Temporospatial effects of acyl-ghrelin on activation of astrocytes after ischaemic brain injury

The protective mechanisms of astrocyte signalling are based on the release of neurotrophic factors and the clearing of toxic substances in the early stages of cerebral ischaemia. However, astrocytes are also responsible for the detrimental effects that occur during the later stages of ischaemia, in which glial scars are formed, thereby impeding neural recovery. Acyl-ghrelin has been found to be neuroprotective after stroke, although the influence of acyl-ghrelin on astrocytes after ischaemic injury is yet to be clarified. In the present study, we used permanent middle cerebral arterial occlusion to establish a brain ischaemia model in vivo, as well as oxygen and glucose deprivation (OGD) to mimic ischaemic insults in vitro. We found that acyl-ghrelin injection significantly increased the number of activated astrocytes in the peri-infarct area at day 3 after brain ischaemia and decreased the number of activated astrocytes after day 9. Moreover, the expression of fibroblast growth factor 2 (FGF2) in the ischaemic hemisphere increased markedly after day 3, and i.c.v. injection of SU5402, an inhibitor of FGF2 signalling, abolished the suppression effects of acyl-ghrelin on astrocyte activation in the peri-infarct region during the later stages of ischaemia. The results from in vitro studies also showed the dual effect of acyl-ghrelin on astrocyte viability. Acyl-ghrelin increased the viability of uninjured astrocytes in an indirect way by stimulating the secretion from OGD-injured astrocytes. It also inhibited the astrocyte viability in the presence of FGF2 in a dose-dependent manner. Furthermore, the expression of acyl-ghrelin receptors on astrocytes was increased after acyl-ghrelin and FGF2 co-treatment. In conclusion, acyl-ghrelin promoted astrocyte activation in the early stages of ischaemia but suppressed the activation in later stages of ischaemic injury. These later effects were likely to be triggered by the increased expression of endogenous FGF2 after brain ischaemia.