Sex-Dependent Effects of Piromelatine Treatment on Sleep-Wake Cycle and Sleep Structure of Prenatally Stressed Rats

Abstract

Prenatal stress (PNS) impairs the circadian rhythm of the sleep/wake cycle. The melatonin (MT) analogue Piromelatine (Pir) was designed for the treatment of insomnia. The present study aimed to explore effects of Pir on circadian rhythmicity, motor activity, and sleep structure in male and female rats with a history of prenatal stress (PNS). In addition, we elucidated the role of MT receptors and brain-derived neurotrophic factor (BDNF) to ascertain the underlying mechanism of the drug. Pregnant rats were exposed to different stressors from day seven until birth. Piromelatine (20 mg/kg/day/14 days) was administered to young adult offspring. Home-cage locomotion, electroencephalographic (EEG) and electromyographic (EMG) recordings were conducted for 24 h. Offspring treated with vehicle showed sex-and phase-dependent disturbed circadian rhythm of motor activity and sleep/wake cycle accompanied by elevated rapid eye movement (REM) pattern and theta power and diminished non-rapid eye movement (NREM) sleep and delta power. While Pir corrected the PNS-induced impaired sleep patterns, the MT receptor antagonist luzindol suppressed its effects in male and female offspring. In addition, Pir increased the BDNF expression in the hippocampus in male and female offspring with PNS. Our findings suggest that the beneficial effect of Pir on PNS-induced impairment of sleep/wake cycle circadian rhythm and sleep structure is exerted via activation of MT receptors and enhanced BDNF expression in the hippocampus in male and female offspring.

Sex-Dependent Effect of Chronic Piromelatine Treatment on Prenatal Stress-Induced Memory Deficits in Rats

“…The drug was chronically injected intraperitoneally at a dose of 20 mg/kg (i.p.) that did not affect locomotor activity [ 15 ], thereby eliminating possible false positive responses. Our results agreed with the report of He et al (2013) [ 31 ], who demonstrated that a single administration of Piromelatine at a dose of 50 mg/kg either in the morning or in the afternoon did not change both the short- and long-term memory in an ORT test of male Sprague–Dawley rats.…”

“…Brain-derived neurotrophic factor (BDNF) is involved in neuronal plasticity, hippocampal synaptogenesis and spatial memory formation [ 12 , 13 , 14 ]. Deterioration of BDNF is associated with depression, disturbed circadian rhythms and cognitive deficits [ 1 , 13 , 15 ]. This essential for brain plasticity molecules, via binding to the receptor tyrosine kinase B (TrkB), activate several signaling pathways such as the Ras-mitogen-activated protein kinase (MAPK), the phosphatidylinositol-3-kinase (PI3K) and the phospholipase Cγ (PLC-γ) pathway [ 16 ].…”

“…While as a transcription factor CREB controls BDNF expression, neurotrophine triggers CREB phosphorylation [ 20 , 21 ]. Moreover, the literature data suggest a sexually dichotomous influence of prenatal stress on CREB and BDNF expression [ 11 , 15 , 22 ]. In addition, CREB activation could be elevated through serotonin (5-HT) activation of the second-messenger cAMP-PKA [ 21 ].…”

“…A phase-II clinical study has indicated a good capacity of the drug for insomnia treatment [ 28 ]. Studies, including our recent ones, demonstrate that Pir improves the negative changes induced by prenatal stress on emotional behavior, disturbed circadian locomotion and sleep/wake cycle rhythm and neuro- and the biochemical profile of offspring with a history of prenatal stress (PNS) in a sex-dependent manner [ 6 , 7 , 15 , 29 , 30 ]. Additionally, preclinical reports suggest that this drug prevents cell loss and exerts a beneficial action on Aβ42-induced cognitive impairment in a rat model of Alzheimer’s disease (AD) [ 31 ].…”

“…Additionally, preclinical reports suggest that this drug prevents cell loss and exerts a beneficial action on Aβ42-induced cognitive impairment in a rat model of Alzheimer’s disease (AD) [ 31 ]. Recently, we reported that Piromelatine augmented BDNF expression in the hippocampus of male and female offspring with a history of prenatal stress [ 15 ]. This novel compound also targets the 5-HT type 1A receptors, which are widely expressed in the brain sections involved in the learning and memory processes [ 32 , 33 ].…”