ZiBuPiYin recipe protects db/db mice from diabetes-associated cognitive decline through improving multiple pathological changes

PLoS One. 2014 Mar 10;9(3):e91680. doi: 10.1371/journal.pone.0091680. eCollection 2014.


Multiple organ systems, including the brain, which undergoes changes that may increase the risk of cognitive decline, are adversely affected by diabetes mellitus (DM). Here, we demonstrate that type 2 diabetes mellitus (T2DM) db/db mice exhibited hippocampus-dependent memory impairment, which might associate with a reduction in dendritic spine density in the pyramidal neurons of brain, Aβ1-42 deposition in the prefrontal cortex (PFC) and hippocampus, and a decreased expression of neurostructural proteins including microtubule-associated protein (MAP2), a marker of dendrites, and postsynaptic density 95 (PSD95), a marker of excitatory synapses. To investigate the effects of the ZiBuPiYin recipe (ZBPYR), a traditional Chinese medicine recipe, on diabetes-related cognitive decline (DACD), db/db mice received daily administration of ZBPYR over an experimental period of 6 weeks. We then confirmed that ZBPYR rescued learning and memory performance impairments, reversed dendritic spine loss, reduced Aβ1-42 deposition and restored the expression levels of MAP2 and PSD95. The present study also revealed that ZBPYR strengthened brain leptin and insulin signaling and inhibited GSK3β overactivity, which may be the potential mechanism or underlying targets of ZBPYR. These findings conclude that ZBPYR prevents DACD, most likely by improving dendritic spine density and attenuating brain leptin and insulin signaling pathway injury. Our findings provide further evidence for the effects of ZBPYR on DACD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / metabolism
  • Animals
  • Brain / drug effects
  • Brain / pathology
  • Cognition Disorders / drug therapy*
  • Cognition Disorders / etiology
  • Cognition Disorders / pathology*
  • Cognition Disorders / prevention & control
  • Cytoskeletal Proteins / metabolism
  • Dendritic Spines / drug effects
  • Dendritic Spines / metabolism
  • Diabetes Mellitus, Experimental / complications*
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / pathology
  • Disks Large Homolog 4 Protein
  • Drugs, Chinese Herbal / therapeutic use*
  • Glucose / metabolism
  • Glycogen Synthase Kinase 3 / metabolism
  • Guanylate Kinases / metabolism
  • Homeostasis / drug effects
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use
  • Insulin / metabolism
  • Leptin / metabolism
  • Male
  • Maze Learning / drug effects
  • Membrane Proteins / metabolism
  • Mice, Inbred C57BL
  • Microtubule-Associated Proteins / metabolism
  • Peptide Fragments / metabolism
  • Signal Transduction / drug effects
  • Spatial Memory / drug effects


  • Amyloid beta-Peptides
  • Cytoskeletal Proteins
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Drugs, Chinese Herbal
  • Hypoglycemic Agents
  • Insulin
  • Leptin
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Mtap2 protein, mouse
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • zibu piyin
  • Glycogen Synthase Kinase 3
  • Guanylate Kinases
  • Glucose

Grants and funding

This work was financially supported by The Key Project of National Natural Science Foundation, China (No. 81230084), The Specialized Research Fund for the Doctoral Program of Higher Education, China (No. 20112105110006) and The Program for Professor of Special Appointment in Liaoning Province. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.