NCAM mimetic peptide P2 synergizes with bone marrow mesenchymal stem cells in promoting functional recovery after stroke

J Cereb Blood Flow Metab. 2024 Jul;44(7):1128-1144. doi: 10.1177/0271678X241226482. Epub 2024 Jan 17.

Abstract

The neural cell adhesion molecule (NCAM) promotes neural development and regeneration. Whether NCAM mimetic peptides could synergize with bone marrow mesenchymal stem cells (BMSCs) in stroke treatment deserves investigation. We found that the NCAM mimetic peptide P2 promoted BMSC proliferation, migration, and neurotrophic factor expression, protected neurons from oxygen-glucose deprivation through ERK and PI3K/AKT activation and anti-apoptotic mechanisms in vitro. Following middle cerebral artery occlusion (MCAO) in rats, P2 alone or in combination with BMSCs inhibited neuronal apoptosis and induced the phosphorylation of ERK and AKT. P2 combined with BMSCs enhanced neurotrophic factor expression and BMSC proliferation in the ischemic boundary zone. Moreover, combined P2 and BMSC therapy induced translocation of nuclear factor erythroid 2-related factor, upregulated heme oxygenase-1 expression, reduced infarct volume, and increased functional recovery as compared to monotreatments. Treatment with LY294002 (PI3K inhibitor) and PD98059 (ERK inhibitor) decreased the neuroprotective effects of combined P2 and BMSC therapy in MCAO rats. Collectively, P2 is neuroprotective while P2 and BMSCs work synergistically to improve functional outcomes after ischemic stroke, which may be attributed to mechanisms involving enhanced BMSC proliferation and neurotrophic factor release, anti-apoptosis, and PI3K/AKT and ERK pathways activation.

Keywords: Ischemic stroke; NCAM mimetic peptide; bone marrow mesenchymal stem cells; middle cerebral artery occlusion; neural cell adhesion molecule.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Infarction, Middle Cerebral Artery / metabolism
  • Infarction, Middle Cerebral Artery / therapy
  • Male
  • Mesenchymal Stem Cell Transplantation* / methods
  • Mesenchymal Stem Cells* / drug effects
  • Mesenchymal Stem Cells* / metabolism
  • Neural Cell Adhesion Molecules* / metabolism
  • Peptides* / pharmacology
  • Peptides* / therapeutic use
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Recovery of Function* / drug effects
  • Recovery of Function* / physiology
  • Stroke* / metabolism
  • Stroke* / therapy

Substances

  • Neural Cell Adhesion Molecules
  • Peptides
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt