A role for growth hormone in neurorestoration and neurogenic processes in the brain

Abstract

The cerebral growth hormone (GH) axis plays an active role following ischemic injury to the brain. Studies have shown that both GH and its receptor are endogenously upregulated in response to ischemic injury and that GH administration post-injury confers significant neuroprotection. Furthermore, there is evidence that GH has trophic effects on neural stem cells (NSCs). However, whether GH can also aid long term recovery and/or have direct effects on neurogenic processes is unclear. Both in vivo and in vitro studies were carried out to address these issues. In vivo studies using the endothelin-1 model of focal ischemic stroke in adult rats demonstrated that a long-term unilateral continuous intracerebroventricular (ICV) infusion of GH is capable of targeting specific areas of active remodelling and neurogenic processes. Immunohistochemistry analyses revealed that ipsilaterally infused GH localised specifically to neuronal and glial progenitor cells within the ipsilateral subventricular zone, white matter tract, lesion and penumbral regions. Treatment with GH commencing 4 days after stroke accelerated recovery in one out three tests of motor function and improved spatial memory on the morris water maze test with no effect on learning. In vitro studies were then carried out to further elucidate the role of GH in mediating neurogenic processes that could potentially contribute to long-term recovery. Studies were also conducted using the hormone prolactin (PRL) since it is closely related to GH and has similar trophic effects on NSCs. Using NSCs with properties of neurogenic radial glia derived from fetal human forebrains, it was determined that exogenously applied GH and PRL promote the proliferation of neural stem cells in the absence of epidermal growth factor or basic fibroblast growth factor. When applied to differentiating NSC’s, they both induce neuronal progenitor proliferation but only PRL has proliferative effects on glial progenitors. Both GH and PRL also promote NSC migration, particularly at higher concentrations. Interestingly, migration studies using receptor antagonists identified that both GH and PRL signal via the PRL receptor to promote migration. In summary, these findings show that delayed treatment with GH may accelerate some aspects of functional recovery and improve spatial memory in the long-term. Furthermore, some of these beneficial effects may be mediated via its trophic effects on NSCs and thus is supportive of a role for GH in post-injury repair processes as well as developmental mechanisms in the brain.