In the central nervous system,
progranulin, a
glycoprotein growth factor, plays a crucial role in maintaining physiological functions, and
progranulin gene mutations cause TAR
DNA-binding protein-43-positive
frontotemporal lobar degeneration. Although several studies have reported that
progranulin plays a protective role against ischaemic
brain injury, little is known about temporal changes in the expression level, cellular localization, and glycosylation status of
progranulin after acute focal cerebral ischaemia. In addition, the precise mechanisms by which
progranulin exerts protective effects on ischaemic
brain injury remains unknown. Furthermore, the therapeutic potential of
progranulin against acute focal cerebral ischaemia, including combination treatment with
tissue plasminogen activator, remains to be elucidated. In the present study, we aimed to determine temporal changes in the expression and localization of
progranulin after ischaemia as well as the
therapeutic effects of
progranulin on ischaemic
brain injury using in vitro and in vivo models. First, we demonstrated a dynamic change in
progranulin expression in ischaemic Sprague-Dawley rats, including increased levels of
progranulin expression in microglia within the ischaemic core, and increased levels of
progranulin expression in viable neurons as well as induction of
progranulin expression in endothelial cells within the ischaemic penumbra. We also demonstrated that the fully glycosylated mature secretory
isoform of
progranulin (∼88 kDa) decreased, whereas the glycosylated immature
isoform of
progranulin (58-68 kDa) markedly increased at 24 h and 72 h after reperfusion. In vitro experiments using primary cells from C57BL/6 mice revealed that the glycosylated immature
isoform was secreted only from the microglia. Second, we demonstrated that
progranulin could protect against acute focal cerebral ischaemia by a variety of mechanisms including attenuation of blood-brain barrier disruption,
neuroinflammation suppression, and neuroprotection. We found that
progranulin could regulate vascular permeability via
vascular endothelial growth factor, suppress
neuroinflammation after ischaemia via anti-inflammatory
interleukin 10 in the microglia, and render neuroprotection in part by inhibition of cytoplasmic redistribution of TAR
DNA-binding protein-43 as demonstrated in
progranulin knockout mice (C57BL/6 background). Finally, we demonstrated the therapeutic potential of
progranulin against acute focal cerebral ischaemia using a rat autologous thrombo-embolic model with delayed
tissue plasminogen activator treatment. Intravenously administered recombinant
progranulin reduced
cerebral infarct and oedema, suppressed haemorrhagic transformation, and improved motor outcomes (P = 0.007, 0.038, 0.007 and 0.004, respectively). In conclusion,
progranulin may be a novel therapeutic target that provides vascular protection, anti-
neuroinflammation, and neuroprotection related in part to
vascular endothelial growth factor,
interleukin 10, and TAR
DNA-binding protein-43, respectively.