Transient focal cerebral ischemia is one of the most common types of ischemic stroke. Efforts to screen for agents/mechanisms that protect against cerebral ischemia/reperfusion (I/R) injury have not produced promising results. Interestingly, chronic heavy alcohol consumption increases the risk of ischemic stroke and produces neurodegeneration, whereas light alcohol consumption (LAC) decreases the risk of ischemic stroke and is neuroprotective. The present application will focus on identifying the cellular mechanisms of neuroprotection by LAC.
Our aim i s to translate these findings to humans suffering from the consequences of ischemic stroke. In our preliminary studies, we found that the neuroprotective effect of LAC appeared to be related to an increase in nuclear peroxisome proliferator-activated receptor gamma (PPAR?). We also found that LAC significantly attenuated transient focal cerebral ischemia-induced expression of inflammatory genes and DNA fragmentation. Further, lipocalin-type prostaglandin D2 synthase (L-PGDS) and manganese superoxide dismutase (MnSOD) were found to be upregulated in cerebral cortex by LAC. Based on these findings, our central hypothesis is that LAC protects against cerebral I/R injury by upregulating MnSOD via L-PGDS-mediated PPAR? activation.
In specific aim #1, we propose to test the hypothesis that LAC attenuates vascular endothelial cell (VEC) inflammation and neuronal apoptosis following transient focal cerebral ischemia via an upregulated MnSOD.
In specific aim #2, we propose to test the hypothesis that LAC attenuates VEC inflammation and neuronal apoptosis following transient focal cerebral ischemia via PPAR?-mediated MnSOD upregulation.
In specific aim #3, we propose to test the hypothesis that LAC upregulates MnSOD and attenuates VEC inflammation and neuronal apoptosis following transient focal cerebral ischemia via L-PGDS-mediated PPAR? activation. The findings from these studies will have far-reaching implications, beyond that for LAC. We believe that by identifying the protective targets of LAC we will be able to apply therapy to manipulate these targets in individuals at risk for ischemic stroke.

Public Health Relevance

Light alcohol consumption not only lowers the incidence of ischemic stroke but also improves the prognosis of ischemic stroke in people with risk factors for cardiovascular disease. We aim to develop novel strategies for the prevention and treatment of ischemic stroke by uncovering how alcohol alters the incidence and prognosis of ischemic stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA023610-02
Application #
9232046
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Orosz, Andras
Project Start
2016-03-01
Project End
2021-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
2
Fiscal Year
2017
Total Cost
$293,625
Indirect Cost
$91,125
Name
Louisiana State University Hsc Shreveport
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
095439774
City
Shreveport
State
LA
Country
United States
Zip Code
71103
McCarter, Kimberly D; Li, Chun; Jiang, Zheng et al. (2017) Effect of Low-Dose Alcohol Consumption on Inflammation Following Transient Focal Cerebral Ischemia in Rats. Sci Rep 7:12547