An Exosome-Based Therapeutic Strategy Targeting Neuroinflammation in Alzheimer's Disease with Berberine and Palmatine

Drug Des Devel Ther. 2023 Aug 17:17:2401-2420. doi: 10.2147/DDDT.S417465. eCollection 2023.

Abstract

Introduction: Neuroinflammation is one of the major pathogeneses in Alzheimer's disease (AD) and mainly involves abnormal inflammatory activation of microglia by multiple pathological stimuli. The treatment of AD remains a major challenge due to the multifactorial characterization of AD and the inefficient ability of therapeutic drugs to permeate through the blood‒brain barrier (BBB). Accordingly, drug combination treatment and drug carrier delivery have become important therapeutic tools for the treatment of multifactorial diseases, especially AD.

Methods: Inflammatory cytokine levels in microglia, including NO, TNF-α, IL-1β, IL-4, and IL-10, were detected. The Morris water maze and object location task were used to investigate the learning and memory functions of APP/PS1 mice in different treatment groups. The number of neurons and plasticity of synapses were evaluated by immunofluorescence double labelling. Additionally, the ratio of β-amyloid plaques and the number of activated microglia were evaluated by immunofluorescence staining. The concentrations of β-amyloid plaques and inflammatory factors in the hippocampus were determined by ELISA. Microglia-derived exosomes (Exos) were extracted and purified by size exclusion chromatography. The distribution of exosomes and drugs was investigated in vitro and in vivo.

Results: Compared to single drug interventions, the combination of Ber and Pal (Ber/Pal) modulated microglial inflammatory cytokine levels. Ber/Pal promoted the recovery of learning and memory impairment in APP/PS1 mice. Immunofluorescence staining indicated that Ber/Pal restored neurons, inhibited Aβ plaque formation and microglial activation, and regulated the secretion of inflammatory factors. Exos promoted the accumulation of drugs in cells and tissues and improved the targeting of drugs across the BBB.

Conclusion: Ber/Pal could offer a synergistic and more comprehensive therapeutic effect in AD. Additionally, the microglia-derived Exos-Ber/Pal delivery system promoted the targeting and permeation of drugs into the brain, suggesting a creative strategy for targeting AD therapy by regulating neuroinflammation in microglial cells.

Keywords: Alzheimer’s disease; BBB permeability; drug combination; exosomes; neuroinflammation; phytoconstituents.

MeSH terms

  • Alzheimer Disease* / drug therapy
  • Amyloid beta-Peptides
  • Animals
  • Berberine* / pharmacology
  • Cytokines
  • Exosomes*
  • Mice
  • Neuroinflammatory Diseases
  • Plaque, Amyloid

Substances

  • palmatine
  • Berberine
  • Amyloid beta-Peptides
  • Cytokines

Grants and funding

This study was financially supported by the National Natural Science Foundation of China (Project Nos. 81873027 and 81573635), the Qing-Lan Project of Jiangsu Province, the Open Project Program of Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica (No. JKLPSE201820), the Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), the Project of the Innovation Research Team of Nanjing University of Chinese Medicine, and the Project Funded by the Six Talent Project in Jiangsu Province.