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.

• Authors: Abdelrahman Y Fouda, Wael Eldahshan, Zhimin Xu, Tahira Lemtalsi, Esraa Shosha, Syed Ah Zaidi, Ammar A Abdelrahman, Paul Ning-Man Cheng, S Priya Narayanan, R William Caldwell, Ruth B Caldwell
• Journal: Experimental neurology (Exp Neurol) Vol. 348 Pg. 113923 (02 2022) ISSN: 1090-2430 [Electronic] United States
• PMID: 34780773 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Neuroprotective Agents
• Recombinant Proteins
• Polyethylene Glycols
• ARG1 protein, human
• Arginase

Topics

• Animals
• Arginase (pharmacokinetics, therapeutic use)
• Blood-Brain Barrier
• Blood-Retinal Barrier
• Brain (metabolism)
• Brain Injuries (drug therapy)
• Brain Ischemia (drug therapy)
• Cell Survival (drug effects)
• Humans
• Infarction, Middle Cerebral Artery (drug therapy)
• Male
• Mice
• Mice, Inbred C57BL
• Neurons (drug effects, metabolism)
• Neuroprotective Agents (pharmacokinetics, therapeutic use)
• Optic Nerve Injuries (drug therapy)
• Polyethylene Glycols
• Recombinant Proteins (therapeutic use)
• Reperfusion Injury (prevention & control)
• Retina (injuries, metabolism)