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

Jul 6, 2017Canadian journal of physiology and pharmacology

Green tea compound may protect newborn mouse brain cells from sevoflurane damage by influencing key growth and survival pathways

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Abstract

EGCG (25, 50, or 75 mg/kg) significantly inhibited sevoflurane-induced neuroapoptosis in neonatal mice.

Sevoflurane exposure in neonatal mice led to neuroapoptosis, indicated by Fluoro-Jade B staining and TUNEL.
EGCG administration resulted in increased expression of anti-apoptotic proteins such as Bcl-2 and survivin.
Activation of the PI3K/Akt pathway was observed following EGCG treatment, with elevated levels of Akt and mTORc1.
EGCG countered the downregulation of cAMP/CREB and BDNF/TrkB signalling caused by sevoflurane.
Increased mRNA levels of BDNF and TrkB were detected after EGCG treatment.
Mice treated with EGCG showed improved performance in learning and memory tests, as measured by the Morris water maze.

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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.

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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

Abstract

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