Methylone regulates fear memory and amygdala activity: A potential treatment for posttraumatic stress disorder?

Methylone (3,4-methylenedioxy-N-methylcathinone) is a rapid-acting entactogen that has demonstrated significant benefits for patients with post-traumatic stress disorder (PTSD) and exhibits good tolerability in phase 1 clinical trials. Despite these promising results, its preclinical effects on fear memory regulation and the underlying mechanisms remain largely unexplored. This study aims to investigate the impact of methylone on auditory fear extinction and its influence on neuronal and synaptic activity in the basolateral amygdala (BLA).

CtBP1 is essential for epigenetic silencing of μ-opioid receptor genes in the dorsal root ganglion in spinal nerve ligation-induced neuropathic pain.

Neuropathic pain poses a significant public health challenge, greatly impacting patients' quality of life. Emerging evidence underscores the involvement of epigenetics in dorsal root ganglion (DRG) neurons relevant to pain modulation. C-terminal binding protein 1 (CtBP1) has emerged as a crucial epigenetic transcriptional coregulator.

Thermodynamic Work of High-Grade Uterine Prolapse Patients Undergoing Transvaginal Mesh Repair with Total Hysterectomy.

The objective benefit of transvaginal mesh with concomitant total hysterectomy (TVM-HTX) repair to high-grade uterine prolapse (UP) patients has not been fully established. This study aimed to clarify the impact of TVM-HTX on the voiding function of high-grade UP patients by comparing pre- and post-operatively measured pressure-flow and pressure-volume investigations. Urodynamic and thermodynamic studies were conducted on 15 high-grade UP patients (stage III/IV, POP-Q system) who underwent TVM-HTX (January 2019-December 2022) in a tertiary-care university hospital.

Bladder Compliance Dynamics of Pelvic Organ Prolapse in Women Undergoing Robotic-Assisted Sacrocolpopexy.

Study Objective: Although mean/static compliance of bladder filling can be readily assayed via cystometry, a protocol measuring compliance dynamics at a specific stage of bladder filling has not been established in human patients. For patients with pelvic organ prolapse (POP), the objective benefits of robotic-assisted sacrocolpopexy (RSCP) surgical intervention for restoring bladder functions, primarily urine storage, have yet to be established. Also, bladder compliance is a viscoelastic parameter that crucially defines the storage function.

The Transcription Factor Tbx5-Dependent Epigenetic Modification Contributes to Neuropathic Allodynia by Activating TRPV1 Expression in the Dorsal Horn.

Nerve injury can induce aberrant changes in the spine; these changes are due to, or at least partly governed by, transcription factors that contribute to the genesis of neuropathic allodynia. Here, we showed that spinal nerve ligation (SNL, a clinical neuropathic allodynia model) increased the expression of the transcription factor Tbx5 in the injured dorsal horn in male Sprague Dawley rats. In contrast, blocking this upregulation alleviated SNL-induced mechanical allodynia, and there was no apparent effect on locomotor function.

Effect of intra-vaginal electric stimulation on bladder compliance in stress urinary incontinence patients: the involvement of autonomic tone.

Objective: In addition to the well-established advantage that strengthened pelvic musculature increases urethral resistance in stress urinary incontinence (SUI) patients, intra-vaginal electrical stimulation (iVES) has been shown in preclinical studies to improve bladder capacity via the pudendal-hypogastric mechanism. This study investigated whether iVES also benefits bladder storage in SUI patients by focusing on compliance, a viscoelastic parameter critically defining the bladder's storage function, in a clinical study. Moreover, the potential involvement of stimulation-induced neuromodulation in iVES-modified compliance was investigated by comparing the therapeutic outcomes of SUI patients treated with iVES to those who underwent a trans-obturator tape (TOT) implantation surgery, where a mid-urethral sling was implanted without electric stimulation.

Lights at night mediate depression-like behavioral and molecular phenotypes in a glucocorticoid-dependent manner in male rats.

Nocturnal light pollution, an underappreciated mood manipulator, disturbs the circadian rhythms of individuals in modern society. Preclinical and clinical studies have suggested that exposure to lights at night (LANs) results in depression-like phenotypes. However, the mechanism underlying the action of LANs remains unclear.

Blue light at night produces stress-evoked heightened aggression by enhancing brain-derived neurotrophic factor in the basolateral amygdala.

Light is an underappreciated mood manipulator. People are often exposed to electronic equipment, which results in nocturnal blue light exposure in modern society. Light pollution drastically shortens the night phase of the circadian rhythm.

Melatonin Relieves Paclitaxel-Induced Neuropathic Pain by Regulating pNEK2-Dependent Epigenetic Pathways in DRG Neurons.

The neurohormone melatonin (MLT) demonstrates promising potential in ameliorating neuropathic pain induced by paclitaxel (PTX) chemotherapy. However, little is known about its protective effect on dorsal root ganglion (DRG) neurons in neuropathic pain resulting from the chemotherapeutic drug PTX. Here, PTX-treated rats revealed that intrathecal administration of MLT dose-dependently elevated hind paw withdrawal thresholds and latency, indicating that MLT significantly reversed PTX-induced neuropathic pain.

Methylone produces antidepressant-relevant actions and prosocial effects.

Methylone (3,4-methylenedioxy-N-methylcathinone) is a rapid-acting entactogen that has been shown to have significant benefits in patients with post-traumatic stress disorder and major depressive disorder and is well tolerated in phase 1 clinical trials. A recent preclinical study reported that methylone produced robust antidepressant-like actions in naïve rats. However, its antidepressant effects on various stress-related psychopathologies and other neuropsychological actions remain unclear.

Pressure-Volume Loop Analysis of Voiding Workload: An Application in Trans-Vaginal Mesh-Repaired Pelvic Organ Prolapse Patients.

Although trans-vaginal mesh (TVM) offers a successful anatomical reconstruction and can subjectively relieve symptoms/signs in pelvic organ prolapse (POP) patients, its objective benefits to the voiding function of the bladder have not been well established. In this study, we investigated the therapeutic advantage of TVM on bladder function by focusing on the thermodynamic workload of voiding. The histories of 31 POP patients who underwent TVM repair were retrospectively reviewed.

Protein Arginine Methyltransferase 5 Contributes to Paclitaxel-Induced Neuropathic Pain by Activating Transient Receptor Potential Vanilloid 1 Epigenetic Modification in Dorsal Root Ganglion.

Background: Paclitaxel (PTX), which is a first-line chemotherapy drug used to treat various types of cancers, exhibits peripheral neuropathy as a common side effect that is difficult to treat. Protein arginine methyltransferase 5 (PRMT 5) is a key regulator of the chemotherapy response, as chemotherapy drugs induce PRMT5 expression. However, little is known about the PRMT5-mediated epigenetic mechanisms involved in PTX-induced neuropathic allodynia.

BTRX-246040 Acts Through the Ventrolateral Periaqueductal Gray to Exert Antidepressant-Relevant Actions in Mice.

Background: BTRX-246040, a nociceptin/orphanin FQ peptide receptor antagonist, is being developed for the treatment of depressive patients. However, the underlying mechanism of this potential antidepressant is still largely unclear. Here, we studied the antidepressant-related actions of BTRX-246040 in the ventrolateral periaqueductal gray (vlPAG).

Phosphorylated Upstream Frameshift 1-dependent Nonsense-mediated μ-Opioid Receptor mRNA Decay in the Spinal Cord Contributes to the Development of Neuropathic Allodynia-like Behavior in Rats.

Background: Nonsense-mediated messenger RNA (mRNA) decay increases targeted mRNA degradation and has been implicated in the regulation of gene expression in neurons. The authors hypothesized that nonsense-mediated μ-opioid receptor mRNA decay in the spinal cord is involved in the development of neuropathic allodynia-like behavior in rats.

Methods: Adult Sprague-Dawley rats of both sexes received spinal nerve ligation to induce neuropathic allodynia-like behavior.

Phosphate NIMA-Related Kinase 2-Dependent Epigenetic Pathways in Dorsal Root Ganglion Neurons Mediates Paclitaxel-Induced Neuropathic Pain.

Background: The microtubule-stabilizing drug paclitaxel (PTX) is an important chemotherapeutic agent for cancer treatment and causes peripheral neuropathy as a common side effect that substantially impacts the functional status and quality of life of patients. The mechanistic role for NIMA-related kinase 2 (NEK2) in the progression of PTX-induced neuropathic pain has not been established.

Methods: Adult male Sprague-Dawley rats intraperitoneally received PTX to induce neuropathic pain.

(2R,6R)-hydroxynorketamine targeting the basolateral amygdala regulates fear memory.

(2R,6R)-Hydroxynorketamine (HNK), a ketamine metabolite, has been proposed as an ideal next-generation antidepressant due to its rapid-acting and long-lasting antidepression-relevant actions. Interestingly, recent studies have shown that (2R,6R)-HNK may have diverse impacts on memory formation. However, its effect on fear memory extinction is still unknown.

Modification of bladder thermodynamics in stress urinary incontinence patients submitted to trans-obturator tape: A retrospective study based on urodynamic assessment.

It needs to be clarified whether trans-obturator tape (TOT)-enhanced urethral resistance could impact the voiding function. Although TOT has been well-recognized for enhancing urethral resistance to restore continence in stress urinary incontinence (SUI) patients, whether the bladder's voiding functions adapt to the TOT-enhanced resistance has not been adequately investigated. This study thereby aimed to investigate whether TOT impacts the bladder's thermodynamic efficacy during the voiding phase.

MicroRNA-489-3p attenuates neuropathic allodynia by regulating oncoprotein DEK/TET1-dependent epigenetic modification in the dorsal horn.

Originally characterized as an oncoprotein overexpressed in many forms of cancer that participates in numerous cellular pathways, DEK has since been well described regarding the regulation of epigenetic markers and transcription factors in neurons. However, its role in neuropathic allodynia processes remain elusive and intriguingly complex. Here, we show that DEK, which is induced in spinal dorsal horn neurons after spinal nerve ligation (SNL), is regulated by miR-489-3p.

Shoulder transcutaneous electric nerve stimulation decreases heart rate via potentiating vagal tone.

By enhancing vagal activity, auricle transcutaneous electric nerve stimulation (TENS) is developed as a non-invasive therapy for heart failure. Nevertheless, though shoulder TENS used for treating adhesive capsulitis could affect vagal tone, its potential impact on heart functions remains unclear. In this study, electrocardiogram (ECG) and heart rate (HR) of subjects in response to sham, right-sided, or left-sided shoulder TENS (TENS-S, TENS-R, and TENS-L, respectively; 5 min) were recorded and analyzed.

Protective Effects of Fucoxanthin Dampen Pathogen-Associated Molecular Pattern (PAMP) Lipopolysaccharide-Induced Inflammatory Action and Elevated Intraocular Pressure by Activating Nrf2 Signaling and Generating Reactive Oxygen Species.

Inflammation and oxidative stress are closely related processes in the pathogenesis of various ocular diseases. Uveitis is a disorder of the uvea and ocular tissues that causes extreme pain, decreases visual acuity, and can eventually lead to blindness. The pharmacological functions of fucoxanthin, isolated from brown algae, induce a variety of therapeutic effects such as oxidative stress reduction and repression of inflammation reactions.

Solifenacin/Mirabegron Induces an Acute Compliance Increase in the Filling Phase of the Capacity-Reduced Urinary Bladder: A Pressure-Volume Analysis in Rats.

Pressure in the bladder, which is a high compliance organ, is only slightly elevated to a considerable filling volume during storage. Although cystometry off-line offers mean compliance, no protocol is available for real-time assays of the dynamics of bladder compliance, and the potential impact of solifenacin and mirabegron on dynamic bladder compliance has not been established. Along with constantly infused cystometry, a pressure-volume analysis (PVA) was performed by plotting intra-vesical volume against pressure in Sprague-Dawley rats.

Cytoprotective Potential of Fucoxanthin in Oxidative Stress-Induced Age-Related Macular Degeneration and Retinal Pigment Epithelial Cell Senescence In Vivo and In Vitro.

Oxidative stress is identified as a major inducer of retinal pigment epithelium (RPE) cell dysregulation and is associated with age-related macular degeneration (AMD). The protection of RPE disorders plays an essential role in the pathological progress of retinal degeneration diseases. The pharmacological functions of fucoxanthin, a characteristic carotenoid, including anti-inflammatory and antioxidant properties, may ameliorate an outstanding bioactivity against premature senescence and cellular dysfunction.

Blocking the Spinal Fbxo3/CARM1/K Channel Epigenetic Silencing Pathway as a Strategy for Neuropathic Pain Relief.

Many epigenetic regulators are involved in pain-associated spinal plasticity. Coactivator-associated arginine methyltransferase 1 (CARM1), an epigenetic regulator of histone arginine methylation, is a highly interesting target in neuroplasticity. However, its potential contribution to spinal plasticity-associated neuropathic pain development remains poorly explored.

NMDA receptor partial agonist GLYX-13 alleviates chronic stress-induced depression-like behavior through enhancement of AMPA receptor function in the periaqueductal gray.

Depression is a common mental disorder affecting more than 300 million people worldwide and is one of the leading causes of disability among all medical illnesses. The accumulation of preclinical data has fueled the revival of interest in targeting glutamatergic neurotransmission for the treatment of major depressive disorder. GLYX-13, a glutamatergic compound that acts as an N-methyl-d-aspartate (NMDA) modulator with glycine-site partial agonist properties, produces rapid and long-lasting antidepressant effects in both animal models and patients.

Inhibiting MLL1-WDR5 interaction ameliorates neuropathic allodynia by attenuating histone H3 lysine 4 trimethylation-dependent spinal mGluR5 transcription.

Mixed lineage leukemia 1 (MLL1)-mediated histone H3 lysine 4 trimethylation (H3K4me3) of a subset of genes has been linked to the transcriptional activation critical for synaptic plasticity, but its potential contribution to neuropathic allodynia development remains poorly explored. Here, we show that MLL1, which is induced in dorsal horn neuron after spinal nerve ligation (SNL), is responsible for mechanical allodynia and increased H3K4me3 at metabotropic glutamate receptor subtype 5 (mGluR5) promoter. Moreover, SNL induced WD (Trp-Asp) repeat domain 5 subunit (WDR5) expression as well as the MLL1-WDR5 interaction accompany with H3K4me3 enrichment and transcription of mGluR5 gene in the dorsal horn in neuropathic allodynia progression.