Neuroglobin (Ngb) is one of the latest discovered globins that preferentially localize to neurons in vertebrate brain with a well-defined neuroprotective effect against a wide range of neurological disorders. However, the mechanism underlying the neuroprotective action of Ngb is still uncertain. Neurons are characterized by high metabolic activity and execute fast-paced energy-demanding processes. Moreover, neurons have poor nutrient storage and are particularly vulnerable to ischemic insult. Ngb expression is at the highest in neonatal brains which is coincident with the peak of lipogenesis in the brain and with the presence of glycogen in neural tissue. Interestingly, the higher Ngb expression in neonatal brain is associated with the long recognized ischemic tolerance in neonates. We have generated stable Ngb overexpression in a neuronal cell line and demonstrated that Ngb overexpression significantly inhibits AMPK signaling and increases cellular glycogen and lipid contents. Consistently, AMPK inhibition and glycogen synthase activation were found in cortical neurons of Ngb overexpression mice. These data provided the first evidence that Ngb might regulate neuron metabolism through AMPK signaling. Enhancing glycogenesis and lipogenesis in neuron could have distinct advantage for ATP production even under anaerobic condition. Our preliminary study further demonstrated that AMPK activation diminished the neuroprotection of Ngb overexpression. Given the well-established function of AMPK signaling in cellular metabolism, the high affinity of Ngb to oxygen, and that both Ngb and AMPK predominately express in neurons at CNS, it is plausible that Ngb might interact with AMPK signaling and play a critical role in neuron metabolism. Our central hypothesis is that Ngb overexpression increases nutrient storage capacity via inhibition of AMPK pathway and, thus, provides neuroprotective action against ischemic stroke. We will address the following two specific aims to test our central hypothesis. 1. Determine the role of Ngb overexpression in neuron metabolism and underlying mechanisms in physiological condition. 2. Determine the involvement of AMPK-mediated anabolic action in the neuroprotective effect of Ngb overexpression against ischemic stroke. The proposed studies are expected to have an important positive impact because they may identify novel therapeutic target that ultimately lead to the discovery of treatment for ischemic stroke.

Public Health Relevance

We have identified that neuroglobin overexpression exerts neuroprotective effect against ischemic stroke. We propose to determine if the protective action of neuroglobin is mediated through enhancing nutrient storage capacity in neuron. This work is expected to have significant positive impact by defining a new strategy to protect the brain from ischemic stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS088596-01
Application #
8765001
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bosetti, Francesca
Project Start
2014-07-01
Project End
2019-04-30
Budget Start
2014-07-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of North Texas
Department
Pharmacology
Type
Graduate Schools
DUNS #
City
Fort Worth
State
TX
Country
United States
Zip Code
76107
Yang, Shao-Hua; Lou, Min; Luo, Benyan et al. (2018) Precision Medicine for Ischemic Stroke, Let Us Move Beyond Time Is Brain. Transl Stroke Res 9:93-95
Li, Wenjun; Roy Choudhury, Gourav; Winters, Ali et al. (2018) Hyperglycemia Alters Astrocyte Metabolism and Inhibits Astrocyte Proliferation. Aging Dis 9:674-684
Lin, Shao-Peng; Li, Wenjun; Winters, Ali et al. (2018) Artemisinin Prevents Glutamate-Induced Neuronal Cell Death Via Akt Pathway Activation. Front Cell Neurosci 12:108
Chen, Zhenglan; Liu, Ran; Yang, Shao-Hua et al. (2017) Methylene blue inhibits GABAA receptors by interaction with GABA binding site. Neuropharmacology 119:100-110
Jia, Jie-Min; Chowdary, Praveen D; Gao, Xiaofei et al. (2017) Control of cerebral ischemia with magnetic nanoparticles. Nat Methods 14:160-166
Yang, Shao-Hua; Li, Wenjun; Sumien, Nathalie et al. (2017) Alternative mitochondrial electron transfer for the treatment of neurodegenerative diseases and cancers: Methylene blue connects the dots. Prog Neurobiol 157:273-291
Zhang, Hongxia; Sun, Fen; Wang, Jixian et al. (2017) Combining Injectable Plasma Scaffold with Mesenchymal Stem/Stromal Cells for Repairing Infarct Cavity after Ischemic Stroke. Aging Dis 8:203-214
Wu, Jinzi; Li, Rongrong; Li, Wenjun et al. (2017) Administration of 5-methoxyindole-2-carboxylic acid that potentially targets mitochondrial dihydrolipoamide dehydrogenase confers cerebral preconditioning against ischemic stroke injury. Free Radic Biol Med 113:244-254
Cai, Bin; Li, Wenjun; Mao, XiaoOu et al. (2016) Neuroglobin Overexpression Inhibits AMPK Signaling and Promotes Cell Anabolism. Mol Neurobiol 53:1254-65
Xie, Luo-Kun; Yang, Shao-Hua (2016) Brain globins in physiology and pathology. Med Gas Res 6:154-163

Showing the most recent 10 out of 17 publications