Protein nanoparticles modified with PDGF-B as a novel therapy after acute cerebral infarction

Abstract

Treatment options for cerebral infarction beyond the time window of reperfusion therapy are limited, and novel approaches are needed. PDGF-B is considered neuroprotective; however, it is difficult to administer at effective concentrations to infarct areas. Nanoparticles (NPs) are small and stable; therefore, we modified PDGF-B to the surface of naturally occurring heat shock protein NPs (HSPNPs) to examine its therapeutic effect in cerebral infarction. PDGF-B modified HSPNPs (PDGF-B HSPNPs) were injected 1 day after transient middle cerebral artery occlusion in CB-17 model mice. We analyzed the infarct volume and motor functional recovery at 3 and 7 days. PDGF-B HSPNPs were specifically distributed in the infarct area, and compared to HSPNPs alone, they significantly reduced infarct volumes and improved neurological function 3 and 7 days after administration. PDGF-B HSPNP administration was associated with strong phosphorylation of Akt in infarct areas and significantly increased neurotrophin-3 production as well as reduced cell apoptosis compared to HSPNPs alone. Moreover, astrogliosis in peri-infarct area was significantly upregulated with PDGF-B HSPNPs compared with HSPNPs alone. Treatment with PDGF-B HSPNPs might be a novel approach for treating cerebral infarction.

Significance Statement

This study involved injection of PDGF-B protein-modified heat shock protein nanoparticles (PDGF-B HSPNPs) 1 day after transient middle cerebral artery occlusion in CB-17 model mice. We demonstrated that PDGF-B HSPNPs significantly reduced the infarct volume and improved motor functional recovery at 3 and 7 days after administration. We also demonstrated that phosphorylation of Akt and increased in pericytes and expression of neurotrophin-3 was promoted with PDGF-B HSPNPs, which may lead to reduce apoptotic neuronal death in peri-infarct area. Additionally, it has been revealed that astrogliosis in peri-infarct area was also promoted with PDGF-B HSPNPs. These results support the use of PDGF-B HSPNPs as a novel therapeutic approach for ischemic stroke.