Stroke is the third leading cause of death and the primary cause of functional disability in the United States. This competitive R01 renewal application requests five years of support to discover a novel therapeutic target against ischemic stroke. Fibrates are peroxisome proliferator-activated receptor alpha (PPARa) agonists and have been prescribed as lipid normalizing drugs. Recent experimental evidence suggests that fibrates are beneficial against neurological diseases including ischemic stroke. In the previous funding cycle, we showed that two fibrates, fenofibrate and gemfibrozil, significantly improved cerebral blood flow after focal ischemia and reduced subsequent infarct size in mice. Fibrates strongly inhibited brain inflammation. The efficacies were independent of their lipid lowering effects but required PPARa expression. Based on these findings, we will further elucidate the downstream linking of PPARa activation to the cerebrovascular efficacies. We are focusing on copper chaperone proteins and superoxide dismutase (SOD) as the mediators of the cerebrovascular efficacies. Both cytosolic isoform (SOD1) and extracellular isoform (SOD3) require copper for their full activity. Our preliminary study showed that fenofibrate and gemfibrozil strongly elevated SOD3 activity levels in the brain. In addition, fenofibrate and gemfibrozil elevated copper chaperone for SOD3, Atox1 mRNA level. These elevations were not seen in PPARa null mice. We hypothesize that Atox1 elevation by PPARa activation pronounces SOD3 activity, which contributes to the cerebrovascular protection by fibrates. We will conduct comprehensive experiments using a well characterized mouse stroke model in several different mutant strains.
Aim 1 is to demonstrate SOD3 as a mediator of cerebrovascular protection by fenofibrate.
Aim 2 is to demonstrate that Atox1 contributes to the SOD3 elevation and subsequent cerebrovascular protection by fibrates.
Aim 3 is to test whether or not peripheral blood cells are additional action sites for the PPARa ->Atox1 ->SOD3 axis activation to lead to the cerebrovascular protection. The proposed study will provide the first evidence that Atox1 may be a potential therapeutic target against ischemic stroke. Obtained knowledge will increase our understanding about the importance of copper trafficking in cerebrovascular diseases.

Public Health Relevance

Stroke is the third leading cause of death and the primary cause for severe functional disability. Ischemic type of stroke represents nearly 80% of all types of stroke. Despite of the great effort to identify a drug that treats stroke even when being given after the onset, tissue plasminogen activator aiming re-canalization of an obstructed cerebral vessel is the only approved drug for stroke. This proposal investigates how fibrates, which were originally developed as lipid normalizing drugs, exert cerebrovascular efficacies against ischemic stroke with a hope to identify a novel therapeutic target.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS048532-07
Application #
8293098
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bosetti, Francesca
Project Start
2004-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
7
Fiscal Year
2012
Total Cost
$289,010
Indirect Cost
$82,170
Name
Morehouse School of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
102005451
City
Atlanta
State
GA
Country
United States
Zip Code
30310
Wang, Guangming; Namura, Shobu (2011) Effects of chronic systemic treatment with peroxisome proliferator-activated receptor ýý activators on neuroinflammation induced by intracerebral injection of lipopolysaccharide in adult mice. Neurosci Res 70:230-7
Wang, Guangming; Liu, Xiaowei; Guo, Qingmin et al. (2010) Chronic treatment with fibrates elevates superoxide dismutase in adult mouse brain microvessels. Brain Res 1359:247-55
Tsukamoto, Tomoko; Nakata, Rieko; Tamura, Emi et al. (2010) Vaticanol C, a resveratrol tetramer, activates PPARalpha and PPARbeta/delta in vitro and in vivo. Nutr Metab (Lond) 7:46
Guo, Qingmin; Wang, Guangming; Namura, Shobu (2010) Fenofibrate improves cerebral blood flow after middle cerebral artery occlusion in mice. J Cereb Blood Flow Metab 30:70-8
Guo, Qingmin; Wang, Guangming; Liu, Xiaowei et al. (2009) Effects of gemfibrozil on outcome after permanent middle cerebral artery occlusion in mice. Brain Res 1279:121-30
Wang, Guangming; Guo, Qingmin; Hossain, Mohammed et al. (2009) Bone marrow-derived cells are the major source of MMP-9 contributing to blood-brain barrier dysfunction and infarct formation after ischemic stroke in mice. Brain Res 1294:183-92
Steele Jr, Ernest C; Guo, Qingmin; Namura, Shobu (2008) Filamentous middle cerebral artery occlusion causes ischemic damage to the retina in mice. Stroke 39:2099-104