Preclinical investigation of Pegylated arginase 1 as a treatment for retina and brain injury

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number113923
JournalExperimental Neurology
Volume348
DOIs
StatePublished - Feb 2022

Keywords

  • Arginase
  • Ischemia-reperfusion injury
  • Neurodegeneration
  • Neuroprotection
  • Retinal ischemia
  • Stroke

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

Fingerprint

Dive into the research topics of 'Preclinical investigation of Pegylated arginase 1 as a treatment for retina and brain injury'. Together they form a unique fingerprint.

Cite this