Protective effects of a green tea polyphenol, epigallocatechin-3-gallate, against sevoflurane-induced neuronal apoptosis involve regulation of CREB/BDNF/TrkB and PI3K/Akt/mTOR signalling pathways in neonatal mice

Can J Physiol Pharmacol. 2017 Dec;95(12):1396-1405. doi: 10.1139/cjpp-2016-0333. Epub 2017 Jul 5.

Abstract

Epigallocatechin-3-gallate (EGCG), a polyphenol in green tea, is an effective antioxidant and possesses neuroprotective effects. Brain-derived neurotrophic factor (BDNF) and cyclic AMP response element-binding protein (CREB) are crucial for neurogenesis and synaptic plasticity. In this study, we aimed to assess the protective effects of EGCG against sevoflurane-induced neurotoxicity in neonatal mice. Distinct groups of C57BL/6 mice were given EGCG (25, 50, or 75 mg/kg body weight) from postnatal day 3 (P3) to P21 and were subjected to sevoflurane (3%; 6 h) exposure on P7. EGCG significantly inhibited sevoflurane-induced neuroapoptosis as determined by Fluoro-Jade B staining and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL). Increased levels of cleaved caspase-3, downregulated Bad and Bax, and significantly enhanced Bcl-2, Bcl-xL, xIAP, c-IAP-1, and survivin expression were observed. EGCG induced activation of the PI3K/Akt pathway as evidenced by increased Akt, phospho-Akt, GSK-3β, phospho-GSK-3β, and mTORc1 levels. Sevoflurane-mediated downregulation of cAMP/CREB and BDNF/TrkB signalling was inhibited by EGCG. Reverse transcription PCR analysis revealed enhanced BDNF and TrkB mRNA levels upon EGCG administration. Improved performance of mice in Morris water maze tests suggested enhanced learning and memory. The study indicates that EGCG was able to effectively inhibit sevoflurane-induced neurodegeneration and improve learning and memory retention of mice via activation of CREB/BDNF/TrkB-PI3K/Akt signalling.

Keywords: brain-derived neurotrophic factor; cAMP response element-binding protein; epigallocatechin-3-gallate; facteur neurotrophique dérivé du cerveau; neurodegeneration; neurodégénérescence; phosphatidylinositol 3-kinase signalling; protéine de liaison d’éléments-AMPc répondante; sevoflurane; voie de signalisation de la phosphatidylinositol 3-kinase; épigallocatéchine-3-gallate.

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis / drug effects
  • Brain-Derived Neurotrophic Factor / metabolism
  • Caspase 3 / genetics
  • Catechin / analogs & derivatives*
  • Catechin / pharmacology
  • Cell Survival / drug effects
  • Cyclic AMP / metabolism
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cytoprotection / drug effects
  • Gene Expression Regulation, Enzymologic / drug effects
  • Memory / drug effects
  • Methyl Ethers / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Neurons / cytology*
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Polyphenols / pharmacology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, trkB / metabolism
  • Sevoflurane
  • Signal Transduction / drug effects*
  • Spatial Behavior / drug effects
  • TOR Serine-Threonine Kinases / metabolism
  • Tea / chemistry*

Substances

  • Brain-Derived Neurotrophic Factor
  • Cyclic AMP Response Element-Binding Protein
  • Methyl Ethers
  • Neuroprotective Agents
  • Polyphenols
  • Tea
  • Sevoflurane
  • Catechin
  • epigallocatechin gallate
  • Cyclic AMP
  • Phosphatidylinositol 3-Kinases
  • TOR Serine-Threonine Kinases
  • Receptor, trkB
  • Proto-Oncogene Proteins c-akt
  • Caspase 3