on Blood-Brain Barrier Stability Following Rodent Neonatal Hypoxia-Ischemia

Fig. 1

Schematic, showing proposed mechanisms involving this preliminary investigation, directives of further study

Fig. 2

OPN reduced brain edema. To determine the effects of OPN on BBB permeability, brain water content, which is a measure of brain edema, was evaluated. Brain edema was significantly increased in the ipsilateral hemisphere following HI induction. OPN significantly reduced brain edema compared with vehicle group. The contralateral hemisphere showed no increase in edema (*p < 0.05 vs. sham; #p < 0.05 vs. vehicle; N = 4/group)

Fig. 3

OPN reduced BBB permeability. To determine the effect of OPN on BBB permeability, Evans blue dye extravasation as a measure of BBB permeability was evaluated. OPN (5 μg) was administered following HI induction, and HI significantly increased Evans blue dye extravasation, as seen in the ipsilateral hemisphere, which was significantly attenuated by OPN treatment

Conclusion

Translational stroke studies, including animal modeling, are greatly needed to safely integrate basic preclinical scientific principles ahead of clinical application [22–26]. Numerous attempts to reduce HI-induced consequences have failed in the clinical setting. Therefore, it is imperative to create translatable studies that incorporate unique characteristics of the immature brain, such as its anatomical structure, physiological function, cellular composition, and its response to injury [14, 25, 27–36].

The specific objective of this study was to determine a mechanism by which rOPN affected BBB permeability and brain edema in a well-established animal model of neonatal HI. Our data demonstrate that administration of rOPN improves recovery after neonatal HI by stabilization of the BBB, possibly via integrin receptor signaling pathway. The long-term goal of this study is to provide a further basis for the clinical translation of rOPN as an effective therapeutic option with long-term benefits.

In summary, this study showed that OPN protected the BBB following nHI, and this was reversed by Rac1 inhibitor (NSC23766). The mechanisms mediating this neuroprotection warrant further study.

Acknowledgment

This study was partially supported by the National Institutes of Health grant RO1 NS078755 (Dr. Zhang) and American Heart Association CRP 17380009 (Dr. Lekic).

Disclosures

None

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