A role for the somatotropic axis in neural development, injury and disease

Abstract

This review article discusses the roles of the somatotropic axis in the growth and development of the normal central nervous system (CNS) and during recovery from brain injury. Classically, the actions of pituitary-derived growth hormone (GH) have been reported to be primarily mediated via the induction of hepatic insulin-like growth factor-I (IGF-I). GH receptors (GHRs), however, have now been identified in many body tissues and shown to have both endocrine and local actions, some of which are IGF-I independent. Within the brain, GHRs are widely located across a range of cellular phenotypes, yet little is known regarding their function or endogenous ligand. It is now becoming accepted that GH, like IGF-I, is integrally involved in the growth and development of the normal CNS. Following brain injury, IGF-I mRNA is induced, primarily within reactive microglia. The resultant IGF-I protein appears to have a dual role, first as an endogenous neurotropic and anti-apoptotic agent acting directly on stressed cells, and second as a prohormone for generation of the N-terminal tripeptide of IGF-I, glycine-proline-glutamate (GPE), and the resulting des-N-(1-3)-IGF-I, both of which have specific neuroprotective properties. Our work on deciphering the upstream regulators of injury-induced IGF-I has revealed that a GH-like substance is strongly upregulated after brain injury and specifically associated with stressed neurons and glia. Subsequent to this finding, GH administered centrally 2 hours after a hypoxic-ischemic brain injury in juvenile rats was found to provide significant neuroprotection, interestingly, in a spatiotemporal pattern distinct from the neuroprotection offered by IGF-I. The implications of these findings in regard to the growth, development and injury response of the CNS are discussed.