| Sumari: | <p><b>Background:</b> Perinatal hypoxic ischaemia is one of the most prevalent causes of neonatal morbidity and mortality worldwide. Hypothermia is currently the only available treatment option. Neuroserpin, an inhibitor of tissue plasminogen activator and an endogenously secreted protein, has been shown to result in a reduction in brain damage and overall functional improvements in models of adult cerebral infarction (Millar et al., 2017). It has therefore been hypothesised that it may also reduce damage caused by perinatal hypoxic ischaemia.</p> <p><b>Methods:</b> We studied a Neuroserpin knock-out mouse (Madani et al., 2003) to shed light on potential neuroprotective properties that this protein may possess. A modified Rice-Vannucci model was employed (Rice et al., 1981) which involves unilateral carotid artery ligation with subsequent 40 minutes of hypoxia to induce hypoxic ischaemic encephalopathy in one brain hemisphere of P8 mice. Mice were sacrificed at P10 and brain sections were stained with Triphenyltetrazolium chloride (TTC) to determine the area of ischaemic damage. Sections of wild-type mice were further used to carry out immunohistochemistry to determine Neuroserpin expression between P4-P14 as well as subsequent to exposure to hypoxic insults. Finally, expression was also explored in a human brain of 38 postconception weeks (pcw).</p> <p><b>Results:</b> Our experiments in the Neuroserpin KO mouse show that Neuroserpin has no statistically significant effect on ischaemic damage following hypoxic-ischaemic injury in the knockout versus the wild-type. When comparing brains exhibiting ischaemic damage as shown by TTC staining, the mean ischaemic volume in the knock-out and wild-type mice were 7.78 mm<sup>3</sup> and 6.71 mm<sup>3</sup> respectively (p=0.69, SEM=1.9, n=25). The region most vulnerable to damage was the hippocampus followed by the striatum. The thalamus and the cortex showed significantly reduced vulnerability in comparison. In wild-type mice, Neuroserpin shows strong expression in layers 5 and 6 of the cortex and peaks at P8 in layer 6B. There are fewer Neuroserpin positive cells in the subplate of the ligated side in comparison to the non-ischaemic control side in mice with exposure to hypoxia. Human Neuroserpin expression at 38 pcw most closely resembles that of P10 mice.</p> <p><b>Conclusions:</b> Neuroserpin was not shown to possess neuroprotective properties in the mouse model for neonatal hypoxic-ischaemic encephalopathy. The reduction in Neuroserpin expression in hypoxicischaemic encephalopathy may be attributed to vulnerability of Neuroserpin secreting cortical layers (McQuillen et al., 2003) as well as tight regulation of expression during neurodevelopment.</p>
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