951 Tacrolimus and Leu-Ile Inhibit Hypoxic-Ischemic Encephalopathy in Newborn Rats

Abstract

We used a neonatal rat hypoxia ischemia (HI)/ reperfusion brain damage model and investigated the neuroprotective effects of the immunosuppressant tacrolimus (FK506) and the hydrophobic peptide Leu-Ile, which has an active site similar to that of FK506 but is not an immunosuppressant. Method: HI was induced in 7- or 8-day-old Wister rat pups by transient right carotid artery occlusion, followed by exposure to 8% O. After HI insult, the rats were intraperitoneally administered FK506, Leu-Ile, a combination of the 2 drugs, or vehicle. Twenty-four hours or 7 d after HI, we analyzed the decreasing ratio of cerebral hemispheric weights and then histologically examined the brain tissue by HE, Iba-1, and caspase-3 staining. Body weight gain was also monitored. Result: The decreasing ratio of cerebral hemispheric weights in the FK506, Leu-Ile, and combination groups was lower than that in the vehicle group, but this ratio was significantly different only between the vehicle and FK506 groups. Pathological analysis showed that neurocytic injury had a strong suppressive effect in the FK506 and combination groups and a mild effect in the Leu-Ile group. During the 7-d experiment, the FK506 group showed lower body weight gain than the other groups. Conclusion: Combination treatment with Leu-Ile and FK506 had a stronger neuroprotective effect and lesser side effects; thus, we concluded that combination therapy might have potential for clinical application in neonatal HIE.