Retina Is Protected by Neuroserpin from Ischemic/Reperfusion-Induced Injury Independent of Tissue-Type Plasminogen Activator

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2015 Jul 16

PMID 26176694

Citations 11

Authors

R P Gu

L L Fu

C H Jiang

Y F Xu

X Wang

J Yu

Affiliations

Soon will be listed here.

Abstract

The purpose of the present study was to investigate the potential neuroprotective effect of neuroserpin (NSP) on acute retinal ischemic/reperfusion-induced (IR) injury. An IR injury model was established by elevating intraocular pressure (IOP) for 60 minutes in wild type and tPA-deficient (tPA-/-) mice. Prior to IR injury, 1 μL of 20 μmol/L NSP or an equal volume of bovine serum albumin (BSA) was intravitreally administered. Retinal function was evaluated by electroretinograph (ERG) and the number of apoptotic neurons was determined via TUNEL labeling. Caspase-3, -8, -9,poly (ADP-ribose) polymerase (PARP)and their cleaved forms were subsequently analyzed. It was found that IR injury significantly damaged retinal function, inducing apoptosis in the retina, while NSP attenuated the loss of retinal function and significantly reduced the number of apoptotic neurons in both wild type and tPA-/- mice. The levels of cleaved caspase-3, cleaved PARP (the substrate of caspase-3) and caspase-9 (the modulator of the caspase-3), which had increased following IR injury, were significantly inhibited by NSP in both wild type and tPA-/- mice. NSP increased ischemic tolerance in the retina at least partially by inhibiting the intrinsic cell death signaling pathway of caspase-3. It was therefore concluded that the protective effect of neuroserpin maybe independent from its canonical interaction with a tissue-type plasminogen activator.

Citing Articles

Neuroserpin and Extracellular Vesicles in Ischemic Stroke: Partners in Neuroprotection?.

Brenna S, Glatzel M, Magnus T, Puig B, Galliciotti G Aging Dis. 2024; 15(5):2191-2204.

PMID: 39191396 PMC: 11346402. DOI: 10.14336/AD.2024.0518.

Neuroserpin normalization by mesenchymal stem cell therapy after encephalopathy of prematurity in neonatal rats.

Wang L, Hsiung C, Chang C, Lin M, Chen S Pediatr Res. 2024; .

PMID: 39085403 DOI: 10.1038/s41390-024-03412-z.

Neuroserpin gene therapy inhibits retinal ganglion cell apoptosis and promotes functional preservation in glaucoma.

Chitranshi N, Rajput R, Godinez A, Pushpitha K, Mirzaei M, Basavarajappa D Mol Ther. 2023; 31(7):2056-2076.

PMID: 36905120 PMC: 10362384. DOI: 10.1016/j.ymthe.2023.03.008.

Quantitative proteomics analysis of human vitreous in rhegmatogenous retinal detachment associated with choroidal detachment by data-independent acquisition mass spectrometry.

Luo S, Xu H, Yang L, Gong X, Shen J, Chen X Mol Cell Biochem. 2022; 477(6):1849-1863.

PMID: 35332395 DOI: 10.1007/s11010-022-04409-0.

Neuroserpin, a crucial regulator for axogenesis, synaptic modelling and cell-cell interactions in the pathophysiology of neurological disease.

Godinez A, Rajput R, Chitranshi N, Gupta V, Basavarajappa D, Sharma S Cell Mol Life Sci. 2022; 79(3):172.

PMID: 35244780 PMC: 8897380. DOI: 10.1007/s00018-022-04185-6.

References

Osterwalder T, Contartese J, Stoeckli E, Kuhn T, Sonderegger P . Neuroserpin, an axonally secreted serine protease inhibitor. EMBO J. 1996; 15(12):2944-53. PMC: 450235. View

Husain S, Liou G, Crosson C . Opioid receptor activation: suppression of ischemia/reperfusion-induced production of TNF-α in the retina. Invest Ophthalmol Vis Sci. 2011; 52(5):2577-83. PMC: 3088550. DOI: 10.1167/iovs.10-5629. View

Hanninen V, Pantcheva M, Freeman E, Poulin N, Grosskreutz C . Activation of caspase 9 in a rat model of experimental glaucoma. Curr Eye Res. 2003; 25(6):389-95. DOI: 10.1076/ceyr.25.6.389.14233. View

Chen S, Yang T, Ho C, Kuo Y, Yip Y, Chao A . Retinal toxicity of intravitreal tissue plasminogen activator: case report and literature review. Ophthalmology. 2003; 110(4):704-8. DOI: 10.1016/S0161-6420(02)01979-6. View

Yepes M, Sandkvist M, Wong M, Coleman T, Smith E, Cohan S . Neuroserpin reduces cerebral infarct volume and protects neurons from ischemia-induced apoptosis. Blood. 2000; 96(2):569-76. View

Shima C, Adachi Y, Minamino K, Okigaki M, Shi M, Imai Y . Neuroprotective effects of granulocyte colony-stimulating factor on ischemia-reperfusion injury of the retina. Ophthalmic Res. 2012; 48(4):199-207. DOI: 10.1159/000340059. View

Sun D, Vingrys A, Kalloniatis M . Metabolic and functional profiling of the ischemic/reperfused rat retina. J Comp Neurol. 2007; 505(1):114-30. DOI: 10.1002/cne.21481. View

Hattenbach L, Allers A, Gumbel H, Scharrer I, Koch F . Vitreous concentrations of TPA and plasminogen activator inhibitor are associated with VEGF in proliferative diabetic vitreoretinopathy. Retina. 1999; 19(5):383-9. DOI: 10.1097/00006982-199909000-00003. View

Gelderblom M, Neumann M, Ludewig P, Bernreuther C, Krasemann S, Arunachalam P . Deficiency in serine protease inhibitor neuroserpin exacerbates ischemic brain injury by increased postischemic inflammation. PLoS One. 2013; 8(5):e63118. PMC: 3643909. DOI: 10.1371/journal.pone.0063118. View

10.

Huang P, Huo Y, Lou L, Li H, Barnstable C, Zhang C . CD4 positive T helper cells contribute to retinal ganglion cell death in mouse model of ischemia reperfusion injury. Exp Eye Res. 2013; 115:131-9. DOI: 10.1016/j.exer.2013.06.015. View

11.

Yepes M, Lawrence D . New functions for an old enzyme: nonhemostatic roles for tissue-type plasminogen activator in the central nervous system. Exp Biol Med (Maywood). 2004; 229(11):1097-104. DOI: 10.1177/153537020422901103. View

12.

Lee T, Coates L, Birch N . Neuroserpin regulates N-cadherin-mediated cell adhesion independently of its activity as an inhibitor of tissue plasminogen activator. J Neurosci Res. 2007; 86(6):1243-53. DOI: 10.1002/jnr.21592. View

13.

Kim Y, Kim H, Jang J, Park C, Lee J, Shin H . Effects of electroacupuncture on apoptotic pathways in a rat model of focal cerebral ischemia. Int J Mol Med. 2013; 32(6):1303-10. DOI: 10.3892/ijmm.2013.1511. View

14.

Rodriguez-Gonzalez R, Millan M, Sobrino T, Miranda E, Brea D, Perez de la Ossa N . The natural tissue plasminogen activator inhibitor neuroserpin and acute ischaemic stroke outcome. Thromb Haemost. 2010; 105(3):421-9. DOI: 10.1160/TH10-09-0621. View

15.

Cinelli P, Madani R, Tsuzuki N, Vallet P, Arras M, Zhao C . Neuroserpin, a neuroprotective factor in focal ischemic stroke. Mol Cell Neurosci. 2002; 18(5):443-57. DOI: 10.1006/mcne.2001.1028. View

16.

White B, Sullivan J, Degracia D, ONeil B, Neumar R, Grossman L . Brain ischemia and reperfusion: molecular mechanisms of neuronal injury. J Neurol Sci. 2000; 179(S 1-2):1-33. DOI: 10.1016/s0022-510x(00)00386-5. View

17.

DOnofrio P, Koeberle P . What can we learn about stroke from retinal ischemia models?. Acta Pharmacol Sin. 2012; 34(1):91-103. PMC: 4086506. DOI: 10.1038/aps.2012.165. View

18.

Yang Y, Duan J, Gui D, Yang H, Gao D . Effect of aminoguanidine on caspase-3 expression in rat retina after ischemia-reperfusion injury. Int J Ophthalmol. 2012; 4(3):259-61. PMC: 3340811. DOI: 10.3980/j.issn.2222-3959.2011.03.09. View

19.

Mitka M . Early treatment of ischemic stroke with intravenous tPA reduces disability risk. JAMA. 2013; 310(11):1111. DOI: 10.1001/jama.2013.278292. View

20.

Nykjaer A, Petersen C, Moller B, Jensen P, Moestrup S, Holtet T . Purified alpha 2-macroglobulin receptor/LDL receptor-related protein binds urokinase.plasminogen activator inhibitor type-1 complex. Evidence that the alpha 2-macroglobulin receptor mediates cellular degradation of urokinase receptor-bound complexes. J Biol Chem. 1992; 267(21):14543-6. View