Neuroserpin Protects Retina From Ischemic/Reperfusion-induced Injury

Objective:Neuroserpin is a functional inhibitory serpin that shows neuron protection in central nervous system. The view that neuroserpin’s neuroprotection is related to itstPA inhibition activity is controversy. The present study was to investigate the potential neuroprotective effect of neuroserpin (NSP) against acute retinal ischemic/reperfusion-induced (IR) injury and explored the potential mechanism in both wild type and tPA knockout mice.Methods:Using wild type and tPA-deficient (tPA7") mice, the IR injury model was established by elevation of the intraocular pressure for 60 minutes.1 μL of 20 μmol/L neuroserpin or an equal volume of bovine serum albumin (BSA) was given intravitreally prior to IR injury. Retinal function was evaluated by an ERG and the number of apoptosis was determined by TUNEL labeling. Retinas were also harvested and caspase-3,-8,-9, PARP, and all their cleaved forms were analyzed.Results:IR injury greatly damaged retinal function and induced apoptosis in the retina,while prophylactically given neuroserpin attenuated the loss of retinal function and significantly reduced the number of apoptoses both in wild type and tPA-/- mice. The levels of cleaved caspase-3 and its modulator, cleaved caspase-9, which were both increased after IR injury, were significantly inhibited by NSP both in wild type and tPA-/- mice.Conclusion:Neuroserpin increased ischemic tolerance in the retina; this effect might be independent from its interaction with a tissue-type plasminogen activator, and at least partly by inhibiting the intrinsic signaling pathway of caspase-3 activation.