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Preclinical investigation of Pegylated arginase 1 as a treatment for retina and brain injury.
- Source :
-
Experimental neurology [Exp Neurol] 2022 Feb; Vol. 348, pp. 113923. Date of Electronic Publication: 2021 Nov 12. - Publication Year :
- 2022
-
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.<br /> (Copyright © 2021 Elsevier Inc. All rights reserved.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2430
- Volume :
- 348
- Database :
- MEDLINE
- Journal :
- Experimental neurology
- Publication Type :
- Academic Journal
- Accession number :
- 34780773
- Full Text :
- https://doi.org/10.1016/j.expneurol.2021.113923