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

• Published in: Experimental neurology Vol. 348; p. 113923
• Main Authors: Fouda, Abdelrahman Y., Eldahshan, Wael, Xu, Zhimin, Lemtalsi, Tahira, Shosha, Esraa, Zaidi, Syed AH, Abdelrahman, Ammar A., Cheng, Paul Ning-Man, Narayanan, S. Priya, Caldwell, R. William, Caldwell, Ruth B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2022
• Subjects: Animals; Arginase; Arginase - pharmacokinetics; Arginase - 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; Ischemia-reperfusion injury; Male; Mice; Mice, Inbred C57BL; Neurodegeneration; Neurons - drug effects; Neurons - metabolism; Neuroprotection; Neuroprotective Agents - pharmacokinetics; Neuroprotective Agents - therapeutic use; Optic Nerve Injuries - drug therapy; Polyethylene Glycols; Recombinant Proteins - therapeutic use; Reperfusion Injury - prevention & control; Retina - injuries; Retina - metabolism; Retinal ischemia; Stroke; Retinal ischemia; Neuroprotection; Arginase; Stroke; Ischemia-reperfusion injury; Neurodegeneration
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2021.113923

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. •PEG-A1 is an investigational drug of the enzyme arginase 1.•PEG-A1 crosses the blood-brain/retina barriers after injury and barrier disruption.•Systemic PEG-A1 is neuroprotective in various acute CNS injury in vivo models.•PEG-A1 is neuroprotective ex-vivo in retina explants but not in neuron cultures.•The study is a proof of concept to develop PEG-A1 as treatment for acute CNS injury.