Activation of Neuronal Voltage-Gated Potassium Kv7/KCNQ/M-Current by a Novel Channel Opener SCR2682 for Alleviation of Chronic Pain.

Treatment of chronic pain remains an unmet medical need. The neuronal voltage-gated potassium Kv7/KCNQ/M channel has been implicated as a therapeutic target for chronic pain. However, whether pharmacological activation of the Kv7 channel can alleviate pain remains elusive. In this study, we show that selective activation of native M-currents by a novel channel opener SCR2682 reduces repetitive firings of dorsal root ganglia (DRG) sensory neurons. Intraperitoneal administration of SCR2682 relieves mechanical allodynia and thermal hyperalgesia in rat models of pain induced by complete Freund's adjuvant (CFA) or spared nerve injury (SNI) in a dose-dependent manner without affecting locomotor activity. The antinociceptive efficacy of SCR2682 can be reversed by the channel-specific blocker XE991. Furthermore, SCR2682 increases Kv7.2/KCNQ2 mRNA and protein expression in DRG neurons from rats in the SNI model of neuropathic pain. Taken together, pharmacological activation of neuronal Kv7 channels by opener SCR2682 can alleviate pain in rats, thus possessing therapeutic potential for chronic pain or hyperexcitability-related neurologic disorders. SIGNIFICANCE STATEMENT: A novel voltage-gated potassium Kv7 channel opener SCR2682 inhibits action potential firings in dorsal root ganglia sensory neurons and exhibits efficacy in antinociception, thus possessing a developmental potential for treatment of chronic pain or epilepsy.

mRNA and miRNA profiles in the nucleus accumbens are associated with psychological stress-induced susceptible and resilient mice.

BACKGROUND: Stress may be one of the main causes of fear and anxiety. Previous studies have shown that the nucleus accumbens is involved in emotional responses. However, in the nucleus accumbens, the mRNA and miRNA profiles of stress susceptibility and resilience of psychological stress still need to be studied. MATERIALS AND METHODS: In this study, by observing the conspecific being attacked, the witness group experienced psychological stress. After five days of psychological stress, the fear memory of mice was measured by social interaction test, and the degree of anxiety was measured by elevated plus maze. mRNA and miRNA profiles in the nucleus accumbens tissue of control, susceptible and resilient mice were established by high-throughput sequencing. RESULTS: In susceptible mice versus resilient mice, the Differentially expressed genes (DEGs) may be related to psychological stress-induced susceptibility. DEGs enriched in Cell adhesion molecules, Neuroactive ligand-receptor interaction, Gap junction, PI3K-Akt, VEGF, Jak-STAT, Ras, and Chemokine pathways were up-regulated. DEGs enriched in cGMP-PKG, B cell receptor, and NOD-like receptor pathways were down- regulated. The sequencing results of mRNAs and miRNAs were verified by qRT-PCR and dual luciferase reporter assay. CONCLUSION: The imbalance of different synapses and pathways in the nucleus accumbens may be related to susceptibility and resilience caused by psychological stress.

Revision to psychopharmacology mRNA and microRNA profiles are associated with stress susceptibility and resilience induced by psychological stress in the prefrontal cortex.

OBJECTIVES: The prefrontal cortex is associated with many mental neurological diseases. The mRNA and microRNA profiles of stress susceptibility and resilience induced by psychological stress in the prefrontal cortex remain to be elucidated. METHODS: The C57 observer was placed in the cage next to the CD1 mouse and suffered psychological stress by watching the CD1 attacking another C57 mouse. After 5 days of psychological stress, the degree of fear memory and anxiety of mice were measured by social interaction test and elevated plus maze (EPM). The prefrontal cortex was extracted and mRNA and microRNA profiles were analyzed by high-throughput sequencing. RESULTS: In susceptible mice versus resilient mice, the downregulation of genes involved in serotonergic synapse may be related to the susceptibility to psychological stress. The imbalanced regulation of genes involved in VEGF, p53, chemokine, Ras, sphingolipid, GnRH, MAPK, and NOD-like receptor signaling pathways may be related to the susceptibility to psychological stress. Compared with control mice, susceptible mice and resilient mice have changed genes involved in serotonergic synapse, neuroactive ligand-receptor interaction, axon guidance, calcium, cAMP, GnRH, estrogen, PI3K-Akt, MAPK, Rap1, and Ras signaling pathways, these changes may be related to psychological stress processing. The sequencing results of mRNAs and microRNAs were verified by qRT-PCR and dual-luciferase reporter assay. CONCLUSIONS: The downregulation of genes involved in serotonergic synapse and imbalance of signaling pathways in the prefrontal cortex may be related to susceptibility to psychological stress.

Correction to: mRNA and microRNA profiles are associated with stress susceptibility and resilience induced by psychological stress in the prefrontal cortex.

The title of this article is "mRNA and microRNA profiles are associated with stress susceptibility and resilience induced by psychological stress in the prefrontal cortex.

mRNA and microRNA Profiles in the Amygdala Are Relevant to Susceptibility and Resilience to Psychological Stress Induced in Mice.

Severe or prolonged stress increases the risk for developing psychopathological disorders. An individual's perception of stress exposure varies greatly, as do its consequences. Numerous individuals demonstrate resilience to psychological stress. The mRNA and microRNA profiles of stress susceptibility and resilience to induced psychological stress in the amygdala remain to be elucidated. In this work, psychological stress was induced in an observer mouse by witnessing a similar individual under attack by an aggressor. After 5 days of psychological stress, the degree of fear memory and anxiety in mice was measured by a social interaction test and elevated plus-maze (EPM) test. mRNA and microRNA profiles were quantified by high-throughput sequencing in amygdala tissue harvested from Control, Susceptible and Resilient mice. In the amygdala of Susceptible versus Resilient mice, the upregulation of peptide, thyrotropin-releasing hormone, ECM receptors, glutamatergic synapse, cytokine-cytokine receptor interaction, long-term depression, PI3K-Akt, oxytocin, GnRH, HIF-1, estrogen, and calcium signaling pathways may be related to psychological stress-induced susceptibility, and their downregulation may be related to resilience. The downregulation of adrenergic synapse, adherens junction, Wnt, sphingolipid, B cell receptor, cAMP, Rap1, and Toll-like receptor signaling pathways may be related to psychological stress-induced susceptibility, and the upregulation may be related to resilience. Results by sequencing of mRNA and microRNA profiles are consistent, in which some are validated by qRT-PCR and dual-luciferase reporter assay. Susceptibility and resilience induced by psychological stresses are caused by the imbalanced regulation of different synapses and signaling pathways in the amygdala.

Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial.

OBJECTIVE: To assess the efficacy and safety of hydroxychloroquine plus standard of care compared with standard of care alone in adults with coronavirus disease 2019 (covid-19). DESIGN: Multicentre, open label, randomised controlled trial. SETTING: 16 government designated covid-19 treatment centres in China, 11 to 29 February 2020. PARTICIPANTS: 150 patients admitted to hospital with laboratory confirmed covid-19 were included in the intention to treat analysis (75 patients assigned to hydroxychloroquine plus standard of care, 75 to standard of care alone). INTERVENTIONS: Hydroxychloroquine administrated at a loading dose of 1200 mg daily for three days followed by a maintenance dose of 800 mg daily (total treatment duration: two or three weeks for patients with mild to moderate or severe disease, respectively). MAIN OUTCOME MEASURE: Negative conversion of severe acute respiratory syndrome coronavirus 2 by 28 days, analysed according to the intention to treat principle. Adverse events were analysed in the safety population in which hydroxychloroquine recipients were participants who received at least one dose of hydroxychloroquine and hydroxychloroquine non-recipients were those managed with standard of care alone. RESULTS: Of 150 patients, 148 had mild to moderate disease and two had severe disease. The mean duration from symptom onset to randomisation was 16.6 (SD 10.5; range 3-41) days. A total of 109 (73%) patients (56 standard of care; 53 standard of care plus hydroxychloroquine) had negative conversion well before 28 days, and the remaining 41 (27%) patients (19 standard of care; 22 standard of care plus hydroxychloroquine) were censored as they did not reach negative conversion of virus. The probability of negative conversion by 28 days in the standard of care plus hydroxychloroquine group was 85.4% (95% confidence interval 73.8% to 93.8%), similar to that in the standard of care group (81.3%, 71.2% to 89.6%). The difference between groups was 4.1% (95% confidence interval -10.3% to 18.5%). In the safety population, adverse events were recorded in 7/80 (9%) hydroxychloroquine non-recipients and in 21/70 (30%) hydroxychloroquine recipients. The most common adverse event in the hydroxychloroquine recipients was diarrhoea, reported in 7/70 (10%) patients. Two hydroxychloroquine recipients reported serious adverse events. CONCLUSIONS: Administration of hydroxychloroquine did not result in a significantly higher probability of negative conversion than standard of care alone in patients admitted to hospital with mainly persistent mild to moderate covid-19. Adverse events were higher in hydroxychloroquine recipients than in non-recipients. TRIAL REGISTRATION: ChiCTR2000029868.