L-theanine protects the APP (Swedish mutation) transgenic SH-SY5Y cell against glutamate-induced excitotoxicity via inhibition of the NMDA receptor pathway

Neuroscience. 2010 Jul 14;168(3):778-86. doi: 10.1016/j.neuroscience.2010.04.019. Epub 2010 Apr 21.


As a natural analogue of glutamate, l-theanine is the unique amino acid derivative in green tea. Although its underlining mechanisms are not yet clear, it has been suggested that l-theanine treatment may prove beneficial to patients with neurodegenerative diseases. In this study, we investigated the neuroprotective effect and its mechanism of l-theanine in an in vitro model of Alzheimer's disease by using the human APP (Swedish mutation) transgenic SH-SY5Y cell. Amyloid beta (Abeta) neurotoxicity was triggered by l-glutamate in this cell line. Additionally, l-theanine significantly attenuated l-glutamate-induced apoptosis at similar levels to those seen with the NMDA receptor inhibitor MK-801 in the stably expressing APP Swedish mutation SH-SY5Y cells which over-generated Abeta. Meanwhile, the activation of c-Jun N-terminal kinase and caspase-3 induced by l-glutamate was suppressed by l-theanine. We also found that cells treated with l-theanine showed decreased production of nitric oxide resulting from the down-regulated protein levels of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS). These results indicate that the inhibition of the NMDA subtype of glutamate receptors and its related pathways is the crucial point of the neuroprotective effect of l-theanine in the cell model. Thus, our present study supports the notion that l-theanine may provide effective prophylaxis and treatment for Alzheimer's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics*
  • Apoptosis / drug effects
  • Calcium / metabolism
  • Caspase 3 / biosynthesis
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dizocilpine Maleate / pharmacology
  • Glutamates / pharmacology*
  • Glutamic Acid / physiology*
  • Glutamic Acid / toxicity
  • Humans
  • JNK Mitogen-Activated Protein Kinases / biosynthesis
  • Mutation
  • Neurons / cytology
  • Neurons / drug effects
  • Neuroprotective Agents / pharmacology*
  • Nitric Oxide / physiology
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitric Oxide Synthase / biosynthesis
  • Peptide Fragments / metabolism
  • Phosphorylation
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Signal Transduction / drug effects
  • Transgenes
  • omega-N-Methylarginine / pharmacology


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Glutamates
  • Neuroprotective Agents
  • Peptide Fragments
  • Receptors, N-Methyl-D-Aspartate
  • amyloid beta-protein (1-40)
  • omega-N-Methylarginine
  • Nitric Oxide
  • Glutamic Acid
  • Dizocilpine Maleate
  • theanine
  • Nitric Oxide Synthase
  • JNK Mitogen-Activated Protein Kinases
  • Caspase 3
  • Calcium