Promotion of sleep by cinnamic acid in parachlorophenylalanine-induced insomnia in rats.

Purpose: This study aimed to examine the efficacy and underlying mechanisms of action of cinnamic acid (CA) in the treatment of insomnia.

Methods: An insomnia model was established using parachlorophenylalanine (PCPA) in rats. Pathological changes in the rat hippocampal CA3 region were assessed using hematoxylin and eosin staining. Sleep duration and sleep-wake states were assessed using a pentobarbital-induced sleep test and electroencephalogram analysis. Neurotransmitters, including 5-hydroxytryptophan (5-HTP), 5-hydroxy tryptamine (5-HT), γ-aminobutyric acid (GABA), and glutamic acid (Glu), were detected via enzyme-linked immunosorbent assay. Changes in glutamic acid decarboxylase (GAD)67, GABAR γ2, GABAR β2, and GABAR α proteins were assessed using western blotting. Bulk RNA sequencing (RNA-seq) analysis and molecular docking were used to explore the mechanism of action of CA in insomnia treatment.

Results: In the rat model with PCPA-induced insomnia, CA treatment increased body weight and food intake, reduced water intake, and alleviated damage to the hippocampal CA3 region. CA treatment also reduced sleep latency and wake time and enhanced sleep duration, rapid eye movement sleep, and non-rapid eye movement sleep. In the hypothalamus, CA treatment increased 5-HTP, 5-HT, GABA, GAD67, GABAAR γ2, GABAAR β2, and GABAAR α1 levels, but reduced Glu levels. Using the data from bulk RNA-seq, GSEA analysis indicated neurotrophin signaling pathway was activated by CA treatment. CA could bind with LHPP and reduced its protein expression.

Conclusion: CA treatment prolonged sleep duration and improved sleep quality in a rat model of insomnia, mediated by LHPP inhibition.