Comparative signaling pathways of insulin‐like growth factor‐1 and brain‐derived neurotrophic factor in hippocampal neurons and the role of the PI3 kinase pathway in cell survival

Abstract

Insulin-like growth factor-1 (IGF-1) and brain-derived neurotrophic factor (BDNF) are trophic factors required for the viability and normal functions of various neuronal cells. However, the detailed intracellular mechanism(s) involved in these effects in neuronal cells remains to be fully elucidated. In present study, the respective intracellular signaling pathway induced by IGF-1 and BDNF and their possible role in neuronal survival were investigated. Both IGF-1 and BDNF protected hippocampal neurons from serum deprivation-induced death with IGF-1 apparently being more potent. Western blot analyses showed that both IGF-1 and BDNF induced the activation of the phosphatidylinositide 3 kinase (PI3)/Akt (protein kinase B) kinase and the mitogen-activated protein kinase (MAPK) pathways. The phosphorylation of Akt and its downstream target, FKHRL1, induced by IGF-1 was rapid and sustained while that of MAPK was transient. The reverse situation was observed for BDNF. Moreover, IGF-1 potently induced the tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and its association with PI3 kinase while BDNF was weak in these assays. In contrast, the tyrosine phosphorylation of Shc proteins was dramatically stimulated by BDNF, with IGF-1 having only a minimal effect. Most interestingly, only the inhibitor of the PI3K/Akt pathway, LY294002, was able to block the survival effects of both IGF-1 and BDNF; an inhibitor of the MAPK pathway inhibitor, PD98059, being ineffective. Taken together, these data reveal that the survival properties of both IGF-1 and BDNF against serum deprivation are mediated by the activation of the PI3K/ Akt, but not the MAPK, pathway in hippocampal neurons.

Interaction of FGF-2 with IGF-1 and BDNF in stimulating Akt, ERK, and neuronal survival in hippocampal cultures

“…The smaller degree of neuroprotection was not the result of a smaller Interestingly, cell survival did not correlate with the magnitude of activation of Akt and ERK. This was somewhat surprising in that the two kinases are thought to play key roles in mediating growth factor-induced neuroprotection (Tamatani et al, 1998;Brunet et al, 1999;Hetman et al, 1999;Matsuzaki et al, 1999;Yamaguchi et al, 2001;Zheng and Quirion, 2004). In our studies, BDNF, IGF-1, and FGF-2 were found to be all approximately equally effective at activating Akt.…”

“…In addition to examining enhancement of cell survival, we have compared the coupling of receptors for these growth factors to activation of Akt (protein kinase B) and the Extracellular-regulated kinase (ERK) mitogen-activated protein (MAP) kinases. These kinases are thought to be key components in mediating growth factorinduced neuroprotection (Tamatani et al, 1998;Brunet et al, 1999;Hetman et al, 1999;Matsuzaki et al, 1999;Yamaguchi et al, 2001;Zheng and Quirion, 2004). We found significant differences in the neuroprotective efficacy of IGF-1, FGF-2, and BDNF and the pattern of receptor coupling to ERK and Akt.…”

“…IGF-1 has been shown, in vitro, to have neurotrophic and neuroprotective properties in hippocampal cultures (Nitta et. al., 2004;Zheng and Quirion, Correspondence should be addressed to Dr. Daniel S. Cowen at the Department of Psychiatry, UMDNJ-Robert Wood Johnson Medical School, 125 Paterson Street, Suite 2200, New Brunswick, NJ 08901;(732) and (732) . Email: cowends@umdnj.edu2004; Johnson-Farley et al, 2006).…”

Somatostatin and Alzheimer's disease

“…Interestingly, IGF-I normalized phosphorylated-Akt (p-Akt) protein levels in the Aβ25-35-treated-rats, and it has been previously demonstrated that IGF-I protects against Aβ-induced cell death through Page 13 of 31 A c c e p t e d M a n u s c r i p t 13 activation of Akt (Dudek et al, 1997). The lack of changes in the MAPK pathway indicates that the survival properties of IGF-I are most likely not mediated via this intracellular mechanism (Zheng and Quirion 2004). Another molecular mechanism by which IGF-I could suppress Aβ toxicity has been recently reported by Wei et al (2002).…”

Rett Syndrome: Reaching for Clinical Trials

“…Unlike BDNF, insulin-like growth factor-1 (IGF-1) and its active peptide (1-3)IGF-1 cross the BBB and activate intracellular signaling cascades similar to those triggered by BDNF a c t i v a t i o n o f Tr k B r e c e p t o r s , w h i c h i n c l u d e s phosphatidylinositol-3 kinase-Akt and mitogen-activated protein kinase [91]. Intraperitoneal injection of (1-3)IGF-1 (glypromate) in male Mecp2 knockout mice improved survival and locomotor activity, as well as social and anxiety behaviors [92].…”