@article{cd036d7c9a0e46baaca64fecbadc3528,
title = "Preclinical investigation of Pegylated arginase 1 as a treatment for retina and brain injury",
abstract = "Arginase 1 (A1) is the enzyme that hydrolyzes the amino acid, L-arginine, to ornithine and urea. We have previously shown that A1 deletion worsens retinal ischemic injury, suggesting a protective role of A1. In this translational study, we aimed to study the utility of systemic pegylated A1 (PEG-A1, recombinant human arginase linked to polyethylene glycol) treatment in mouse models of acute retinal and brain injury. Cohorts of WT mice were subjected to retinal ischemia-reperfusion (IR) injury, traumatic optic neuropathy (TON) or brain cerebral ischemia via middle cerebral artery occlusion (MCAO) and treated with intraperitoneal injections of PEG-A1 or vehicle (PEG only). Drug penetration into retina and brain tissues was measured by western blotting and immunolabeling for PEG. Neuroprotection was measured in a blinded fashion by quantitation of NeuN (neuronal marker) immunolabeling of retina flat-mounts and brain infarct area using triphenyl tetrazolium chloride (TTC) staining. Furthermore, ex vivo retina explants and in vitro retina neuron cultures were subjected to oxygen-glucose deprivation (OGD) followed by reoxygenation (R) and treated with PEG-A1. PEG-A1 given systemically did not cross the intact blood-retina/brain barriers in sham controls but reached the retina and brain after injury. PEG-A1 provided neuroprotection after retinal IR injury, TON and cerebral ischemia. PEG-A1 treatment was also neuroprotective in retina explants subjected to OGD/R but did not improve survival in retinal neuronal cultures exposed to OGD/R. In summary, systemic PEG-A1 administration is neuroprotective and provides an excellent route to deliver the drug to the retina and the brain after acute injury.",
keywords = "Arginase, Ischemia-reperfusion injury, Neurodegeneration, Neuroprotection, Retinal ischemia, Stroke",
author = "Fouda, {Abdelrahman Y.} and Wael Eldahshan and Zhimin Xu and Tahira Lemtalsi and Esraa Shosha and Zaidi, {Syed AH} and Abdelrahman, {Ammar A.} and Cheng, {Paul Ning Man} and Narayanan, {S. Priya} and Caldwell, {R. William} and Caldwell, {Ruth B.}",
note = "Funding Information: This work was supported by grants from the National Institute of Health (NIH grant R01-EY11766 to RBC, RWC), the Department of Veterans Affairs, Veterans Health Administration (RBC), Office of Research and Development, Biomedical Laboratory Research and Development (BX001233 to RBC), K99 award (1K99EY029373-01A1 to AYF) and the Culver Vision Discovery Institute at Augusta University. The research reported in this publication was also supported by the NIH core grant number P30EY031631. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. R. B. Caldwell is the recipient of a Research Career Scientist Award from the Department of Veterans Affairs. The contents do not represent the views of the Department of Veterans Affairs or the United States Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors would like to thank Dr. Tauheed Ishrat at the University of Tennessee Health Science Center (UTHSC) for his help with standardizing the mouse MCAO model. Funding Information: This work was supported by grants from the National Institute of Health (NIH grant R01-EY11766 to RBC, RWC), the Department of Veterans Affairs , Veterans Health Administration (RBC) , Office of Research and Development , Biomedical Laboratory Research and Development ( BX001233 to RBC), K99 award ( 1K99EY029373-01A1 to AYF) and the Culver Vision Discovery Institute at Augusta University . The research reported in this publication was also supported by the NIH core grant number P30EY031631 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. R. B. Caldwell is the recipient of a Research Career Scientist Award from the Department of Veterans Affairs. The contents do not represent the views of the Department of Veterans Affairs or the United States Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors would like to thank Dr. Tauheed Ishrat at the University of Tennessee Health Science Center (UTHSC) for his help with standardizing the mouse MCAO model. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2022",
month = feb,
doi = "10.1016/j.expneurol.2021.113923",
language = "English (US)",
volume = "348",
journal = "Neurodegeneration",
issn = "0014-4886",
publisher = "Academic Press Inc.",
}