Delayed administration of guanosine improves long-term functional recovery and enhances neurogenesis and angiogenesis in a mouse model of photothrombotic stroke

Abstract

Guanosine (GUO) is neuroprotective when administered acutely for the treatment of cerebral ischemia. The aim of the present study was to investigate whether delayed administration of GUO improved long-term functional recovery following stroke, as well as to explore the potential underlying mechanisms. GUO (8 mg/kg) or a vehicle was administered intraperitoneally for 7 consecutive days beginning 24 h prior to photothrombosis-induced stroke in male C57/B6J mice. Behaviour tests were performed at days 1, 3, 7, 14 and 28 post-stroke. Infarct volume was measured using Nissl staining at day 7 post-stroke. Neurogenesis and angiogenesis were evaluated by co-labelling bromodeoxyuridine (BrdU) with doublecortin (DCX), neuronal nuclei (NeuN) and von Willebrand factor, in immunohistochemical studies. Brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) levels in the ipsilesional brain at day 28 post-stroke were detected by western blot analysis. Delayed administration of GUO did not reduce infarct volume or affect neurological function at day 7 post-stroke; however, it did improve functional recovery from day 14 post-stroke, when compared with the vehicle group. GUO significantly increased the number of BrdU+ and BrdU+/DCX+ cells in the subventricular zone and subgranular zone at all examined time points, the number of Brdu+/NeuN+ cells in the peri-infarction region at days 14 and 28 post-stroke and microvessel density in the peri-infarction region at day 28 post-stroke compared with the vehicle group. In addition, the BDNF and VEGF levels in the ipsilesional brain were significantly elevated. Delayed administration of GUO at 24 h post-stroke enhanced neurogenesis and angiogenesis, and increased BDNF and VEGF levels, which likely contributes to long-term functional recovery following stroke.