Central Mechanism Of Action Research Articles

Central neural mechanisms of cancer cachexia.

Cachexia is a devasting syndrome which impacts a large number of patients with cancer. This review aims to provide a comprehensive overview of the central mechanisms of cancer cachexia. In particular, it focuses on the role of the central nervous system (CNS), the melanocortin system, circulating hormones and molecules which are produced by and act on the CNS and the psychological symptoms of cancer cachexia. A growing body of evidence suggests that a central mechanism of action underpins this multi-system disorder. Recent research has focused on the role of neuroinflammation that drives the sickness behaviour seen in cancer cachexia, with emphasis on the role of the hypothalamus. Melanocortin receptor antagonists are showing promise in preclinical studies. There are also new pharmacological developments to overcome the short half-life of ghrelin. GDF-15 has been identified as a core target and trials of compounds that interfere with its signalling or its central receptor are underway. Understanding the central mechanisms of cancer cachexia is pivotal for enhancing treatment outcomes in patients. While emerging pharmacological interventions targeting these pathways have shown promise, further research is essential.

The Emerging Role of Neurosteroids: Novel Drugs Brexanalone, Sepranolone, Zuranolone, and Ganaxolone in Mood and Neurological Disorders.

Thisreview investigates the potential of neurosteroids, including brexanolone, zuranolone, sepranolone, and ganaxalone, as therapeutic agents for a range of mood and neurological disorders. Notably, these disorders encompass postpartum depression, post-traumatic stress disorder (PTSD), major depressive disorder (MDD), epilepsy, and Alzheimer's disease. Brexanolone and zuranolone have emerged as frontrunners in the treatment of postpartum depression, offering rapid relief from debilitating symptoms. Their mechanism of action involves modulation of the gamma-aminobutyric acid (GABA) system, which plays a pivotal role in mood regulation. Clinical trials have demonstrated their efficacy, heralding a potential breakthrough in addressing this often-overlooked condition. In the context of PTSD and MDD, neurosteroids have demonstrated significant promise. Their positive allosteric modulation of GABA-A receptors translates into improved mood stabilization and reduced symptoms. This novel approach represents a departure from conventional treatments and could offer newfound hope for individuals grappling with these disorders. Beyond mood disorders, neurosteroids, especially ganaxalone, exhibit potential in the realm of epilepsy management. Ganaxalone's capacity to control seizures is attributed to its GABAergic activity, which helps restore the delicate balance of neurotransmission in epileptic brains. Moreover, neurosteroids have revealed neuroprotective properties in Alzheimer's disease models. By influencing the GABAergic system, they mitigate excitotoxicity, a hallmark of Alzheimer's pathology. This neuroprotection opens a novel avenue for slowing neurodegeneration, although further research and clinical validation are essential. In conclusion, this review underscores the substantial therapeutic promise of neurosteroids in mood and neurological disorders. Their modulation of the GABA system emerges as a central mechanism of action, emphasizing the importance of GABAergic signaling in these conditions. The path forward entails continued investigation and clinical trials to fully unlock the potential of neurosteroids, offering hope for enhanced treatments in these challenging clinical domains.

Angiotensin-(1-7) Mas Receptors are Highly Colocalized to GABAergic Proopiomelanocortin Neurons in the Arcuate Nucleus of the Hypothalamus

Previous studies from our laboratory have shown that circulating levels of angiotensin (Ang)-(1-7), a protective hormone of the renin-angiotensin system, are greatly reduced in obese hypertensive mice. Additionally, restoration of this hormone reduces cardiovascular sympathetic tone and lowers blood pressure in this model suggesting a central mechanism of action. In support of this, our recent data show that the sympatho-inhibitory and blood pressure lowering effects of Ang-(1-7) involve activation of mas receptors (masR) within the arcuate nucleus of the hypothalamus (ARC). More specifically, we have found that masR are highly colocalized to proopiomelanocortin (POMC) neurons in the ARC. Due to the heterogeneous nature of POMC neuron subtypes, we wanted to explore the neurotransmitter phenotype of these POMCmasR neurons. We hypothesized that due to the blood pressure lowering effects of Ang-(1-7), POMCmasR are likely colocalized to inhibitory GABAergic neurons. To test this, we performed RNAscope in-situ hybridization in male C57Bl/6J mice after twelve weeks of either a 60% high fat diet (HFD) or matched control diet (n=12-18/group). We used RNAscope to colocalize expression of POMC, masR, and the vesicular GABA transporter, Vgat, mRNA transcripts within the ARC. Colocalization of POMCmasR and Vgat was quantified and percent-colocalization compared between control and HFD groups. We found that POMCmasR are highly colocalized with the GABAergic marker, Vgat, to a similar extent in control and HFD groups (84±4 vs. 90±2% of neurons, respectively; p=0.294 unpaired t-test). The population of POMC neurons that did not express masR also did not colocalize with Vgat. As an initial step to determine if masR modulates GABAergic signaling in the ARC, we assessed gene expression of glutamate decarboxylase 2 (Gad2; a GABA synthetic enzyme) in the ARC following chronic six-week treatment with systemic Ang-(1-7) versus saline infusion in male mice fed a control diet versus HFD (n=9-13/group). We found that Ang-(1-7) increases ARC Gad2 mRNA in HFD mice (1.03±0.09 control diet vs. 0.93±0.07 HFD vs. 1.23±0.07 HFD plus Ang-(1-7); p=0.023 one-way ANOVA). Supporting specificity of these actions, Ang-(1-7) did not alter POMC mRNA in the ARC. These overall data suggest that masR primarily localize to GABA-expressing POMC neurons in the ARC, and Ang-(1-7) may directly modulate GABA synthesis pathways in this brain region. Further studies are needed to elucidate the functional importance of these ARC POMC GABAergic neurocircuits to the depressor effects of Ang-(1-7) in obesity. Funding: NIH R01 HL156986. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Repurposing GSK3B Small Molecule Inhibitors for Refractory Lymphoid Malignancies

Background: Small molecule GSK3B inhibitors were developed for solid tumors and neurological conditions, including Alzheimer's and Parkinson disease. Five GSK3B inhibitors achieved favorable safety and PK/PD profiles in a total of 22 Phase 1 and 2 clinical trials but no clinical response for any of these indications. GSK3B is the kinase that phosphorylates β-catenin to initiate its degradation, hence GSK3B small molecule inhibition results in rapid nuclear accumulation of β-catenin protein. Significance: Activating mutations in the Wnt/β-catenin pathway are common oncogenic drivers throughout all main types of cancer (n=64,812) but not found in B- and T-lymphoid malignancies (n=2,137). Studying tissue microarrays by β-catenin immunohistochemistry, lung, colon, breast, and melanoma specimen (n=57) showed consistently high levels of nuclear β-catenin, whereas B- and T-cell lymphomas (n=84) lacked β-catenin signal. Despite comparable mRNA levels, proteomic analyses revealed 60-400-fold lower β-catenin levels in lymphoid compared to epithelial tumors (n=1,389) suggesting that lymphoid malignancies rely on powerful mechanisms for β-catenin degradation, e.g. by GSK3B. Results: To study the effects of β-catenin activation in human cells, we induced expression of stabilized form of β-catenin in 18 lymphoid (B- and T-ALL, MCL, DLBCL, PTCL) and four myeloid leukemia cell lines. In B- and T-lymphoid cells, β-catenin accumulation compromised clonal fitness, colony formation and induced cell death, but increased competitive fitness and colony formation in myeloid leukemia cells. CEBPα-mediated reprogramming of B-ALL cells into a myeloid phenotype reversed the deleterious effects highlighting that effects of β-catenin-accumulation strictly depend on lymphoid lineage-identity. RNA-seq studies upon inducible activation of β-catenin in lymphoid cells, revealed transcriptional repression of Myc and Myc target genes as principal gene expression change. Unlike activating β-catenin:TCF7 complexes in epithelial cells, our global interactome studies in B- and T-ALL and lymphoma cells identified repressive β-catenin complexes with lymphoid-specific Ikaros zinc finger (IKZF1/2/3) proteins and several components of the NuRD complex including Mta1/2, Gatad2a/b, Chd4, HDAC1/2. Interactome and ChIP-seq analyses revealed that β-catenin together with lymphoid-specific Ikaros factors recruited repressive NuRD complex members to deacetylate H3K27 and repress MYC superenhancer (SE) regions. Genetic deletion of both IKZF1 and IKZF3 or HDRT-based mutation of Ikaros binding motifs within the Myc-SE enabled resistance to β-catenin accumulation. To leverage this previously unrecognized vulnerability of lymphoid malignancies, we examined five clinically approved GSK3B small molecule inhibitors that achieved favorable safety profiles at micromolar plasma concentrations in clinical trials for neurological disorders and solid tumors. Strikingly, LY2090314 and CHIR99021 were effective at low nanomolar concentrations in B- and T-cell malignancies that expressed lymphoid Ikaros factors. At IC50 concentrations of <5 nM, GSK3B-inhibitors induced massive accumulation of β-catenin, repression of MYC and acute cell death. In B-ALL cells with IKZF1-deletion, expression of the remaining IKZF3 factor was sufficient to retain full sensitivity to GSK3B-inhibition. Deletion of β-catenin, however, abolished the effects of GSK3B inhibitors and relieved suppression of MYC, demonstrating accumulation of β-catenin represents as central mechanism of action. Preclinical in vivo treatment experiments of refractory B-ALL and mantle cell lymphoma PDX validated small molecule GSK3B-inhibition as strategy to overcome conventional mechanisms of drug-resistance. Conclusions: B- and T-lymphoid malignancies not only lacked expression of β-catenin but critically depend on GSK3B for effective β-catenin degradation. Our interactome studies in lymphoid tumors revealed that β-catenin formed repressive complexes with lymphoid-specific Ikaros and NuRD complex factors. Strikingly, GSK3B small molecule inhibitors engage this new pathway at low nanomolar concentrations and demonstrated favorable safety profiles in Phase 1 and Phase 2 trials. Safety and efficacy of GSK3B-inhibitors opens up an immediate path for repurposing these agents towards refractory B-cell malignancies.

Novel N-Acylethanolamide Derivatives Affect Body Weight and Energy Balance.

Introduction - The obesity pandemic is multifactorial. Nutritional, pharmacologic and surgical interventions are limited in reach and efficacy, raising need for new therapeutics. Aims - Characterization of anorexigenic and cognitive effect and central mechanism of action of novel N-acylethanolamide derivatives. Methods - Sabra mice divided to similar experimental groups, injected IP with: oleyl-L-leucinolamide (1 A), linoleyl-L-leucinolamide (4 A), linoleyl-L-valinolamide (5 A), oleyl-oxycarbonyl-L-valinolamide (1 B), oleyl-oxycarbonyl-D-valinolamide (2 B), oleylamine-carbonyl-L-valinolamide (3 B), oleylamine-carbonyl-D-valinolamide (4 B), and oleyl-L-hydroxyvalineamide (5 B). Control group with vehicle. Body weight and food consumption followed for 39 days. Motor activity and cognitive function by open field test and eight-arm maze. Mice sacrificed and mechanism of action investigated by qPCR. The genes analyzed involved in energy balance and regulation of appetite. Catecholamines and serotonin evaluated. Results - Compounds 1 A, 5 A, 1 B-4 B, caused significant weight loss of 4.2-5.6 % and 5 A, 1 B-4 B, improved cognitive function following 8 i. p. injections of 1 mg/kg during 39 days, by different mechanisms. 5 A, 3 B and 4 B decreased food consumption, whereas 1 A, 5 A and 2 B increased motor activity. 1 A, 4 A, 1 B and 3 B elevated SIRT-1, associated with survival. POMC upregulated by 1 B and 2 B, CART by 1 B, 2 B and 1 A. NPY and CAMKK2 downregulated by 5 A. 4 B enhanced 5-HT levels. 4 A, 5 A, 1 B, 4 B, 5 B decreased FAAH, showing long lasting effect. Conclusions - These new compounds might be developed for the treatment of obesity and for improved cognitive function.

Structural and functional improvement of amygdala sub-regions in postpartum depression after acupuncture.

This study aimed to analyze the changes in structure and function in amygdala sub-regions in patients with postpartum depression (PPD) before and after acupuncture. A total of 52 patients with PPD (All-PPD group) were included in this trial, 22 of which completed 8 weeks of acupuncture treatment (Acu-PPD group). An age-matched control group of 24 healthy postpartum women (HPW) from the hospital and community were also included. Results from the 17-Hamilton Depression Scale (17-HAMD) and the Edinburgh Postnatal Depression Scale (EPDS) were evaluated, and resting-state functional magnetic resonance imaging (rs-fMRI) scans were performed at baseline and after the acupuncture treatment. Sub-regions of the amygdala were used as seed regions to measure gray matter volume (GMV) and analyzed for resting-state functional connectivity (RSFC) values separately. Finally, correlation analyses were performed on all patients with PPD to evaluate association values between the clinical scale scores, GMV, and RSFC values, while controlling for age and education. Pearson's correlation analyses were conducted to investigate the relevance between GMV and RSFC values of brain regions that differed before and after acupuncture treatment and clinical scale scores in Acu-PPD patients. The HAMD scores for Acu-PPD were reduced after acupuncture treatment (P < 0.05), suggesting the positive effects of acupuncture on depression symptoms. Structurally, the All-PPD group showed significantly decreased GMV in the left lateral part of the amygdala (lAMG.L) and the right lateral part of the amygdala (lAMG.R) compared to the HPW group (P < 0.05). In addition, the GMV of lAMG.R was marginally increased in the Acu-PPD group after acupuncture (P < 0.05). Functionally, the Acu-PPD group showed a significantly enhanced RSFC between the left medial part of the amygdala (mAMG.L) and the left vermis_6, an increased RSFC between the right medial part of the amygdala (mAMG.R) and left vermis_6, and an increased RSFC between the lAMG.R and left cerebelum_crus1 (P < 0.05). Moreover, correlation studies revealed that the GMV in the lAMG.R was significantly related to the EPDS scores in the All-PPD group (P < 0.05). Our findings demonstrated that the structure of amygdala sub-regions is impaired in patients with PPD. Acupuncture may improve depressive symptoms in patients with PPD, and the mechanism may be attributed to changes in the amygdala sub-region structure and the functional connections of brain areas linked to the processing of negative emotions. The fMRI-based technique can provide comprehensive neuroimaging evidence to visualize the central mechanism of action of acupuncture in PPD.

Real-time changes in brain activity during tibial nerve stimulation for overactive bladder: Evidence from functional near-infrared spectroscopy hype scanning.

To use functional near-infrared spectroscopy (fNIRS) to identify changes in brain activity during tibial nerve stimulation (TNS) in patients with overactive bladder (OAB) responsive to therapy. Eighteen patients with refractory idiopathic OAB patients were recruited consecutively for this pilot study. At baseline, all patients completed 3 days voiding diary, Quality-of-Life score, Perception-of-Bladder-Condition, and Overactive-Bladder-Symptom score. Then 4 region-of-interest (ROI) fNIRS scans with 3 blocks were conducted for each patient. The block design was used: 60 s each for the task and rest periods and 3 to 5 repetitions of each period. A total of 360 s of data were collected. During the task period, patients used transcutaneous tibial nerve stimulation (TTNS) of 20-Hz frequency and a 0.2-millisecond pulse width and 30-milliamp stimulatory current to complete the experiment. The initial scan was obtained with a sham stimulation with an empty bladder, and a second was obtained with a verum stimulation with an empty bladder. Patients were given water till strong desire to void, and the third fNIRS scan with a verum stimulation was performed. The patients then needed to urinate since they could not tolerate the SDV condition for a long time. After a period of rest, the patients then were given water until they exhibited SDV state. The fourth scan with sham fNIRS scan in the SDV state was performed. NIRS_KIT software was used to analyze prefrontal activity, corrected by false discovery rate (FDR, p < 0.05). Statistical analyses were performed using GraphPad Prism software; p < 0.05 was considered significant. TTNS treatment was successful in 16 OAB patients and unsuccessful in 2. The 3 days voiding diary, Quality-of-Life score, Perception-of-Bladder-Condition, and Overactive-Bladder-Symptom score were significantly improved after TNS in the successfully treated group but not in the unsuccessfully treated group. The dorsolateral prefrontal cortex (DLPFC) (BA 9, Chapters 25 and 26) and the frontopolar area (FA) (BA 10, Chapters 35, 45, and 46) were significantly activated during TNS treatment with an empty bladder rather than with an SDV. Compared with the successfully treated group, the unsuccessfully treated group did not achieve statistical significance with an empty bladder and an SDV state. fNIRS confirms that TNS influences brain activity in patients with OAB who respond to therapy. That may be the central mechanism of action of TNS.

An Updated Review on the Metabolite (AM404)-Mediated Central Mechanism of Action of Paracetamol (Acetaminophen): Experimental Evidence and Potential Clinical Impact.

Paracetamol remains the recommended first-line option for mild-to-moderate acute pain in general population and particularly in vulnerable populations. Despite its wide use, debate exists regarding the analgesic mechanism of action (MoA) of paracetamol. A growing body of evidence challenged the notion that paracetamol exerts its analgesic effect through cyclooxygenase (COX)-dependent inhibitory effect. It is now more evident that paracetamol analgesia has multiple pathways and is mediated by the formation of the bioactive AM404 metabolite in the central nervous system (CNS). AM404 is a potent activator of TRPV1, a major contributor to neuronal response to pain in the brain and dorsal horn. In the periaqueductal grey, the bioactive metabolite AM404 activated the TRPV1 channel-mGlu5 receptor-PLC-DAGL-CB1 receptor signaling cascade. The present article provides a comprehensive literature review of the centrally located, COX-independent, analgesic MoA of paracetamol and relates how the current experimental evidence can be translated into clinical practice. The evidence discussed in this review established paracetamol as a central, COX-independent, antinociceptive medication that has a distinct MoA from non-steroidal anti-inflammatory drugs (NSAIDs) and a more tolerable safety profile. With the establishment of the central MoA of paracetamol, we believe that paracetamol remains the preferred first-line option for mild-to-moderate acute pain for healthy adults, children, and patients with health concerns. However, safety concerns remain with the high dose of paracetamol due to the NAPQI-mediated liver necrosis. Centrally acting paracetamol/p-aminophenol derivatives could potentiate the analgesic effect of paracetamol without increasing the risk of hepatoxicity. Moreover, the specific central MoA of paracetamol allows its combination with other analgesics, including NSAIDs, with a different MoA. Future experiments to better explain the central actions of paracetamol could pave the way for discovering new central analgesics with a better benefit-to-risk ratio.

Dihydroquercetin as a systemic neuroprotector for the prevention and treatment of β-amyloid-associated brain diseases

Dihydroquercetin (DHQ) is a plant-derived polyphenol belonging to the group of flavonoids. In models associated with abnormal accumulation of β-amyloid in the brain (Alzheimer's disease and cerebral amyloid angiopathy), DHQ demonstrates the ability to disaggregate toxic forms of β-amyloid and prevent their formation. It is believed that this phenomenon underlies the protective effect of DHQ on brain neurons. However, pharmacokinetic data doubt the central mechanism of action of DHQ because this compound does not penetrate well into the brain. A hypothesis is put forward about the systemic nature of the neuroprotective action of DHQ, since this compound has multiple biological activities at the level of the whole organism. To characterize DHQ (and similar compounds), it is proposed to introduce the term «systemic neuroprotector».

Effect of Bladder Injection of OnabotulinumtoxinA on the Central Expression of Genes Associated with the Control of the Lower Urinary Tract: A Study in Normal Rats.

To investigate a possible central mechanism of action of Botulinum toxin A (BoNT/A) following injection in the bladder, complementary to the acknowledged peripheral bladder effect, we studied changes in the expression of neuropeptides and receptors involved in lower urinary tract function in the spinal cord (SC) and dorsal root ganglia (DRG) of normal rats following BoNT/A bladder injection. Thirty-six Sprague-Dawley rats, divided into three groups of n = 12, received bladder injections of 2U or 5U OnabotulinumtoxinA (BOTOX®), or saline. Six animals from each group were sacrificed on days 7 and 14. Expression of Tachykinin 1 (Tac1), capsaicin receptor (TRPV1), neuropeptide Y (NPY), proenkephalin (PENK) and muscarinic receptors M1, M2, M3, was evaluated in the bladder, L6-S1 DRG, and SC segments using real-time PCR and Western blotting. Real-time PCR revealed increased expression of NPY in all tissues except for SC, and increased TRPV1 and PENK expression in DRG and SC, whereas expression of Tac1, M1 and M2 was decreased. Less significant changes were noted in protein levels. These findings suggest that bladder injections of OnabotulinumtoxinA may be followed by changes in the expression of sensory, sympathetic and cholinergic bladder function regulators at the DRG/SC level.

Bruton's Tyrosine Kinase Inhibition in Multiple Sclerosis.

Purpose of ReviewMultiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) with a chronic and often progressive disease course. The current disease-modifying treatments (DMTs) limit disease progression primarily by dampening immune cell activity in the peripheral blood or hindering their migration from the periphery into the CNS. New therapies are needed to target CNS immunopathology, which is a key driver of disability progression in MS. This article reviews Bruton’s Tyrosine Kinase Inhibitors (BTKIs), a new class of experimental therapy that is being intensely evaluated in MS. We focus on the potential peripheral and central mechanisms of action of BTKIs and their use in recent clinical trials in MS.Recent FindingsThere is evidence that some BTKIs cross the blood–brain barrier and may be superior to currently available DMTs at dampening the chronic neuroinflammatory processes compartmentalized within the CNS that contribute to progressive worsening in people withMS (pwMS). Recently, evobrutinib and tolebrutinib have shown efficacy in phase II clinical trials, and there are numerous ongoing phase III clinical trials of various BTKIs in relapsing and progressive forms of MS. Results from these clinical trials will be essential to understand the efficacy and safety of BTKIs across the spectrum of MS and keydifferences between specific BTKIs when treating pwMS.SummaryInhibition of BTK has emerged as an attractive strategy to target cells of the adaptive and innate immune system outside and within the CNS. BTKIs carry great therapeutic potential across the MS spectrum, where key pathobiology aspects seem confined to the CNS compartment.

Sensory brain activation during rectal balloon distention: a pilot study in healthy volunteers to assess safety and feasibility at 1.5T

ObjectiveAlthough increasing evidence suggests a central mechanism of action for sacral neuromodulation, the exact mechanism remains unclear. We set up a scanning paradigm to measure brain activation related to various stages of rectal filling using rectal balloon distention.Materials and MethodsSix healthy volunteers underwent rectal balloon distention during MRI scanning at a 1.5T scanner with a Tx/Rx head coil. MR images were collected at four levels of distention: empty balloon (EB), first sensation volume (FSV), desire to defecate volume (DDV), maximum tolerable volume (MTV). Data were analyzed using BrainVoyager 20.4. Whole brain and ROI-based fixed-effects general linear model analyses were performed on the fMRI time-course data from all participants.ResultsRectal filling until FSV evoked the most blood-oxygen-level-dependent responses in several clusters throughout the cortex, followed by the responses evoked by rectal filling until DDV. Interestingly, rectal filling until MTV evoked negative responses compared to baseline throughout the cortex. No negative side effects were found.DiscussionThis study shows that a standardized paradigm for functional MRI combined with rectal filling is feasible and safe in healthy volunteers and is ready to be used in fecal incontinent patients to assess whether their brain activity differs from healthy controls.

Contemplating movement: A randomized control trial of yoga training for mental health

Yoga is increasingly recognized for both its physical and mental health benefits, yet its central mechanisms of action remain unclear. In addition to benefits generally associated with physical exercise, yoga may also cultivate interoception, the sense of the body's internal state, the ability to notice and respond adaptively to physiological cues. Complicating matters, yoga training varies in the relative emphasis on physical movement and the cultivation of interoceptive awareness, yet few studies have explored whether differences in emphasis impact yoga's benefits. A randomized trial explored the effects of interoceptive emphasis in yoga training on attention and subjective wellbeing. Over a 10-week period featuring classes twice each week, community-dwelling adult participants with moderate depressive symptoms (N = 58) were randomized to attend either more Movement-Focused yoga or Interoception-Focused yoga. Assessments were conducted at baseline, post-intervention, and at a one-month follow-up, which included both self-reports of mood and interoception, and task-performance on a Sustained Attention to Response Task. Relative to Movement-Focused yoga, Interoception-Focused yoga practitioners showed greater improvements in sustained attention, but no differences in self-reported mood or interoception. Yet sustained attention improvements in the Interoception-Focused group were greatest for those endorsing high levels of interoception, an effect that was absent in the Movement-Focused group. Despite an exploratory sample size, these findings support the potential for an interoceptive focus to extend yoga's attentional benefits, particularly for those who report high interoceptive awareness.

Association between road traffic accidents and drugs belonging to the antiseizure medications class: A pharmacovigilance analysis in VigiBase.

Due to their central mechanism of action, antiseizure medications (ASMs) could lead to adverse effects likely to impair driving skills. Their extended use to neuropsychiatric disorders makes it a class of drugs to monitor for their road traffic accidental (RTA) potential. We aimed to assess the reporting association between ASMs and RTAs using the World Health Organization pharmacovigilance database (VigiBase). We performed a disproportionality analysis to compute adjusted reporting odds ratios to evaluate the strength of reporting association between ASMs and RTAs. A univariate analysis using the reporting odds-ratio was used to assess drug-drug interactions between ASMs and RTAs. There were 1 341 509 reports associated with at least 1 ASM in VigiBase of whom 2.91‰ were RTAs reports. Eight ASMs were associated with higher reporting of RTAs compared to others (ranging from 1.35 [95% confidence interval 1.11-1.64] for lamotrigine to 4.36 [95% confidence interval 3.56-5.32] for cannabis). Eight significant drug-drug interactions were found between ASMs and the onset of RTA, mainly involving CYP450 induction. A significant safety signal between RTAs and some ASMs was identified. Association of several ASMs might further increase the occurrence of RTA. ASMs prescription in patients with identified risk factors of RTA should be considered with caution. Study number: ClinicalTrials.gov, NCT04480996.

Sacral Neuromodulation Improves Abnormal Prefrontal Brain Activity in Patients with Overactive Bladder: A Possible Central Mechanism.

We explored the central pathogenesis of overactive bladder (OAB) and the central mechanism of action of sacral neuromodulation (SNM). We prospectively enrolled patients with OAB who chose SNM and healthy controls (HCs). At baseline, all subjects completed a 72-hour voiding diary, OAB symptom score and prefrontal cortex functional near-infrared spectroscopy scan synchronous urodynamic monitoring. All OAB patients were tested after implantation of the SNM electrode, and both success and failure groups were reevaluated. NIRS_KIT software was used to analyze prefrontal activity (p <0.05 and corrected by false discovery rate). SPSS® 22.0 was used to analyze clinical parameters, and p <0.05 was considered statistically significant. A total of 16 HC and 20 OAB patients were enrolled. SNM treatment was successful in 18 OAB patients and failed in 2. The parameters of the voiding diary, OAB symptom score and urodynamic monitoring of OAB group were significantly improved after SNM treatment in success group, not in the failure group. Compared with HCs, Brodmann's area 9 (left dorsolateral prefrontal cortex [DLPFC]) was significantly deactivated in the preoperative OAB success group and significantly activated after SNM treatment. Before surgery, compared with the success group, the failure group showed significantly deactivated Brodmann's area 9 (left DLPFC). Our study provides novel neuroimaging evidence for the possible central pathogenesis of OAB (ie abnormal deactivation of the left DLPFC) and the possible central mechanism of action of SNM (ie restore activation of the left DLPFC).

Free Papers Compiled

BACKGROUNDThe association between testosterone and depression is extensively debated1. Testosterone being a neuro-active steroid hormone, is responsible for growth and development of male primary sexual organs2, musculoskeletal system and influencing mood and appetitive behaviour1. Several lines of research have examined the potential role of testosterone therapy in alleviating depressive symptoms1. Thus, considering hypo-testosteronism as a differential diagnosis of depressive disorders in males or testosterone supplementation in such cases as treatment for depression is important but not commonly practiced.CASE SERIESIn this case series, we describe two male patients with young onset depression, who did not respond to adequate trials of multiple antidepressants, were evaluated independently elsewhere by endocrinologist,and detected to have low levels of testosterone. The depressive symptoms improved with initiation of testosterone supplementation in both the cases.DISCUSSION & CONCLUSIONThis case series provides insight into this clinical phenomenon where low testosterone may be associated with depressive mood symptoms, thus testosterone supplementation being imperative in such cases. Testosterone causes increased serotonin release in the dorsal raphe nuclei and facilitates general and antidepressant-induced neuroplasticity in the hippocampal formation, which can be considered as central mechanisms of action against depression1. The beneficial role of testosterone use may thus be independent of hypogonal state as well.However, further studies are needed to ascertain the utility of initiating testosterone use in certain patient groups and develop guidelines to assess for hypo-testosteronism in young males with treatment resistant depression.Reference1. Walther A, Breidenstein J, Miller R. Association of testosterone treatment with alleviation of depressive symptoms in men: a systematic review and meta-analysis. JAMA psychiatry. 2019 Jan 1;76(1):31-40.2. Ravan JP, Pattnaik JI, Nath S, Kumar S. Intervention Strategy for Amennorhoea, Galactorrhoea, osteopenia and Sexual dysfunction caused by Antipsychotic induced Hyperprolactinemia. In indian journal of psychiatry 2019 jan 1 (vol. 61, no. 9, pp. S443-s443). Wolters kluwer india pvt ltd, a-202, 2nd flr, qube, cts no 1498a-2 village marol, andheri east, mumbai, 400059, india: wolters kluwer medknow publications.

Study of the efficacy and tolerability of injectable muscle relaxants with a central mechanism of action in non-specific back pain with muscle-tonic syndrome and in myofascial back pain syndrome

The study aimed to compare the efficacy and tolerability of injectable thiocolchicoside and methocarbamol (Dorsum) in non-specific back pain with muscle-tonic syndrome and myofascial back pain syndrome. Materials and methods. A multicenter comparative study was conducted. Ninety patients with non-specific back pain with muscle-tonic syndrome or myofascial back pain syndrome were examined, who were divided into groups of 30 patients: active group 1 — methocarbamol (Dorsum), active group 2 — thiocolchicoside, group 3 (control) — NSAIDs. The dynamics of pain syndrome were evaluated by VAS; the dynamics by needle ENMG (in half of patients in each group), and tolerability (evaluated only in active groups) were also assessed. Results. After 3 days of treatment, back pain decreased: by 48.9% in the injectable methocarbamol (Dorsum) group, by 35.5 % in the injectable thiocolchicoside group, and by 16.7 % in the NSAIDs group. After 3 days of treatment, the electromyographic signs of muscle spasm according to needle ENMG data disappeared: in 80 % (12 out of 15) of patients in the injectable methocarbamol (Dorsum) group, in 53.3 % (8 out of 15) of patients in the injectable thiocolchicoside group, and in 46.7 % (7 out of 15) of patients in the NSAIDs group. In the injectable methocarbamol (Dorsum) group, no complaints of tolerability were reported; in the injectable thiocolchicoside group, 23.3 % of patients (7 out of 30) reported side effects: 10 % (3 out of 30) — drowsiness, 6.7 % (2 out of 30) — nausea, of which 3.3 % (1 out of 30) —single vomiting and 6.7 % (2 out of 30) — epigastric pain. Conclusions. Injectable methocarbamol (Dorsum) was more effective than injectable thiocolchicoside in patients with non-specific back pain with muscle-tonic syndrome or myofascial back pain syndrome and showed better tolerability.

Multimodal cerebral imaging study on the effects of \u201cAdjust Zang Dredge Meridian\u201d electroacupuncture on cerebral central sensitization in PDPN patients: a study protocol for a sham-controlled, randomized trial

BackgroundPainful diabetic peripheral neuropathy (PDPN) has a great impact on an individual’s quality of life. The current researchers’ previous trial suggested that acupuncture was a promising adjunctive treatment for PDPN. However, the underlying mechanism of action of acupuncture treatment for PDPN is still unclear, especially its effects at the cerebral level. The aim of this trial will be to explore how acupuncture works in treating PDPN by using multimodal cerebral imaging.Method and designThis will be a randomized controlled trial. A total of 150 participants will be recruited and assigned to one of three groups: the healthy group, the DM without PDPN group and the DM with PDPN group. Participants in the DM without PDPN and the DM with PDPN groups will each be further divided between an electroacupuncture group and a sham electroacupuncture group. Participants will receive six treatment sessions per week for 4 weeks. Multimodal cerebral imaging includes resting-state functional magnetic resonance imaging (rs-fMRI), diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS); this neurophysiological testing will be the primary outcome measure. Subjective pain scales and blood analysis will be a secondary outcome measure and will be used to assess the clinical efficacy of the intervention. Multimodal cerebral imaging will be used to detect cerebral activity changes in each treatment group. The clinical data and fMRI data will be analysed for all the groups. Multiple correlation regression analyses will be used to assess the association between changes in cerebral functional activity and the improvement of clinical outcomes after acupuncture treatment.DiscussionThis study is based on the results of the researchers’ previous study, and using combined clinical and cerebral function changes, it will help evaluate the effects of acupuncture on PDPN. The investigation of acupuncture’s central mechanism of action will further expand the understanding of acupuncture treatment of PDPN.Trial registrationChinese Clinical Trial Registry ChiCTR1900024109. Registered on 26 June 2019.

New insights into methoxetamine mechanisms of action: Focus on serotonergic 5-HT2 receptors in pharmacological and behavioral effects in the rat

Methoxetamine (MXE) is a dissociative substance of the arylcyclohexylamine class that has been present on the designer drug market as a ketamine-substitute since 2010. We have previously shown that MXE (i) possesses ketamine-like discriminative and positive rewarding effects in rats, (ii) affects brain processing involved in cognition and emotional responses, (iii) causes long-lasting behavioral abnormalities and neurotoxicity in rats and (iv) induces neurological, sensorimotor and cardiorespiratory alterations in mice. To shed light on the mechanisms through which MXE exerts its effects, we conducted a multidisciplinary study to evaluate the various neurotransmitter systems presumably involved in its actions on the brain. In vivo microdialysis study first showed that a single administration of MXE (0.25 and 0.5 mg/kg, i.v.) is able to significantly alter serotonin levels in the rat medial prefrontal cortex (mPFC) and nucleus accumbens. Then, we observed that blockade of the serotonin 5-HT2 receptors through two selective antagonists, ketanserin (0.1 mg/kg, i.p.) and MDL 100907 (0.03 mg/kg, i.p.), at doses not affecting animals behavior per se, attenuated the facilitatory motor effect and the inhibition on visual sensory responses induced by MXE (3 mg/kg, i.p.) and ketamine (3 mg/kg, i.p.), and prevented MXE-induced reduction of the prepulse inhibition in rats, pointing to the 5-HT2 receptors as a key target for the recently described MXE-induced sensorimotor effects. Finally, in-vitro electrophysiological studies revealed that the GABAergic and glutamatergic systems are also likely involved in the mechanisms through which MXE exerts its central effects since MXE inhibits, in a concentration-dependent manner, NMDA-mediated field postsynaptic potentials and GABA-mediated spontaneous currents. Conversely, MXE failed to alter both the AMPA component of field potentials and presynaptic glutamate release, and seems not to interfere with the endocannabinoid-mediated effects on mPFC GABAergic synapses. Altogether, our results support the notion of MXE as a NMDA receptor antagonist and shed further lights into the central mechanisms of action of this ketamine-substitute by pointing to serotonin 5-HT2 receptors as crucial players in the expression of its sensorimotor altering effects and to the NMDA and GABA receptors as potential further important targets of action.

Apigenin Improves Hypertension and Cardiac Hypertrophy Through Modulating NADPH Oxidase-Dependent ROS Generation and Cytokines in Hypothalamic Paraventricular Nucleus.

Apigenin, identified as 4', 5, 7-trihydroxyflavone, is a natural flavonoid compound that has many interesting pharmacological activities and nutraceutical potential including anti-inflammatory and antioxidant functions. Chronic, low-grade inflammation and oxidative stress are involved in both the initiation and progression of hypertension and hypertension-induced cardiac hypertrophy. However, whether or not apigenin improves hypertension and cardiac hypertrophy through modulating NADPH oxidase-dependent reactive oxygen species (ROS) generation and inflammation in hypothalamic paraventricular nucleus (PVN) has not been reported. This study aimed to investigate the effects of apigenin on hypertension in spontaneously hypertensive rats (SHRs) and its possible central mechanism of action. SHRs and Wistar-Kyoto (WKY) rats were randomly assigned and treated with bilateral PVN infusion of apigenin or vehicle (artificial cerebrospinal fluid) via osmotic minipumps (20μg/h) for 4weeks. The results showed that after PVN infusion of apigenin, the mean arterial pressure (MAP), heart rate, plasma norepinephrine (NE), Beta 1 receptor in kidneys, level of phosphorylation of PKA in the ventricular tissue and cardiac hypertrophy, perivascular fibrosis, heart level of oxidative stress, PVN levels of oxidative stress, interleukin 1β (IL-1β), interleukin 6 (IL-6), iNOS, monocyte chemotactic protein 1 (MCP-1), tyrosine hydroxylase (TH), NOX2 and NOX4 were attenuated and PVN levels of interleukin 10 (IL-10), superoxide dismutase 1 (Cu/Zn-SOD) and the 67-kDa isoform of glutamate decarboxylase (GAD67) were increased. These results revealed that apigenin improves hypertension and cardiac hypertrophy in SHRs which are associated with the down-regulation of NADPH oxidase-dependent ROS generation and inflammation in the PVN.