M9, a novel region of amino-Nogo-A, attenuates cerebral ischemic injury by inhibiting NADPH oxidase-derived superoxide production in mice.

Abstract

AIMS:

In acute stroke, neurological damage is due to oxidative stress and neuronal apoptotic death. This study investigated whether Nogo-A 290-562 residues region (M9), fused to the transduction domain of the HIV trans-activator (TAT) protein, is neuroprotective against cerebral ischemia and the mechanisms.

METHODS:

Transient focal cerebral ischemia was induced by middle cerebral artery occlusion in male C57BL/6J mice. TAT-M9, its mutation or vehicle was applied via intraperitoneal injection at the onset of reperfusion. The neurobehavioral scores, infarction volumes, neuronal apoptosis, and the ratio of Bax/Bcl-2 were evaluated. Malondialdehyde (MDA), reactive oxygen species (ROS) levels, and NADPH oxidase activation were measured in the presence or absence of the NADPH oxidase inhibitor apocynin or activator tetrabromocinnamic acid (TBCA).

RESULTS:

Immunofluorescence results confirmed that TAT-M9 was transduced into brain parenchyma, and it significantly improved neurological behavior, reduced infarct volumes, protected neuronal cells from apoptosis, inhibited activation of NADPH oxidase, and decreased MDA and ROS contents. Furthermore, apocynin imitated the beneficial effects of TAT-M9, while TBCA abolished them.

CONCLUSIONS:

Our results demonstrate that TAT-M9 administration attenuates cerebral ischemia by inhibiting NADPH oxidase-mediated oxidative damage and neuronal apoptosis in mice. TAT-M9 may be a potential treatment for cerebrovascular disease.

• Authors: Fan Guo, Wei-Lin Jin, Li-Ya Li, Wen-Ying Song, Hui-Wen Wang, Xing-Chun Gou, Ya-Jing Mi, Qiang Wang, Lize Xiong
• Journal: CNS neuroscience & therapeutics (CNS Neurosci Ther) Vol. 19 Issue 5 Pg. 319-28 (May 2013) ISSN: 1755-5949 [Electronic] England
• PMID: 23490284 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 Blackwell Publishing Ltd.

Chemical References

• Myelin Proteins
• Neuroprotective Agents
• Nogo Proteins
• Peptide Fragments
• RTN4 protein, human
• Rtn4 protein, mouse
• tat Gene Products, Human Immunodeficiency Virus
• Superoxides
• NADPH Oxidases

Topics

• Animals
• Apoptosis (drug effects)
• Brain Ischemia (drug therapy, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Myelin Proteins (therapeutic use)
• NADPH Oxidases (antagonists & inhibitors, physiology)
• Neuroprotective Agents (therapeutic use)
• Nogo Proteins
• Peptide Fragments (therapeutic use)
• Superoxides (metabolism)
• tat Gene Products, Human Immunodeficiency Virus (therapeutic use)