Tier 3 — preclinical

Flavonoid fisetin promotes ERK-dependent long-term potentiation and enhances memory

Maher P, Akaishi T, Abe K
Proceedings of the National Academy of Sciences of the United States of America 2006 Volume 103, issue 44, pages 16568-16573

Bibliography

PubMed
PMID 17050681
PubMed Central
PMC1637622
DOI
10.1073/pnas.0607822103
Funding
U.S. Public Health Service Grants NS28121 and AG025337 (to P.M.) and by MEXT.HAITEKU (2004-2008) (to K.A.).
Competing interests
The authors declare no conflict of interest.

Study snapshot

DesignEx vivo rat hippocampal slice immunoblotting and electrophysiology (long-term potentiation recordings), plus an in vivo object-recognition memory task in mice with oral fisetin dosing.
ModelHippocampal slices from male Wistar rats (5-7 weeks old); male C57BL/6J mice for object-recognition behavioural testing.
SampleElectrophysiology experiments with 5-14 slices per condition; behavioural study with 10 mice per treatment group.
InterventionHippocampal slices treated with 0.1-10 micromolar fisetin; mice dosed orally with fisetin 5, 10 or 25 mg/kg 60 minutes before training, with rolipram 0.1 mg/kg i.p. as positive control.
DurationSlice experiments over 5-60 minutes; object-recognition task run over a 3-day protocol (habituation, training, testing) with a 10-minute test period.
EndpointsERK1/ERK2 and CREB phosphorylation in hippocampal slices; Field excitatory postsynaptic potential (fEPSP) slope / long-term potentiation magnitude; NMDA receptor-mediated synaptic responses; Hippocampal slice cAMP levels; Object-recognition index in mice

What the study showed, in plain terms

This Salk Institute study asked whether fisetin, already known to help nerve cells survive and differentiate, can also strengthen the biological process that underlies memory formation: long-term potentiation, or LTP, in the hippocampus.

In isolated rat brain slices, fisetin rapidly switched on a signalling cascade (ERK, then the memory-linked transcription factor CREB) and helped weak electrical stimulation successfully trigger LTP, an effect blocked by drugs that inhibit ERK activation.

When given by mouth to mice before a training session, fisetin at 10 and 25 mg/kg improved how well the mice remembered a familiar object the next day, similar in direction to the reference memory-enhancing drug rolipram, but through a different mechanism - fisetin did not raise cAMP levels the way rolipram does.

This is one of the foundational papers behind fisetin's reputation as a nerve-protective, memory-supporting flavonoid, but the memory-enhancement doses here were researcher-formulated oral gavage doses in healthy young mice, not typical human supplement doses, and no human cognitive data exist for fisetin from this study.

Key findings

  • Fisetin rapidly activated ERK1/ERK2 and CREB phosphorylation in rat hippocampal slices
  • Fisetin facilitated induction of long-term potentiation (LTP) after otherwise sub-threshold stimulation
  • MEK inhibitors (PD98059, U0126) blocked fisetin's ERK/CREB activation and LTP facilitation
  • Fisetin had no effect on basal synaptic transmission or NMDA receptor-mediated responses
  • Oral fisetin (10 and 25 mg/kg) significantly improved object-recognition memory in mice
  • Unlike the PDE4 inhibitor rolipram, fisetin did not increase hippocampal cAMP levels

What this study can and cannot tell us

Memory enhancement was tested only in young, healthy mice using a single behavioural paradigm (object recognition), not in aged animals or disease models.

Fisetin was dissolved in an ethanol/Solutol/PBS vehicle and dosed by oral gavage at researcher-selected doses; no pharmacokinetic or dose-translation data to typical human oral fisetin supplement intakes are provided.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology