BACKGROUND: The Nogo-66 antagonistic peptide (NEP1-40) is a potential candidate for therapeutic intervention of neuronal injury. However, delivery of the proteins across the blood-brain barrier is severely limited by its size and biochemical properties. The current study was designed to evaluate the transducible effects of the trans-activator of transcription (TAT) transduction system for NEP1-40 to cross the blood-brain barrier and to clarify whether intraperitoneal administration of TAT-NEP1-40 could protect cerebral neurons from ischemic injury. METHODS: Adult male Sprague-Dawley rats were submitted to a 120-min focal ischemia and received an intraperitoneal injection of No-TAT-NEP1-40, TAT-NEP1-40, TAT-beta-galactosidase, or vehicle. The existence of the proteins in the brain was analyzed with immunofluorescence and Western blot techniques at 6 h after injection. Brain ischemic injury was evaluated by neurologic deficit scores, infarction volumes, terminal deoxynucleotidyl transferase-mediated dUDP-biotin nick end labeling staining, and assay of caspase-3 activity. RESULTS: Western blot analysis and immunofluorescence staining confirmed the presence of TAT-NEP1-40 protein in the brains 6 h after injection. Intraperitoneal injection of TAT-NEP1-40 could attenuate the numbers of terminal deoxynucleotidyl transferase-mediated dUDP-biotin nick end labeling-positive cells and activated caspase-3 positive cells, and increase the viability of the cells in the ischemic bounder zone, compared with that treated with No-TAT-NEP1-40, TAT-beta-Gal, or vehicle. Furthermore, treatment with TAT-NEP1-40 significantly improved the neurologic outcomes and reduced the size of the infarction in rats. CONCLUSIONS: The results demonstrate that the TAT-NEP1-40 could be efficiently delivered into the rat brains and improve ischemia-induced neurologic outcomes through attenuating cell apoptosis in ischemic brains.