Astrocytes can be reacted to “reactive astrocytes” after ischemia-reperfusion injury, in which A1 phenotype causes neuronal and oligodendrocyte death, whereas the A2 phenotype exerts neuroprotective effects, thus regulating reactive astrocyte to A2 type is a potential target for stroke therapy. Lcn2 level is highly associated with the phenotypic polarization of astrocytes. We found that silencing the Lcn2 gene by adeno-associated virus (AAV)-Lcn2 shRNA adenovirus resulted in a dramatic decrease in A1-type astrocytes and increase in A2 astrocytes in MCAO mice. Hence, a nanoplatform was developed for stroke therapy by inhibiting Lcn2. This system was fabricated by N-acetyl Pro-Gly-Pro peptide-decorated rod-shaped poly (lactic-co-glycolic acid) nanoparticles loading with rolipram (AP@R). The nanodrug can be efficiently taken up by neutrophils simultaneously through morphology-mediated passive targeting and Cxcr2 receptor-mediated active targeting, subsequently crossing the blood-brain barrier (BBB) by hitchhiking neutrophils. When accumulating at the brain parenchyma, the released rolipram can inhibit the Lcn2 level, thereby reversing the astrocyte phenotype to alleviate neuroinflammation and promote BBB repair. This work provides a new strategy for treating ischemic stroke.
The effect of lipopolysaccharide (LPS)-based neuroinflammation following cerebral ischemia/reperfusion (I/R) on the genotypic transformation of reactive astrocytes and its relationship with endogenous hydrogen sulfide (H 2 S) were investigated in present study. We found that LPS promoted the cerebral I/R-induced A1 astrocytes proliferation in mouse hippocampal tissues and deteriorated the reduction of hydrogen sulfide (H 2 S) content in mouse sera, H 2 S donor NaHS could inhibit A1 astrocytes proliferation. Similarly, knockout of cystathionine γ-lyase (CSE), one of endogenous H 2 S synthases, likewise up-regulated the cerebral I/R-induced A1 astrocytes proliferation, which could also be blocked by NaHS. Besides, supplement with H 2 S promoted the A2 astrocytes proliferation in hippocampal tissues of CSE knockout (CSE KO) mice or LPS-treated mice following cerebral I/R. In the oxygen glucose deprivation/reoxygenation (OGD/R) model of astrocytes, H 2 S also promoted the transformation of astrocytes into A2 subtype. Moreover, we found that H 2 S could up-regulate the expression of α-subunit of large-conductance Ca 2+ -activated K + (BK Ca ) channels in astrocytes, and the channel opener BMS-191011 likewise promoted the transformation of astrocyte into A2 subtype. In conclusion, H 2 S inhibits the proliferation of A1 astrocytes induced by LPS-based neuroinflammation following cerebral I/R and promotes the transformation of astrocytes into A2 subtype, which may be related to up-regulation of BK Ca channels.
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