Abstract
Glutamate (Glu) and γ-aminobutyric acid (GABA) are the major excitatory and inhibitory neurotransmitters that control information flow in the brain. GABA dysfunction is a general vulnerability factor for mental illness. Cinnamaldehyde (CA) was found to have sedation in a mental illness model. However, the specific targets and molecular mechanisms related to the sedative effects of CA have not been elucidated. Metabolomics analysis and target fishing showed CA could increase the expression of GABA in vivo, and α-enolase (ENO1) was the primary target protein of CA associated with sedation. CA mainly binds with ENO1 in the cerebellar granular layer of brain, which influences the first transformations of the input signals arriving in the cerebellar cortex. The α,β-unsaturated aldehyde group of CA blocked the hydroxy group of Ser40, which induced a loss in ENO1 activation. CA also disturbed the glycolysis pathway and influenced the tricarboxylic acid cycle and oxidative phosphorylation, which activate gluconeogenesis to provide energy to the brain. This mechanism was verified in zebrafish with ENO1 or glutamic acid decarboxylase (GAD) deficiency. CA demonstrated sedation and alleviated GABA dysfunction via covalent binding ENO1, which shows the potential to improve the therapy of mental illness. This article is protected by copyright. All rights reserved.
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