Sleep and Neurochemical Modulation by DZNep and GSK-J1: Potential Link With Histone Methylation Status

Abstract

Histone methylation/demethylation plays an important modulatory role in chromatin restructuring, RNA transcription and is essential for controlling a plethora of biological processes. Due to many human diseases have been related to histone methylation/demethylation, several compounds such as 3-deazaneplanocin A (DZNep) or 3-((6-(4,5-Dihydro-1H-benzo[d]azepin-3(2H)-yl)-2-(pyridin-2-yl)pyrimidin-4-yl)amino)propanoic acid; N-[2-(2-pyridinyl)-6-(1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)-4-pyrimidinyl]-β-Alanine (GSK-J1), have been designed to inhibit histone methylase or suppress histone demethylase, respectively. In the present study, we investigated the effects on the sleep-wake cycle and sleep-related neurochemical levels after systemic injections of DZNep or GSK-J1 given during the light or dark phase in rats. DZNep dose-dependently (0.1, 1.0, or 10 mg/kg, i.p.) prolonged wakefulness (W) duration while decreased slow wave sleep (SWS) and rapid eye movement sleep (REMS) time spent during the lights-on period with no changes observed in dark phase. In opposite direction, GSK-J1 (0.1, 1.0, or 10 mg/kg, i.p.) injected at the beginning of the lights-on period induced no statistical changes in W, SWS, or REMS whereas if administered at darkness, we found a diminution in W and an enhancement in SWS and REMS. Finally, brain microdialysis experiments in freely moving animals were used to evaluate the effects of DZNep or GSK-J1 treatments on contents of sleep-related neurochemicals. The results showed that DZNep boosted extracellular levels of dopamine, norepinephrine, epinephrine, serotonin, adenosine, and acetylcholine if injected at the beginning of the lights-on period whereas GSK-J1 exerted similar outcomes but when administered at darkness. In summary, DZNep and GSK-J1 may control the sleep-wake cycle and sleep-related neurochemicals through histone methylation/demethylation activity.

In vivo brain levels of acetylcholine and 5‐hydroxytryptamine after oleoylethanolamide or palmitoylethanolamide administrations are mediated by PPARα engagement

“…In this regard, several reports have suggested an equilibration period of the microdialysis probes of >10 h before beginning the sample collection for obtaining reliable measurements (Hammarlund‐Udenaes, 2017; Leenaars et al, 2018; Murillo‐Rodriguez et al, 2004). In the current report, the microdialysis probes were stabilized for 24 h, and samples were collected as previously reported (Hambrecht‐Wiedbusch et al, 2014; Murillo‐Rodríguez et al, 2018, 2019, 2020; Schäble et al, 2011). During the whole microdialysis experiments, water and standard chow pellets (Purina, México) were available ad libitum for all rats.…”

“…The total estimation of ACh contents was determined by adding the concentration values from all collected samples taken during four continuous hours. The HPLC procedure for separation, detection and measurement of ACh was achieved as previously reported (Murillo‐Rodríguez et al, 2018, 2019, 2020). To avoid experimental bias, a laboratory member that analysed the samples was not aware of the identity of the individual dialysates.…”

“…The separation of 5‐HT was achieved by using a microbore column (octadecyl silica [3 μm, 100 × 1 mm]; BAS, West Lafayette, IN, USA) with temperature controlled (22°C) using an oven (CTO‐20A, Shimadzu, Kyoto, Japan). The detection of 5‐HT was achieved by using an electrochemical detector (LC‐4C, BAS, West Lafayette, IN, USA) as previously reported (Murillo‐Rodríguez et al, 2019). To determine the concentrations of 5‐HT, a series of external standards were prepared and injected into HPLC following previous procedures (Murillo‐Rodriguez, 2017).…”

“…For the analysis of ACh contents, the dialysates from all experiments were filtered (Millipore 0.22 mm; Merck Millipore, Darmstadt, Germany) and automatically injected into the stainless seal automatic sample injector loop (10 μl; SIL-20A HT Prominence HPLC, Shimadzu, Kyoto, Japan) into the high-performance liquid chromatography (HPLC; Modular Prominence, Shimadzu, Kyoto, Japan). The separation was achieved through the HPLC with controlled temperature of oven (28 C; CTO-20A, Shimadzu, Kyoto, Japan), and mobile -Rodríguez et al, 2018-Rodríguez et al, , 2019-Rodríguez et al, , 2020. To avoid experimental bias, a laboratory member that analysed the samples was not aware of the identity of the individual dialysates.…”

Epigenetics of Sleep Disruption

“…For example, studies have suggested that compounds such as 3deazaneplanocin A (DZNep) inhibit histone trimethylation of lysine 27 on histone H3 and lysine 20 on histone H4. DZNep is shown to control the sleep-wake cycle and release sleep-related neurochemicals via the histone methylation process [93].…”