Abstract
Apart from regulating somatic growth and metabolic processes, accumulating evidence suggests that the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis is involved in the regulation of brain growth, development, and myelination. In addition, both GH and IGF-I affect cognition and biochemistry in the adult brain. Some of the effects of GH are attributable to circulating IGF-I, while others may be due to IGF-I produced locally within the brain. Some of the shared effects in common to GH and IGF-I may also be explained by cross-talk between the GH and IGF-I transduction pathways, as indicated by recent data from other cell systems. Otherwise, it also seems that GH may act directly without involving IGF-I (either circulating or locally). Plasticity in the central nervous system (CNS) may be viewed as changes in the functional interplay between the major cell types, neurons, astrocytes, and oligodendrocytes. GH and IGF-I affect all three of these cell types in several ways. Apart from the neuroprotective effects of GH and IGF-I posited in different experimental models of CNS injury, IGF-I has been found to increase progenitor cell proliferation and new neurons, oligodendrocytes, and blood vessels in the dentate gyrus of the hippocampus. It appears that the MAPK signaling pathway is required for IGF-I—stimulated proliferation in vitro, whereas the PI3K/Akt or MAPK/Erk signaling pathway appears to mediate antiapoptotic effects. The increase of IGF-I on endothelial cell phenotype may explain the increase in cerebral arteriole density observed after GH treatment. The functional role of GH and IGF-I in the adult brain will be reviewed with reference to neurotransmitters, glucose metabolism, cerebral blood flow, gap junctional communication, dendritic arborization, exercise, enriched environment, depression, learning, memory, and aging.Briefly, these findings suggest that IGF-I functions as a putative regenerative agent in the adult CNS. Hitherto less studied regarding in these aspects, GH may have similar effects, especially as it is the main regulator of IGF-I in vivo. Some of the positive cognitive features of GH treatment are likely attributable to the mechanisms reviewed here.
Highlights
A recent in vivo study showed that intracerebroventricular administration of insulin-like growth factor (IGF)-I for 3 days after the insult reduced hypoxic-ischemic injury (HI) brain injury by 40% compared to controls and that the neuroprotective effect was accompanied by increased levels of phosphorylated Akt and Erk, inactivation of the proapoptotic glycogen synthase kinase kinase 3 β (GSK3β), and with reduced caspase-3– and caspase-9–like activity[209]
It may be that exercise, via running, influences neurogenesis by a common source of a vascular intermediate, where the initial proliferative response in the subgranular zone (SGZ) could be caused by exercise-elevated peripheral factors, e.g., vascular endothelial growth factor-A (VEGF-A) or IGF-I[71,116,132,135]
In addition to IGF-I[159], that increases in the hippocampus after exercise is fibroblast growth factor-2 (FGF-2), which is a well-known mitogen of adult neural progenitors[99]
Summary
The majority of circulating IGF-I is bound to a variety of different IGF binding proteins (IGFBPs), of which six have been characterized to date. A wide range of different functions for the IGFBPs have been proposed and they are considered to be of importance for the pharmacokinetics of IGF-I, both in circulation and at the tissue level. At the cell surface or in the extracellular cell matrix, IGFBPs can either inhibit or enhance the presentation of IGF-I to its receptor. Reports have suggested additional IGF-I independent actions of the IGFBPs (for review, see [168]). Colocalization of IGFBPs and IGF-I has been reported to occur during brain development and has been suggested to be a mechanism for. Modulating the actions of IGF-I[119,131]. IGFBP-2[95], IGFBP-4[64], and IGFBP-5[64] appear to be the predominant binding proteins, low expression of IGFBP-1[131], IGFBP-3[95],
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