Abstracts Biological Sciences

Studies on the GH/IGF axis in the infant rat brain following hypoxic ischemic injury

by Arjan Scheepens

Brain injuries, be they hypoxic, ischemic, traumatic or neurodegenerative result in permanent neurological deficit and presently there are few or no therapeutic interventions available. Recent research into how and why brain cells die after an insult has elucidated that a significant number of cells die in an apoptotic manner. Following a transient brain injury cells continue to die for upto 5 days after the insult thereby giving a window of opportunity for treatment. In response to injury, the brain produces a range of neurotrophic hormones including insulin-like growth factor 1 (IGF-I), which are thought to act as endogenous neuroprotective agents. This response occurs earlier and to a greater extent in the young. Studies have shown that the exogenous administration of these neurotrophic hormones after brain injury can prevent some cell death, likely through an inhibition of apoptosis. In these studies a well characterised model of HI brain injury in the juvenile rat was used to investigate the response of the IGF-I and growth hormone (GH) axes to brain injury. The action and transport of IGF-I is partly regulated by six binding proteins (IGFBP1-6) for which the response of IGFBP 1-5 to neural injury has been shown. The starting point therefore is a description of the response of IGFBP-6 to HI brain injury. Although the GH receptor is widely expressed in the brain on both neurones and glia, no reports have definitively shown the existence of its ligand, GH within the brain. Here I show that the GH receptor is differentially regulated after neural injury and that its immunolocalisation suggests an importation mechanisms for peripheral GH into the injured CNS, via the choroid plexus. Furthermore I show that a GH-like substance is strongly upregulated after injury, specifically associated with stressed and dying neurones and glia. Subsequently, I show that intracerebral infusions of rat GH into the injured rat brain conveys significant protection exclusively to GH receptor bearing neurones. In summary, these data show a GH-like substance may be acting as a new neurotrophic factor which is upregulated after brain injury and may act as an endogenous neuroprotective agent.