Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 638, Issue -, Pages 176-183Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2022.11.062
Keywords
Bromovalerylurea; Hypnotic; sedative; Electroencephalography; Gamma-aminobutyric acid; Slice electrophysiology; Miniature inhibitory postsynaptic current
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Bromovalerylurea (BU) is an acyl urea derivative originally developed as a hypnotic/sedative. Recent research has shown that BU improves sepsis, Parkinson's disease, and traumatic brain injury in Wistar rat models through anti-inflammatory actions on microglia and macrophages. However, the hypnotic mechanism and characteristics of BU are poorly understood due to its long history of development.
Bromovalerylurea (BU), an acyl urea derivative, was originally developed as a hypnotic/sedative. We recently reported that BU at a dose of 50 mg/kg ameliorates sepsis, Parkinson's disease, and traumatic brain injury in Wistar rat models through its anti-inflammatory actions on microglia and macrophages. However, since BU was developed more than 100 years ago, its hypnotic mechanism and characteristics are poorly understood. Herein, we conducted an electroencephalogram (EEG) study and found that BU, when administered at a dose of more than 125 mg/kg but not at a dose of 50 mg/kg in Wistar rats, significantly increased non-rapid eye movement (NREM) sleep duration and dose-dependently decreased rapid eye movement (REM) sleep duration. This characteristic of sleep induced by BU is similar to the effect of compounds such as barbiturate, benzodiazepine, and z-drugs, all of which require g-aminobutyric acid A receptors (GABAAR) for hypnotic/sedative activity. To investigate whether BU could potentiate GABAAergic neurotransmission, we conducted a whole-cell patch-clamp recording from py-ramidal neurons in rat cortical slices to detect spontaneous GABAAR-mediated inhibitory postsynaptic currents (IPSCs). We found that BU dose-dependently prolonged IPSCs. Importantly, the prolonged IPSCs were not attenuated by flumazenil, a benzodiazepine receptor antagonist, suggesting that modulation of IPSCs by BU is mediated by different mechanisms from that of benzodiazepine. Taken together, these data elucidate the basic characteristics of the hypnotic effects of BU and suggest that the enhancement of GABAAR-mediated Cl- flux may be a possible mechanism that contributes to its hypnotic/sedative activity.(c) 2022 Elsevier Inc. All rights reserved.
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