| 1. |
- Gustafsson Brywe, Katarina, 1965, et al.
(författare)
-
IGF-I neuroprotection in the immature brain after hypoxia-ischemia, involvement of Akt and GSK3beta?
- 2005
-
Ingår i: Eur J Neurosci. - : Wiley. - 0953-816X. ; 21:6, s. 1489-502
-
Tidskriftsartikel (refereegranskat)abstract
- Insulin-like growth factor I (IGF-I) is a neurotrophic factor that promotes neuronal growth, differentiation and survival. Neuroprotective effects of IGF-I have previously been shown in adult and juvenile rat models of brain injury. We wanted to investigate the neuroprotective effect of IGF-I after hypoxia-ischemia (HI) in 7-day-old neonatal rats and the mechanisms of IGF-I actions in vivo. We also wanted to study effects of HI and/or IGF-I on the serine/threonine kinases Akt and glycogen synthase kinase 3beta (GSK3beta) in the phophatidylinositol-3 kinase (PI3K) pathway. Immediately after HI, phosphorylated Akt (pAkt) and phosphorylated GSK3beta (pGSK3beta) immunoreactivity was lost in the ipsilateral and reduced in the contralateral hemisphere. After 45 min, pAkt levels were restored to control values, whereas pGSK3beta remained low 4 h after HI. Administration of IGF-I (50 microg i.c.v.) after HI resulted in a 40% reduction in brain damage (loss of microtubule-associated protein) compared with vehicle-treated animals. IGF-I treatment without HI was shown to increase pAkt whereas pGSK3beta decreased in the cytosol, but increased in the nuclear fraction. IGF-I treatment after HI increased pAkt in the cytosol and pGSK3beta in both the cytosol and the nuclear fraction in the ipsilateral hemisphere compared with vehicle-treated rats, concomitant with a reduced caspase-3- and caspase-9-like activity. In conclusion, IGF-I induces activation of Akt during recovery after HI which, in combination with inactivation of GSK3beta, may explain the attenuated activation of caspases and reduction of injury in the immature brain.
|
|
| 2. |
- Gustafsson Brywe, Katarina, 1965, et al.
(författare)
-
Growth hormone-releasing peptide hexarelin reduces neonatal brain injury and alters Akt/glycogen synthase kinase-3beta phosphorylation
- 2005
-
Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 146:11, s. 4665-72
-
Tidskriftsartikel (refereegranskat)abstract
- 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-3beta, 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-3beta activity and caspase-dependent cell death.
|
|
