1. Preclinical investigation of Pegylated arginase 1 as a treatment for retina and brain injury.
- Author
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Fouda AY, Eldahshan W, Xu Z, Lemtalsi T, Shosha E, Zaidi SA, Abdelrahman AA, Cheng PN, Narayanan SP, Caldwell RW, and Caldwell RB
- Subjects
- Animals, Arginase pharmacokinetics, Blood-Brain Barrier, Blood-Retinal Barrier, Brain metabolism, Brain Ischemia drug therapy, Cell Survival drug effects, Humans, Infarction, Middle Cerebral Artery drug therapy, Male, Mice, Mice, Inbred C57BL, Neurons drug effects, Neurons metabolism, Neuroprotective Agents pharmacokinetics, Optic Nerve Injuries drug therapy, Polyethylene Glycols, Recombinant Proteins therapeutic use, Reperfusion Injury prevention & control, Retina metabolism, Arginase therapeutic use, Brain Injuries drug therapy, Neuroprotective Agents therapeutic use, Retina injuries
- 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., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2022
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