Neuroprotective effect of flavanol (-)-epicatechin after intracerebral hemorrhage Dietary polyphenols such as flavanols have been reported to help prevent diseases of the cardiovascular and central nervous systems. Cocoa and green tea are rich in flavanols, including (-)-epicatechin. A recent study from colleagues in our stroke group demonstrated that the flavanol (-)-epicatechin given orally reduces ischemic stroke damage through activation of Nrf2, a transcription factor that regulates the expression of endogenous antioxidant enzymes in the brain. We have demonstrated that mice lacking Nrf2 are more susceptible than wild-type control mice to brain damage from intracerebral hemorrhage (ICH). Additionally we showed that the exacerbation of brain injury in Nrf2 knockout mice was associated with increases in production of reactive oxygen species. The overall objective of this R01 is to address whether the flavanol (-)-epicatechin can be used as neuroprotective therapy in ICH, and if so, to generate preclinical efficacy data for its use and elucidate the underlying mechanisms. Our working hypothesis is that (-)-epicatechin reduces ICH injury through the Nrf2 pathway. We have designed three specific aims that utilize the collagenase-induced and autologous blood models of ICH. This research will be carried out in young and aged mice to enhance the clinical relevance.
Aim 1 will determine whether daily (-)-epicatechin treatment after ICH improves outcomes in young male mice.
Aim 2 will determine whether post-treatment with the optimal dose of (-)-epicatechin is effective in young female and aged mice.
Aim 3 will determine whether the Nrf2 pathway contributes to the neuroprotective effect of (-)- epicatechin in ICH models and in in vitro models of hemoglobin-induced toxicity. Through pharmacologic, genetic, imaging, histologic, molecular, and cellular biologic approaches, we will provide novel information about the efficacy of (-)-epicatechin in the two mouse ICH models and about the underlying mechanisms. Such information is required to plan more detailed preclinical trials and could influence clinical practices regarding flavanol use. Ultimately, the data may help the general public and healthcare providers make informed decisions on whether (-)-epicatechin could be accepted as an adjunct treatment in patients with ICH.

Public Health Relevance

Dietary supplements such as flavanols are commonly used by the general public because they are thought to reduce the risk of certain diseases. The major goal of this proposal is to determine whether the flavanol (-)- epicatechin can reduce brain injury from intracerebral hemorrhage in two mouse models and to elucidate the underlying mechanisms. This work will provide the rationale for future clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Project (R01)
Project #
5R01AT007317-02
Application #
8537823
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Glowa, John R
Project Start
2012-09-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$384,993
Indirect Cost
$147,343
Name
Johns Hopkins University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Cheng, Tian; Wang, Wenzhu; Li, Qian et al. (2016) Cerebroprotection of flavanol (-)-epicatechin after traumatic brain injury via Nrf2-dependent and -independent pathways. Free Radic Biol Med 92:15-28
Wang, Wenzhu; Li, Haigang; Yu, Jintao et al. (2016) Protective Effects of Chinese Herbal Medicine Rhizoma drynariae in Rats After Traumatic Brain Injury and Identification of Active Compound. Mol Neurobiol 53:4809-20
Horti, Andrew G; Wang, Yuchuan; Minn, Il et al. (2016) 18F-FNDP for PET Imaging of Soluble Epoxide Hydrolase. J Nucl Med 57:1817-1822
Cui, Kefei; Ma, Xiao; Yu, Lie et al. (2016) Autologous Bone Marrow Mononuclear Cell Transplantation Delays Progression of Carotid Atherosclerosis in Rabbits. Mol Neurobiol 53:4387-96
Jiang, Chao; Zuo, Fangfang; Wang, Yuejuan et al. (2016) Progesterone exerts neuroprotective effects and improves long-term neurologic outcome after intracerebral hemorrhage in middle-aged mice. Neurobiol Aging 42:13-24
Wang, Wei; Li, Mingchang; Wang, Yuefei et al. (2016) GSK-3β inhibitor TWS119 attenuates rtPA-induced hemorrhagic transformation and activates the Wnt/β-catenin signaling pathway after acute ischemic stroke in rats. Mol Neurobiol 53:7028-7036
Wang, Jianping; Fu, Xiaojie; Yu, Lie et al. (2016) Preconditioning with VEGF Enhances Angiogenic and Neuroprotective Effects of Bone Marrow Mononuclear Cell Transplantation in a Rat Model of Chronic Cerebral Hypoperfusion. Mol Neurobiol 53:6057-6068
Zhang, Zhen; Song, Yuejia; Zhang, Ze et al. (2016) Distinct role of heme oxygenase-1 in early- and late-stage intracerebral hemorrhage in 12-month-old mice. J Cereb Blood Flow Metab :
Li, Dongpeng; Ma, Shanshan; Guo, Dewei et al. (2016) Environmental Circadian Disruption Worsens Neurologic Impairment and Inhibits Hippocampal Neurogenesis in Adult Rats After Traumatic Brain Injury. Cell Mol Neurobiol 36:1045-55
Jiang, Chao; Zuo, Fangfang; Wang, Yuejuan et al. (2016) Progesterone Changes VEGF and BDNF Expression and Promotes Neurogenesis After Ischemic Stroke. Mol Neurobiol :

Showing the most recent 10 out of 38 publications