Regulating astrocyte phenotype by Lcn2 inhibition toward ischemic stroke therapy

Area of Science:

• Neuroscience
• Biomedical Engineering
• Pharmacology

Background:

• Ischemia-reperfusion injury causes reactive astrocytes, with A1 phenotypes inducing neuronal death and A2 phenotypes offering neuroprotection.
• Regulating reactive astrocytes towards the A2 phenotype presents a potential therapeutic target for stroke treatment.
• Lipocalin 2 (Lcn2) levels are closely linked to astrocyte phenotypic polarization.

Purpose of the Study:

• To investigate the role of Lcn2 in astrocyte polarization following ischemic stroke.
• To develop and evaluate a novel nanoplatform for inhibiting Lcn2 and modulating astrocyte phenotypes for stroke therapy.

Main Methods:

• Silencing the Lcn2 gene using adeno-associated virus (AAV)-Lcn2 shRNA in MCAO mouse models.
• Fabrication of a nanodrug (AP@R) comprising N-acetyl Pro-Gly-Pro peptide-decorated nanoparticles loaded with rolipram.
• Utilizing neutrophil-mediated transport across the blood-brain barrier (BBB) for targeted drug delivery.

Main Results:

• Silencing Lcn2 significantly reduced A1 astrocytes and increased A2 astrocytes in MCAO mice.
• The AP@R nanodrug effectively targeted neutrophils and crossed the BBB.
• Rolipram released from nanoparticles inhibited Lcn2, reversed astrocyte phenotype, alleviated neuroinflammation, and promoted BBB repair.

Conclusions:

• Inhibiting Lcn2 is a viable strategy to shift astrocyte phenotype towards a neuroprotective A2 state.
• The developed nanoplatform offers a targeted approach for delivering therapeutic agents across the BBB.
• This study presents a novel therapeutic strategy for ischemic stroke by modulating astrocyte polarization and neuroinflammation.