Prevention of streptozotocin‑induced Neuro‑2a cell death by C8‑B4 microglia transformed with repetitive low‑dose lipopolysaccharide

Mol Med Rep. 2021 Oct;24(4):687. doi: 10.3892/mmr.2021.12328. Epub 2021 Jul 30.


Diabetes‑associated neuronal dysfunction (DAND) is one of the serious complications of diabetes, but there is currently no remedy for it. Streptozotocin [2‑deoxy‑2‑(3‑methy1‑3‑nitrosoureido) D‑glucopyranose; STZ] is one of the most well‑established diabetes inducers and has been used in vivo and in vitro DAND models. The aim of the present study was to demonstrate that C8‑B4 microglia transformed by the stimulus of repetitive low‑dose lipopolysaccharide (LPSx3‑microglia) prevent STZ‑induced Neuro‑2a neuronal cell death in vitro. The ELISA results showed that neurotrophin‑4/5 (NT‑4/5) secretion was promoted in LPSx3‑microglia and the cell viability assay with trypan blue staining revealed that the culture supernatant of LPSx3‑microglia prevented STZ‑induced neuronal cell death. In addition, reverse transcription‑quantitative PCR showed that neurons treated with the culture supernatant of LPSx3‑microglia promoted the gene expression of B‑cell lymphoma‑extra large and glucose‑dependent insulinotropic polypeptide receptor. Furthermore, the inhibition of tyrosine kinase receptor B, a receptor of NT‑4/5, suppressed the neuroprotective effect of LPSx3‑microglia. Taken together, the present study demonstrated that LPSx3‑microglia prevent STZ‑induced neuronal death and that NT‑4/5 may be involved in the neuroprotective mechanism of LPSx3‑microglia.

Keywords: diabetes‑associated; immunomodulation; neuroprotection; neurotrophin‑4/5; pretreatment; tyrosine kinase receptor B.

MeSH terms

  • Animals
  • Cell Death / drug effects*
  • Cell Line
  • Cell Survival / drug effects
  • Lipopolysaccharides / pharmacology*
  • Membrane Glycoproteins / antagonists & inhibitors
  • Mice
  • Microglia / metabolism*
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neuroprotective Agents / pharmacology
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptors, Gastrointestinal Hormone / genetics
  • Streptozocin / pharmacology
  • bcl-X Protein / genetics


  • Bcl2l1 protein, mouse
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Nerve Growth Factors
  • Neuroprotective Agents
  • Receptors, Gastrointestinal Hormone
  • bcl-X Protein
  • neurotrophin 5
  • Streptozocin
  • gastric inhibitory polypeptide receptor
  • Ntrk2 protein, mouse
  • Protein-Tyrosine Kinases
  • neurotrophin 4