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Department of Obstetrics and Gynecology, Perinatal Center (K.G.B., H.H.), Department of Physiology and Pharmacology (K.G.B., A.-L.L., M.G., C.M., H.H.), and Research Center for Endocrinology and Metabolism, Department of Internal Medicine (J.I.), Sahlgrenska Academy, 405 30 Göteborg, Sweden; and Departments of Internal Medicine (R.G., S.D., E.G.) and Biomedical Sciences & Oncology (M.V.), University of Turin, 8-10124 Turin, Italy
Address all correspondence and requests for reprints to: Dr. Katarina G. Brywe, Perinatal Center, Department of Physiology and Pharmacology, Box 432, 405 30 Göteborg, Sweden. E-mail: katarina.g.brywe{at}medfak.gu.se.
Hexarelin (HEX) is a peptide GH secretagogue with a potent ability to stimulate GH secretion and recently reported cardioprotective actions. However, its effects in the brain are largely unknown, and the aim of the present study was to examine the potential protective effect of HEX on the central nervous system after injury, as well as on caspase-3, Akt, and extracellular signal-regulated protein kinase (ERK) signaling cascades in a rat model of neonatal hypoxia-ischemia. Hypoxic-ischemic insult was induced by unilateral carotid ligation and hypoxic exposure (7.7% oxygen), and HEX treatment was administered intracerebroventricularly, directly after the insult. Brain damage was quantified at four coronal levels and by regional neuropathological scoring. Brain damage was reduced by 39% in the treatment group, compared with vehicle group, and injury was significantly reduced in the cerebral cortex, hippocampus, and thalamus but not in the striatum. The cerebroprotective effect was accompanied by a significant reduction of caspase-3 activity and an increased phosphorylation of Akt and glycogen synthase kinase-3ß, whereas ERK was unaffected. In conclusion, we demonstrate for the first time that HEX is neuroprotective in the neonatal setting in vivo and that increased Akt signaling is associated with downstream attenuation of glycogen synthase kinase-3ß activity and caspase-dependent cell death.
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