Piperlongumine decreases cognitive impairment and improves hippocampal function in aged mice

Int J Mol Med. 2018 Oct;42(4):1875-1884. doi: 10.3892/ijmm.2018.3782. Epub 2018 Jul 18.


Piperlongumine (PL), a biologically active compound from the Piper species, has been shown to exert various pharmacological effects in a number of conditions, including tumours, diabetes, pain, psychiatric disorders and neurodegenerative disease. In this study, we evaluated the therapeutic effects of PL on hippocampal function and cognition decline in aged mice. PL (50 mg/kg/day) was intragastrically administrated to 23‑month‑old female C57BL/6J mice for 8 weeks. Novel object recognition and nest building behaviour tests were used to assess cognitive and social functions. Additionally, immunohistochemistry and western blot analysis were performed to examine the effects of PL on the hippocampus. We found that the oral administration of PL significantly improved novel object recognition and nest building behaviour in aged mice. Although neither the percentage area occupied by astrocytes and microglia nor the level of 4‑hydroxynonenal protein, a specific marker of lipid peroxidation, were altered by PL treatment, the phosphorylation levels of N‑methyl‑D‑aspartate receptor subtype 2B (NR2B), calmodulin‑dependent protein kinase II alpha (CaMKIIα) and extracellular signal‑regulated kinase 1/2 (ERK1/2) were markedly increased in the hippocampus of aged mice following the administration of PL. We also found that PL treatment resulted in a CA3‑specific increase in the phosphorylation level of cyclic AMP response element binding protein, which is recognized as a potent marker of neuronal plasticity, learning and memory. Moreover, the number of doublecortin‑positive cells, a specific marker of neurogenesis, was significantly increased following PL treatment in the dentate gyrus of the hippocampus. On the whole, these data demonstrate that PL treatment may be a potential novel approach in the treatment of age‑related cognitive impairment and hippocampal changes.

MeSH terms

  • Aging / metabolism*
  • Aging / pathology
  • Animals
  • Astrocytes / metabolism*
  • Astrocytes / pathology
  • CA3 Region, Hippocampal / metabolism*
  • CA3 Region, Hippocampal / pathology
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Cognitive Dysfunction / drug therapy*
  • Cognitive Dysfunction / metabolism
  • Cognitive Dysfunction / pathology
  • Dioxolanes / pharmacology*
  • Female
  • MAP Kinase Signaling System / drug effects*
  • Mice
  • Mitogen-Activated Protein Kinase 3 / metabolism


  • Dioxolanes
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Mitogen-Activated Protein Kinase 3
  • piperlonguminine