Arginase overexpression in neurons and its effect on traumatic brain injury.

Abstract

Arginine is a semi-essential amino acid which serves as a substrate for nitric oxide (NO) production by nitric oxide synthase (NOS) and a precursor for various metabolites including ornithine, creatine, polyamines, and agmatine. Arginase competes with nitric oxide synthase for substrate arginine to produce orthinine and urea. There is contradictory evidence in the literature on the role of nitric oxide in the pathophysiology of traumatic brain injury (TBI). These contradictory perspectives are likely due to different NOS isoforms - endothelial (eNOS), inducible (iNOS) and neuronal (nNOS) which are expressed in the central nervous system. Of these, the role of nNOS in acute injury remains less clear. This study aimed to employ a genetic approach by overexpressing arginase isoforms specifically in neurons using a Thy-1 promoter to manipulate cell autonomous NO production in the context of TBI. The hypothesis was that increased arginase would divert arginine from pathological NO production. We generated 2 mouse lines that overexpress arginase I (a cytoplasmic enzyme) or arginase II (a mitochondrial enzyme) in neurons of FVB mice. We found that two-weeks after induction of controlled cortical injury, overexpressing arginase I but not arginase II in neurons significantly reduced contusion size and contusion index compared to wild-type (WT) mice. This study establishes enhanced neuronal arginase levels as a strategy to affect the course of TBI and provides support for the potential role of neuronal NO production in this condition.

• Authors: Simran Madan, Bettina Kron, Zixue Jin, George Al Shamy, Philippe M Campeau, Qin Sun, Shan Chen, Leela Cherian, Yuqing Chen, Elda Munivez, Ming-Ming Jiang, Claudia Robertson, Clay Goodman, Rajiv R Ratan, Brendan Lee
• Journal: Molecular genetics and metabolism (Mol Genet Metab) Vol. 125 Issue 1-2 Pg. 112-117 (09 2018) ISSN: 1096-7206 [Electronic] United States
• PMID: 30055993 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Thy-1 Antigens
• Nitric Oxide
• Arginine
• Nitric Oxide Synthase Type I
• Nitric Oxide Synthase Type II
• Nitric Oxide Synthase Type III
• Arginase

Topics

• Animals
• Arginase (genetics)
• Arginine (metabolism)
• Brain Injuries, Traumatic (genetics, pathology)
• Cell Line
• Disease Models, Animal
• Gene Expression Regulation, Enzymologic
• Humans
• Mice
• Neurons (enzymology, pathology)
• Nitric Oxide (genetics, metabolism)
• Nitric Oxide Synthase Type I (genetics)
• Nitric Oxide Synthase Type II (genetics)
• Nitric Oxide Synthase Type III (genetics)
• Thy-1 Antigens (genetics)