Growth hormone receptor immunoreactivity is increased in the subventricular zone of juvenile rat brain after focal ischemia: A potential role for growth hormone in injury-induced neurogenesis

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During recovery from an ischemic brain injury, a cerebral growth hormone (GH) axis is activated. Whilst GH has been demonstrated to be neuroprotective both in vitro and in vivo, a role for GH in neuro-restorative processes after brain injury has yet to be studied. To explore a role for GH in injury-induced neurogenesis by examining GH receptor (GH-R) immunoreactivity within the subventricular zone (SVZ) of juvenile rats after brain injury and by testing the proliferative capacity of GH on embryonic mouse neural stem cells. Twenty-one day old rats were subjected to unilateral hypoxic-ischemia of the brain and sacrificed 1-15days later. Coronal brain sections from these animals and age-matched naïve controls were immunostained for GH-R and cell markers of neurogenesis. The level of GH-R immunoreactivity in the ipsilateral and contralateral SVZ of each animal was semi-quantified both by independent blinded scoring by two examiners and blinded image analysis. To examine the effect of GH on proliferation of embryonic mouse neural stem cells, cells were treated with increasing concentrations of rat pituitary GH for 48h in the presence of 5'-bromo-2'-deoxyuridine. The level of GH-R immunoreactivity in the ipsilateral SVZ was significantly increased 5days after injury vs. the contralateral SVZ, coinciding both spatially and temporally with injury-induced neurogenesis. The population of GH-R immunopositive cells in the ipsilateral SVZ at this time was found to include proliferating cells (Ki67 immunopositive), neural progenitor cells (nestin immunopositive) and post-proliferative migratory neuroblasts (doublecortin immunopositive). Stimulation of embryonic mouse NSCs with physiological concentrations of rat pituitary GH elicited a dose-dependent proliferative response. These results indicate a novel role for GH and its receptor in injury-induced neurogenesis, and suggest that GH treatment may potentiate endogenous neuro-restorative processes after brain injury.