Profiling the combination of bupropion and dextromethorphan as a treatment option for major depressive disorder.

INTRODUCTION: Major Depressive Disorder (MDD) is a common mental health disorder marked by sadness, hopelessness, and anhedonia. Various therapies exist, but their effectiveness is limited. Dextromethorphan hydrobromide combined with bupropion hydrochloride (Auvelity®) is a recently approved alternative for treating this condition in adults. AREAS COVERED: This review summarizes the neurobiology of major depression and delves into the pharmacology, efficacy, safety, and tolerability of dextromethorphan plus bupropion in adult patients. It is based on observational studies, clinical trials, and other secondary studies obtained through systematic literature searches. EXPERT OPINION: The combination of bupropion and dextromethorphan as a new pharmacotherapy for mental health is an interesting addition to the treatment options that can be used for MDD. The combination can be used in a range of scenarios, including as a first line therapy, as a second option when a patient has failed to achieve remission with a serotonin targeting agent, and for treatment resistant depression. Further research for other indications, including addiction disorders, may provide exciting results. Although a new combination, clinicians will be very familiar with both agents, increasing their acceptability. This pharmacotherapy also may bring increased impetus for discovering other combinations that may have beneficial synergistic effects.

SCA44- and SCAR13-associated GRM1 mutations affect metabotropic glutamate receptor 1 function through distinct mechanisms.

BACKGROUND AND PURPOSE: Metabotropic glutamate receptor 1 (mGlu1) is a promising therapeutic target for neurodegenerative CNS disorders including spinocerebellar ataxias (SCAs). Clinical reports have identified naturally-occurring mGlu1 mutations in rare SCA subtypes and linked symptoms to mGlu1 mutations. However, how mutations alter mGlu1 function remains unknown, as does amenability of receptor function to pharmacological rescue. Here, we explored SCA-associated mutation effects on mGlu1 cell surface expression, canonical signal transduction and allosteric ligand pharmacology. EXPERIMENTAL APPROACH: Orthosteric agonists, positive allosteric modulators (PAMs) and negative allosteric modulators (NAMs) were assessed at two functional endpoints (iCa2+ mobilisation and inositol 1-phosphate [IP1] accumulation) in FlpIn Trex HEK293A cell lines expressing five mutant mGlu1 subtypes. Key pharmacological parameters including ligand potency, affinity and cooperativity were derived using operational models of agonism and allostery. KEY RESULTS: mGlu1 mutants exhibited differential impacts on mGlu1 expression, with a C-terminus truncation significantly reducing surface expression. Mutations differentially influenced orthosteric ligand affinity, efficacy and functional cooperativity between allosteric and orthosteric ligands. Loss-of-function mutations L454F and N885del reduced orthosteric affinity and efficacy, respectively. A gain-of-function Y792C mutant mGlu1 displayed enhanced constitutive activity in IP1 assays, which manifested as reduced orthosteric agonist activity. The mGlu1 PAMs restored glutamate potency in iCa2+ mobilisation for loss-of-function mutations and mGlu1 NAMs displayed enhanced inverse agonist activity at Y792C relative to wild-type mGlu1. CONCLUSION AND IMPLICATIONS: Collectively, these data highlight distinct mechanisms by which mGlu1 mutations affect receptor function and show allosteric modulators may present a therapeutic strategy to restore aberrant mGlu1 function in rare SCA subtypes.

Gut microbiota signatures of vulnerability to food addiction in mice and humans.

OBJECTIVE: Food addiction is a multifactorial disorder characterised by a loss of control over food intake that may promote obesity and alter gut microbiota composition. We have investigated the potential involvement of the gut microbiota in the mechanisms underlying food addiction. DESIGN: We used the Yale Food Addiction Scale (YFAS) 2.0 criteria to classify extreme food addiction in mouse and human subpopulations to identify gut microbiota signatures associated with vulnerability to this disorder. RESULTS: Both animal and human cohorts showed important similarities in the gut microbiota signatures linked to food addiction. The signatures suggested possible non-beneficial effects of bacteria belonging to the Proteobacteria phylum and potential protective effects of Actinobacteria against the development of food addiction in both cohorts of humans and mice. A decreased relative abundance of the species Blautia wexlerae was observed in addicted humans and of Blautia genus in addicted mice. Administration of the non-digestible carbohydrates, lactulose and rhamnose, known to favour Blautia growth, led to increased relative abundance of Blautia in mice faeces in parallel with dramatic improvements in food addiction. A similar improvement was revealed after oral administration of Blautia wexlerae as a beneficial microbe. CONCLUSION: By understanding the crosstalk between this behavioural alteration and gut microbiota, these findings constitute a step forward to future treatments for food addiction and related eating disorders.

Symptomatic Treatment of Extrapyramidal Hyperkinetic Movement Disorders.

Extrapyramidal hyperkinetic movement disorders comprise a broad range of phenotypic phenomena, including chorea, dystonia, and tics. Treatment is generally challenging and individualized, given the overlapping phenomenology, limited evidence regarding efficacy, and concerns regarding the tolerability and safety of most treatments. Over the past decade, the treatment has become even more intricate due to advancements in the field of deep brain stimulation as well as optimized dopamine- depleting agents. Here, we review the current evidence for treatment modalities of extrapyramidal hyperkinetic movement disorders and provide a comprehensive and practical overview to aid the choice of therapy. Mechanism of action and practical intricacies of each treatment modality are discussed, focusing on dosing and adverse effect management. Finally, future therapeutic developments are also discussed.

Kratom safety and toxicology in the public health context: research needs to better inform regulation.

Although kratom use has been part of life for centuries in Southeast Asia, the availability and use of kratom in the United States (US) increased substantially since the early 2000s when there was little information on kratom pharmacology, use patterns, and effects, all critical to guiding regulation and policy. Here we provide a synthesis of research with several hundred English-language papers published in the past 5 years drawing from basic research, epidemiological and surveillance data, and recent clinical research. This review of available literature aims to provide an integrated update regarding our current understanding of kratom's benefits, risks, pharmacology, and epidemiology, which may inform United States-based kratom regulation. Recent surveillance indicates there are likely several million past-year kratom consumers, though estimates vary widely. Even without precise prevalence data, kratom use is no longer a niche, with millions of United States adults using it for myriad reasons. Despite its botanical origins in the coffee tree family and its polypharmacy, kratom is popularly characterized as an opioid with presumed opioid-system-based risks for addiction or overdose. Neuropharmacology, toxicology, and epidemiology studies show that kratom is more accurately characterized as a substance with diverse and complex pharmacology. Taken together the work reviewed here provides a foundation for future scientific studies, as well as a guide for ongoing efforts to regulate kratom. This work also informs much-needed federal oversight, including by the United States Food and Drug Administration. We conclude with recommendations for kratom regulation and research priorities needed to address current policy and knowledge gaps around this increasingly used botanical product.

Evidence for sodium valproate toxicity in mitochondrial diseases: a systematic analysis.

Background: We aimed to determine whether sodium valproate (VPA) should be contraindicated in all mitochondrial diseases, due to known VPA-induced severe hepatotoxicity in some mitochondrial diseases. Methods: We systematically reviewed the published literature for mitochondrial DNA (mtDNA) and common nuclear genotypes of mitochondrial diseases using PubMed, Ovid Embase, Ovid Medline and MitoPhen databases. We extracted patient-level data from peer-reviewed articles, published until July 2022, using the Human Phenotype Ontology to manually code clinical presentations for 156 patients with genetic diagnoses from 90 publications. Results: There were no fatal adverse drug reactions (ADRs) in the mtDNA disease group (35 patients), and only 1 out of 54 patients with a non-POLG mitochondrial disease developed acute liver failure. There were fatal outcomes in 53/102 (52%) POLG VPA-exposed patients who all harboured recessive mutations. Conclusions: Our findings confirm the high risk of severe ADRs in any patient with recessive POLG variants irrespective of the phenotype, and therefore recommend that VPA is contraindicated in this group. However, there was limited evidence of toxicity to support a similar recommendation in other genotypes of mitochondrial diseases.

Mapping the molecular motions of 5-HT3 serotonin-gated channel by voltage-clamp fluorometry.

The serotonin-gated ion channel (5-HT3R) mediates excitatory neuronal communication in the gut and the brain. It is the target for setrons, a class of competitive antagonists widely used as antiemetics, and is involved in several neurological diseases. Cryo-electron microscopy (cryo-EM) of the 5-HT3R in complex with serotonin or setrons revealed that the protein has access to a wide conformational landscape. However, assigning known high-resolution structures to actual states contributing to the physiological response remains a challenge. In the present study, we used voltage-clamp fluorometry (VCF) to measure simultaneously, for 5-HT3R expressed at a cell membrane, conformational changes by fluorescence and channel opening by electrophysiology. Four positions identified by mutational screening report motions around and outside the serotonin-binding site through incorporation of cysteine-tethered rhodamine dyes with or without a nearby quenching tryptophan. VCF recordings show that the 5-HT3R has access to four families of conformations endowed with distinct fluorescence signatures: 'resting-like' without ligand, 'inhibited-like' with setrons, 'pre-active-like' with partial agonists, and 'active-like' (open channel) with partial and strong agonists. Data are remarkably consistent with cryo-EM structures, the fluorescence partners matching respectively apo, setron-bound, 5-HT bound-closed, and 5-HT-bound-open conformations. Data show that strong agonists promote a concerted motion of all fluorescently labeled sensors during activation, while partial agonists, especially when loss-of-function mutations are engineered, stabilize both active and pre-active conformations. In conclusion, VCF, though the monitoring of electrophysiologically silent conformational changes, illuminates allosteric mechanisms contributing to signal transduction and their differential regulation by important classes of physiological and clinical effectors.

Multimodal data fusion reveals functional and neurochemical correlates of Parkinson's disease.

BACKGROUND: Neurotransmitter deficits and spatial associations among neurotransmitter distribution, brain activity, and clinical features in Parkinson's disease (PD) remain unclear. Better understanding of neurotransmitter impairments in PD may provide potential therapeutic targets. Therefore, we aimed to investigate the spatial relationship between PD-related patterns and neurotransmitter deficits. METHODS: We included 59 patients with PD and 41 age- and sex-matched healthy controls (HCs). The voxel-wise mean amplitude of the low-frequency fluctuation (mALFF) was calculated and compared between the two groups. The JuSpace toolbox was used to test whether spatial patterns of mALFF alterations in patients with PD were associated with specific neurotransmitter receptor/transporter densities. RESULTS: Compared to HCs, patients with PD showed reduced mALFF in the sensorimotor- and visual-related regions. In addition, mALFF alteration patterns were significantly associated with the spatial distribution of the serotonergic, dopaminergic, noradrenergic, glutamatergic, cannabinoid, and acetylcholinergic neurotransmitter systems (p < 0.05, false discovery rate-corrected). CONCLUSIONS: Our results revealed abnormal brain activity patterns and specific neurotransmitter deficits in patients with PD, which may provide new insights into the mechanisms and potential targets for pharmacotherapy.

Expression of the apelin receptor, a novel potential therapeutic target, and its endogenous ligands in diverse stem cell populations in human glioblastoma.

Glioblastoma multiforme (GBM) is one of the most common and lethal forms of brain cancer, carrying a very poor prognosis (median survival of ~15 months post-diagnosis). Treatment typically involves invasive surgical resection of the tumour mass, followed by radiotherapy and adjuvant chemotherapy using the alkylating agent temozolomide, but over half of patients do not respond to this drug and considerable resistance is observed. Tumour heterogeneity is the main cause of therapeutic failure, where diverse progenitor glioblastoma stem cell (GSC) lineages in the microenvironment drive tumour recurrence and therapeutic resistance. The apelin receptor is a class A GPCR that binds two endogenous peptide ligands, apelin and ELA, and plays a role in the proliferation and survival of cancer cells. Here, we used quantitative whole slide immunofluorescent imaging of human GBM samples to characterise expression of the apelin receptor and both its ligands in the distinct GSC lineages, namely neural-progenitor-like cells (NPCs), oligodendrocyte-progenitor-like cells (OPCs), and mesenchymal-like cells (MES), as well as reactive astrocytic cells. The data confirm the presence of the apelin receptor as a tractable drug target that is common across the key cell populations driving tumour growth and maintenance, offering a potential novel therapeutic approach for patients with GBM.

Enhancing Cognitive Functions and Neuronal Growth through NPY1R Agonist and Ketamine Co-Administration: Evidence for NPY1R-TrkB Heteroreceptor Complexes in Rats.

This study investigates the combined effects of the neuropeptide Y Y1 receptor (NPY1R) agonist [Leu31-Pro34]NPY at a dose of 132 µg and Ketamine at 10 mg/Kg on cognitive functions and neuronal proliferation, against a backdrop where neurodegenerative diseases present an escalating challenge to global health systems. Utilizing male Sprague-Dawley rats in a physiological model, this research employed a single-dose administration of these compounds and assessed their impact 24 h after treatment on object-in-place memory tasks, alongside cellular proliferation within the dorsal hippocampus dentate gyrus. Methods such as the in situ proximity ligation assay and immunohistochemistry for proliferating a cell nuclear antigen (PCNA) and doublecortin (DCX) were utilized. The results demonstrated that co-administration significantly enhanced memory consolidation and increased neuronal proliferation, specifically neuroblasts, without affecting quiescent neural progenitors and astrocytes. These effects were mediated by the potential formation of NPY1R-TrkB heteroreceptor complexes, as suggested by receptor co-localization studies, although further investigation is required to conclusively prove this interaction. The findings also highlighted the pivotal role of brain-derived neurotrophic factor (BDNF) in mediating these effects. In conclusion, this study presents a promising avenue for enhancing cognitive functions and neuronal proliferation through the synergistic action of the NPY1R agonist and Ketamine, potentially via NPY1R-TrkB heteroreceptor complex formation, offering new insights into therapeutic strategies for neurodegenerative diseases.

Effects of sex and hydration status on kappa opioid receptor-mediated diuresis in rats.

Understanding the function of the kappa opioid receptor (KOP) is crucial for the development of novel therapeutic interventions that target KOP for the treatment of pain, stress-related disorders and other indications. Activation of KOP produces diuretic effects in rodents and man. Sex is a vital factor to consider when assessing drug response in pre-clinical and clinical studies. In this study, the diuretic effect of the KOP agonist, U50488 (1-10 mg/kg), was investigated in both adult female and male Wistar rats that were either normally hydrated or water-loaded. The KOP antagonist norbinaltorphimine (norBNI, 10 mg/kg) was administered 24 h prior to U50488 to confirm the involvement of KOP. U50488 elicited a significant diuretic response at doses ≥ 3 mg/kg in both female and male rats independent of hydration status. U50488 diuretic effects were inhibited by norBNI pre-administration. Water-loading reduced data variability for urine volume in males, but not in females, compared with normally hydrated rats. Sex differences were also evident in U50488 eliciting a significant increase in sodium and potassium ion excretion only in males. This may suggest different mechanisms of U50488 diuretic action in males where renal excretion mechanisms are directly affected more than in females.

Building a pediatric neurocritical care program: The role of the clinical pharmacist practitioner on clinical practice and education. A curriculum for neuropharmacology training.

Clinical pharmacists are a part of the integrated health care team and provide valuable input on medication management for patients with acute and chronic disease states. Using epilepsy as a model, pharmacist involvement in patient care has been associated with significant reductions in monthly seizure frequency. Given differences in etiology, pediatric patients with epilepsy are likely to have higher number of treatments, with additional pharmacodynamic and pharmacokinetic differences, adding to the importance of utilizing a pediatric clinical pharmacist practitioner with neuropharmacology expertise. There is an increasing exposure to critically ill patients with epilepsy and other neurological disorders in the pediatric intensive care unit (PICU). These patients are more medically complex, increasing the risk for medication errors and increased health care costs. Emphasis on neurocritical care education is a vital component to improving patient outcomes. Inclusion of a clinical pharmacist practitioner in these settings yields a positive impact on major health outcomes. In 2018, the Neurocritical Care Society developed consensus recommendations on the standards for the development of adult neurocritical care units. A pharmacist-delivered pediatric critical care neuropharmacology rotation represents a novel approach to expanding physician education to improve patient outcomes. While there are sparse publications highlighting the importance of adult critical care and NCC pharmacists, no such literature exists describing the benefits of pediatric neurocritical care (PNCC) pharmacists. To the best of our knowledge, this is the first manuscript describing the role of clinical pharmacist practitioners in the development of PNCC program and the benefits they provide to patient care and education.

Neuropharmacological assessment and identification of possible lead compound (apomorphine) from Hygrophila spinosa through in-vivo and in-silico approaches.

The aim of this research is to examine possible neurological activity of methanol, ethyl acetate, and aqueous extracts of Hygrophila spinosa and identify possible lead compounds through in silico analysis. In vivo, neuropharmacological activity was evaluated by using four distinct neuropharmacological assessment assays. Previously reported GC-MS data and earlier literature were utilized to identify the phytochemicals present in Hygrophila spinosa. Computational studies notably molecular docking and molecular dynamic simulations were conducted with responsible receptors to assess the stability of the best interacting compound. Pharmacokinetics properties like absorption, distribution, metabolism, excretion, and toxicity were considered to evaluate the drug likeliness properties of the identified compounds. All the in vivo results support the notion that different extracts (methanol, ethyl acetate, and aqueous) of Hygrophila spinosa have significant (*p = 0.05) sedative-hypnotic, anxiolytic, and anti-depressant activity. Among all the extracts, specifically methanol extracts of Hygrophila spinosa (MHS 400 mg/kg.b.w.) showed better sedative, anxiolytic and antidepressant activity than aqueous and ethyl acetate extracts. In silico molecular docking analysis revealed that among 53 compounds 7 compounds showed good binding affinities and one compound, namely apomorphine (CID: 6005), surprisingly showed promising binding affinity to all the receptors . An analysis of molecular dynamics simulations confirmed that apomorphine (CID: 6005) had a high level of stability at the protein binding site. Evidence suggests that Hygrophila spinosa has significant sedative, anxiolytic, and antidepressant activity. In silico analysis revealed that a particular compound (apomorphine) is responsible for this action. Further research is required in order to establish apomorphine as a drug for anxiety, depression, and sleep disorders.Communicated by Ramaswamy H. Sarma.

Neurogenin-2 induced neuronal differentiation in co-cultured bone marrow stromal and neonatal cortical cells.

Objective: To explore a novel and dynamic role for neurogenin-2 in promoting cortical neurogenesis in cells produced from co-culturing neonatal cortical neural progenitor cells with bone marrow stromal cells. METHODS: The experimental study was conducted from June 2016 to January 2019 at the neuropharmacology laboratory of the Hussein Ebrahim Jamal Research Institute of Chemistry, International Centre for Chemical and Biological Sciences, Karachi. The growth of cells at different stages in harvested cells was determined by 3-(4, 5- dimethyl thiazol-2-yl)-2, 5-diphenyl tetrazolium bromide assay. Immunocytochemistry was used to evaluate the protein expressions of neuronal markers and transcription factors. Data was analysed using SPSS 20. RESULTS: Data showed significant generation of neuronal cells and this was also verified by increased expression of nesting in cortical co-cultures with bone marrow stromal cells. Immunoreactive outcomes showed over expressions in co-cultured chlorotoxin cells. Subsequently, neurogenin-2 was found intermixed with induced expressions of transcriptional factor NeuroD1 and reduced glial fibrillary acidic protein-labelled cells. Conclusion: Better understanding of the mechanisms underlying transcriptional modulation of neurogenic events hold the key for emerging treatment approaches towards neurodegeneration.

Alzheimer's therapeutic development: shifting neurodegeneration to neuroregeneration.

Alzheimer's disease (AD), similar to AD-related dementias, is characterized by impaired/lost neuronal structures and functions due to a long progression of neurodegeneration. Derailed endogenous signal pathways and disease processes have critical roles in neurodegeneration and are pharmacological targets in inducing neuroregeneration. Pharmacologically switching/shifting the brain status from neurodegeneration to neuroregeneration is emerging as a new therapeutic concept, one that is not only achievable, but also essential for effective therapy for AD. The results of the pharmacological-induced shift from neurodegeneration to neuroregeneration are twofold: arresting cognitive deterioration (and directing the brain toward cognitive recovery) in established AD, and preventing neurodegeneration through building up cognitive resilience in patients with preclinical or probable AD. In this review, we discuss these new developments in AD pharmacology and relevant clinical trials.

Evaluation of Medication Exposure on Exacerbation of Disease in Patients With Myasthenia Gravis.

Background and Purpose: In patients with myasthenia gravis (MG), worsening of symptoms poses a risk of respiratory failure which can be precipitated by medication use. Although purported, the risks associated with administration of certain medications are not fully elucidated. Thus, clinical decision support involving a best practice alert was executed to caution providers of drug-disease interactions when ordering a potentially harmful medication. We performed an analysis of the alert overrides with subsequent medication exposure to determine the incidence of MG exacerbations. Methods: This retrospective chart-review evaluated adult patients with MG at 2 large academic medical centers via electronic health records between November-2019 and November-2021 who received a medication following override of the clinical decision support tool. The primary outcome was proportion of patient encounters complicated by myasthenic exacerbations after potentially harmful medication administration. Secondary outcomes included changes in motor strength, length of stay, discharge disposition, unplanned level-of-care escalations, and changes to immunosuppressant therapy following medication administration. Results: A total of 70 orders were assessed in 38 patients across 55 encounters. Medications administered during these encounters included macrolides, fluoroquinolones, ß-blockers, calcium channel blockers, and magnesium sulfate. Exacerbation of disease occurred in 7 patient encounters (12.7%) and occurred after intravenous magnesium or intravenous labetalol. In 5/7 events, at least 1 other risk factor associated with a myasthenic exacerbation was present. Conclusions: Of the medications reported to potentially worsen MG, intravenous labetalol and intravenous magnesium were the 2 agents associated with myasthenic exacerbations with a higher incidence in patients harboring additional risk factors.