Progranulin promotes functional recovery and neurogenesis in the subventricular zone of adult mice after cerebral ischemia

Progranulin (PGRN), a secreted glycosylated protein, has been reported to attenuate ischemia-induced cerebral injury through anti-inflammation, attenuation of blood-brain barrier disruption and neuroprotection. However, the effect of PGRN on neurogenesis in the subventricular zone (SVZ) after cerebral ischemia remains unclear. In this study, adult C57BL/6 mice were subjected to permanent middle cerebral artery occlusion (pMCAO), and different doses of recombinant mouse PGRN (r-PGRN, 0.3 ng, 1 ng, 5 ng) were intracerebroventricularly administered 30 min after pMCAO. Results showed that 1 ng r-PGRN markedly reduced infarct volume and rescued functional deficits 24 h after pMCAO. Meanwhile, 1 ng r-PGRN increased SVZ cell proliferation, as shown by a high number of bromodeoxyuridine-positive (BrdU+) cells and Ki-67+ cells in the ischemic ipsilateral SVZ 7 d after pMCAO. Additionally, PGRN increased the percentage of BrdU+/Doublecortin (DCX)+ cells in the ipsilateral SVZ 14 d after pMCAO and increased the percentage of new neurons (BrdU+/NeuN+ cells) in the peri-infarct striatum 28 d after pMCAO, suggesting that PGRN promotes neuronal differentiation. PGRN also upregulated phosphorylation of ERK1/2 and Akt in the ipsilateral SVZ 3 d after pMCAO. Our data indicate that PGRN treatment promotes acute functional recovery; most importantly, it also stimulates neurogenesis in the SVZ, which could be beneficial for long-term recovery after cerebral ischemia. The increase in neurogenesis could be associated with activation of the MAPK/ERK and PI3K/Akt pathways. These results suggest a potential new strategy utilizing PGRN in ischemic stroke therapy.