The Seed of Zizyphus jujuba var. spinosa Attenuates Alzheimer's Disease-Associated Hippocampal Synaptic Deficits through BDNF/TrkB Signaling

Biol Pharm Bull. 2017;40(12):2096-2104. doi: 10.1248/bpb.b17-00378.


Ziziphus jujuba is a plant, which bears fruits and seeds that are used for medicinal purposes in Traditional oriental medicine. The seed of Zizyphus jujuba var. spinosa (EZJ) has been also traditionally used for psychiatric disorders in Chinese and Korean medicines. Recent findings have indicated that EZJ improves memory impairment, a common symptom of various neurological diseases. However, the effects of EZJ on amyloid β (Aβ) toxicity, which is a main cause of Alzheimer's disease (AD), remain to be elucidated. To illuminate the potential anti-AD effect and mechanism in the mouse hippocampal tissue, we examined the effect of standardized EZJ on Aβ-induced synaptic long-term potentiation (LTP) deficit in the hippocampal tissue. EZJ blocked Aβ-induced LTP deficits in a concentration-dependent manner. Moreover, EZJ increased brain-derived neurotrophic factor (BDNF) level in naïve hippocampal slices. The finding that the blockade of BDNF receptor reduced the effect of EZJ suggests that EZJ ameliorates the Aβ-induced LTP deficit through BDNF/topomyosin receptor kinase B (TrkB) signaling. However, transcription or translation inhibitors failed to block the effect of EZJ, suggesting that BDNF synthesis is not required for the action of EZJ on LTP. Finally, we found that EZJ stimulates plasmin activity. In contrast, plasmin inhibitor blocked the effect of EZJ on the Aβ-induced LTP deficit. Our findings indicate that EZJ ameliorates Aβ-induced LTP deficits through BDNF/TrkB signaling. This phenomenon is induced by a regulatory effect of EZJ on the post-translation modification of BDNF.

Keywords: Zizyphus jujuba var. spinosa; amyloid β (Aβ); brain-derived neurotrophic factor (BDNF); long-term potentiation; plasmin.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / physiopathology
  • Aminocaproic Acid / pharmacology
  • Amyloid beta-Peptides / pharmacology
  • Animals
  • Brain-Derived Neurotrophic Factor / metabolism
  • Dose-Response Relationship, Drug
  • Fibrinolysin / antagonists & inhibitors
  • Fibrinolysin / metabolism
  • Hippocampus / drug effects*
  • Hippocampus / pathology
  • Hippocampus / physiopathology
  • Humans
  • Long-Term Potentiation / drug effects*
  • Male
  • Medicine, East Asian Traditional / methods
  • Mice
  • Plant Extracts / pharmacology*
  • Plant Extracts / therapeutic use
  • Protein Processing, Post-Translational / drug effects
  • Receptor, trkB / metabolism
  • Seeds
  • Signal Transduction / drug effects*
  • Ziziphus / chemistry*


  • Amyloid beta-Peptides
  • Brain-Derived Neurotrophic Factor
  • Plant Extracts
  • Ntrk2 protein, rat
  • Receptor, trkB
  • Fibrinolysin
  • Aminocaproic Acid