Protective Role of Arginase II in Cerebral Ischemia and Excitotoxicity.
BACKGROUND
Arginase (Arg), one of the enzymes involved in the urea cycle, provides an essential route for the disposal of excess nitrogen resulting from amino acid and nucleotide metabolism. Two reported subtypes of Arg (ArgI and II) compete with nitric oxide synthase (NOS) to use L-arginine as a substrate, and subsequently regulate NOS activity. It has been reported that Arg has significant effects on circulation that suggest the potential role of this enzyme in regulating vascular function. However, the role of Arg following brain damage has not been elucidated. In this study, we hypothesize that the deletion of ArgII will lead to aggravated brain injury following cerebral ischemia and excitotoxicity.


RESULTS
To test our hypothesis, male C57BL/6 wildtype (WT) and ArgII-/-mice were subjected to permanent distal middle cerebral artery occlusion and survived for 7 d. Cerebral blood flow (CBF) data revealed a statistically non-significant decrease in CBF in ArgII-/-mice. However, ArgII-/-mice had significantly higher neurologic deficit scores and brain infarctions. The hypothesis was further tested in a more specific N-methyl-D-aspartate (NMDA)-induced acute excitotoxic model. WT and ArgII-/-mice were given a single intrastriatal injection of 15 nmol NMDA. Forty-eight hours later, the excitotoxic brain damage was significantly worse in ArgII-/-mice. The data from both models confirm the neuroprotective effect of ArgII.


CONCLUSIONS
Targeting ArgII could be considered an integrative part of a multi-modal approach to fight acute brain damage excitotoxicity, ischemic brain injury, and other forms of brain trauma.
Department of Anesthesiology, University of Florida, Gainesville, 32610, FL, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, 32610, FL, USA.
Abdullah Shafique
AS
Ahmad
Department of Medicinal and Biological Chemistry, University of Toledo, Toledo 43614, OH, USA.
Zahoor Ahmad
ZA
Shah
Department of Anesthesiology, University of Florida, Gainesville, 32610, FL, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, 32610, FL, USA; Departments of Neurology, Psychiatry, Psychology, Pharmaceutics, and Neuroscience, University of Florida, Gainesville, 32610 FL, USA.
Sylvain
S
Doré
Cerebral blood flow; Mice; NMDA; Neuroprotection; Nitric oxide synthase; Stroke; Vasodilation