Neonatal encephalopathy due to perinatal hypoxia-ischemia (HI) is a severe condition, and current treatment options are limited. Expression of endogenous osteopontin (OPN), a multifunction glycoprotein, is strongly upregulated in the brain after neonatal HI. Intracerebrally administered OPN has been shown to be neuroprotective following experimental neonatal HI and adult stroke. In the present study, we determined whether intranasal, intraperitoneal or intracerebral treatment with a smaller TAT-OPN peptide is neuroprotective in neonatal mice with HI brain damage. The TAT-OPN peptide exerts bioactivity as it was as potent as full-length OPN in inducing cell adhesion in an in vitro adhesion assay. Intranasal administration of TAT-OPN peptide immediately after HI (T0) or in a repetitive treatment schedule of T0, 3 h, day (D) 1, 2 and 3 after HI did not protect cerebral gray or white matter after HI. Intraperitoneal TAT-OPN treatment at T0 or in two extended treatment schedules (D5, 7, 9, 11, 13, 15 after HI or T0, D1, 3, 5, 7, 9, 11, 13 and 15 after HI) did not result in neuroprotection either. Moreover, no functional improvement (cylinder rearing test and adhesive removal task) was observed following TAT-OPN treatment in any of the intraperitoneal treatment schedules. We validated that the TAT-OPN peptide reached the brain after intranasal or intraperitoneal administration by using an HIV-TAT staining. Finally, also intracerebral administration of the TAT-OPN peptide 1 h after HI did not reduce cerebral damage. Our data show that administration of the TAT-OPN peptide did not exert neuroprotective effects on neonatal HI-induced brain injury or sensorimotor behavioral deficits.

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