Preclinical investigation of Pegylated arginase 1 as a treatment for retina and brain injury.
Preclinical investigation of Pegylated arginase 1 as a treatment for retina and brain injury.
复制标题
DOI：
10.1016/j.expneurol.2021.113923
复制
发表时间：
2022-03
影响因子：
5.3
通讯作者：
Caldwell, Ruth B.
中科院分区：
文献类型：
--
作者：
Fouda, Abdelrahman Y.;Eldahshan, Wael;Xu, Zhimin;Lemtalsi, Tahira;Shosha, Esraa;Zaidi, Syed A. H.;Abdelrahman, Ammar A.;Cheng, Paul Ning-Man;Narayanan, S. Priya;Caldwell, R. William;Caldwell, Ruth B.
精氨酸酶1 （A1）是将氨基酸l -精氨酸水解为鸟氨酸和尿素的酶。我们之前的研究表明，A1缺失会加重视网膜缺血性损伤，这表明A1具有保护作用。在这项转化研究中，我们旨在研究系统性聚乙二醇化A1 （PEG-A1，重组人精氨酸酶与聚乙二醇连接）治疗急性视网膜和脑损伤小鼠模型的实用性。各组WT小鼠分别遭受视网膜缺血再灌注（IR）损伤、外创伤性视神经病变（TON）或大脑中动脉闭塞（MCAO）引起的脑缺血，并通过腹腔注射PEG- a1或载体（仅PEG）进行治疗。采用免疫印迹法和PEG免疫标记法测定药物对视网膜和脑组织的渗透程度。采用三苯四唑氯（TTC）染色法对视网膜平支架和脑梗死区进行NeuN（神经元标记物）免疫标记定量，以盲法测量神经保护作用。此外，体外视网膜外植体和体外视网膜神经元培养进行氧葡萄糖剥夺（OGD）后再氧合(R)和PEG-A1处理。在假对照组中，系统给予PEG-A1不能穿过完整的血-视网膜/脑屏障，但在损伤后到达视网膜和脑。PEG-A1在视网膜IR损伤、TON和脑缺血后具有神经保护作用。PEG-A1处理对OGD/R视网膜外植体也有神经保护作用，但不能提高OGD/R视网膜神经元培养物的存活率。总之，全身给药PEG-A1具有神经保护作用，为急性损伤后将药物输送到视网膜和大脑提供了良好的途径。
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.
登录
查看更多内容
影响因子：
16.6
作者：
Brunner, Julia S.;Vulliard, Loan;Schabbauer, Gernot
通讯作者：
Schabbauer, Gernot
影响因子：
8
作者：
Cai, Wei;Dai, Xuejiao;Chen, Jun
通讯作者：
Chen, Jun
影响因子：
8.3
作者：
Bieber, Michael;Gronewold, Janine;Hermann, Dirk M.
通讯作者：
Hermann, Dirk M.
影响因子：
4.8
作者：
Clarkson, AN;Liu, HZ;Appleton, I
通讯作者：
Appleton, I
影响因子：
4.4
作者：
Han, Guoge;Casson, Robert J.;Wood, John P. M.
通讯作者：
Wood, John P. M.