic damage after middle cerebral artery occlusion. This application will focus on how female gender and estradiol-specific effects lead to a detrimental response in ARC female ischemic brain using a mouse isoflurane preconditioning (IsoPC) model.
In Aim 1, we will examine the effects of gender and estradiol on ischemic histological and functional outcomes in IsoPC brain.
In Aim 2, we will determine if IsoPC neuroprotection in males is mediated by Akt activation and if estradiol increases expression of neuronal cell death-inducible putative kinase (NIPK), a negative modulator of Akt, thus leading to decreased Akt activation in IsoPC females. These novel studies will yield new information about Akt regulation in IsoPC brain.
In Aim 3, we will utilize female estrogen receptor (ER) alpha knockout mice and a selective ER alpha agonist to determine if estradiol acts via an ER alpha-dependent mechanism to attenuate Akt activation and increase NIPK gene expression in IsoPC mouse brain, thus leading to increased ischemic damage.
In Aim 4, we hypothesize that IsoPC suppresses neuronal nitric oxide synthase (nNOS) activity and consequent peroxynitrite (ONOO) formation, and that the sexually dimorphic response to nNOS-derived nitric oxide cell-mediated death results in reduced infarct injury in IsoPC males and enhanced ischemic damage in IsoPC females. We will also demonstrate that loss of nNOS and reduced ONOO formation leads to greater superoxide-mediated injury in IsoPC female brain. Our findings will elucidate the mechanisms by which female stroke outcomes are worsened by preischemic isoflurane exposure. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS054684-03
Application #
7442324
Study Section
Special Emphasis Panel (ZRG1-BDCN-N (02))
Program Officer
Jacobs, Tom P
Project Start
2006-07-01
Project End
2011-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
3
Fiscal Year
2008
Total Cost
$336,452
Indirect Cost
Name
Oregon Health and Science University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Johnsen, Dustin; Murphy, Stephanie J (2011) Isoflurane preconditioning protects astrocytes from oxygen and glucose deprivation independent of innate cell sex. J Neurosurg Anesthesiol 23:335-40
Johnsen, D; Murphy, S J (2011) Isoflurane preconditioning protects neurons from male and female mice against oxygen and glucose deprivation and is modulated by estradiol only in neurons from female mice. Neuroscience 199:368-74
Zhu, W; Wang, L; Zhang, L et al. (2010) Isoflurane preconditioning neuroprotection in experimental focal stroke is androgen-dependent in male mice. Neuroscience 169:758-69
Wang, Lan; Kitano, Hideto; Hurn, Patricia D et al. (2008) Estradiol attenuates neuroprotective benefits of isoflurane preconditioning in ischemic mouse brain. J Cereb Blood Flow Metab 28:1824-34
Wang, Lan; Traystman, Richard J; Murphy, Stephanie J (2008) Inhalational anesthetics as preconditioning agents in ischemic brain. Curr Opin Pharmacol 8:104-10
Kitano, Hideto; Young, Jennifer M; Cheng, Jian et al. (2007) Gender-specific response to isoflurane preconditioning in focal cerebral ischemia. J Cereb Blood Flow Metab 27:1377-86
Kitano, Hideto; Kirsch, Jeffrey R; Hurn, Patricia D et al. (2007) Inhalational anesthetics as neuroprotectants or chemical preconditioning agents in ischemic brain. J Cereb Blood Flow Metab 27:1108-28