Muscarinic Research Articles

Development and Scale-Up of an Enabling Synthetic Route to KTX-005, a Muscarinic Acetylcholine Receptor Agonist for the Potential Treatment of Schizophrenia

Development and Scale-Up of an Enabling Synthetic Route to <b>KTX-005</b>, a Muscarinic Acetylcholine Receptor Agonist for the Potential Treatment of Schizophrenia

Distinct Effects of Olanzapine Depot Treatment on Behavior and Muscarinic M1 Receptor Expression in the Triple-Hit Wisket Rat Model of Schizophrenia.

This study aimed to characterize the triple-hit schizophrenia-like model rats (Wisket) by the assessment of (1) behavioral parameters in different test conditions (reward-based Ambitus test and HomeManner system) for a prolonged period, (2) cerebral muscarinic M1 receptor (M1R) expression, and (3) the effects of olanzapine treatment on these parameters. Wistar (control) and Wisket rats were injected for three consecutive weeks with olanzapine depot (100 mg/kg) and spent 4 weeks in large cages with environmental enrichment (HomeManner). The vehicle-treated Wisket rats spent longer time awake with decreased grooming activity compared to controls, without changes in their active social behavior (sniffing, playing, fighting) obtained in HomeManner. Olanzapine treatment decreased most of these parameters, only the passive social interaction (huddling during sleeping) enhanced mostly in the Wisket rats on the injection day, which recovered within 4 days. In the Ambitus test, vehicle-treated Wisket rats showed lower locomotor and exploratory activities and impaired cognition compared to control rats, deteriorating by olanzapine in both groups. In Wisket brain samples, the M1R mRNA expression was significantly lower in the cerebral cortex and elevated in the hippocampus, with no difference in the prefrontal cortex versus control. Olanzapine normalized the hippocampal M1R expression, but enhanced it in the prefrontal cortex. The triple-hit Wisket model rats had impaired behavioral characteristics in both acute reward-based test and undisturbed circumstances investigated for prolonged periods, and altered cerebral M1R expression. Chronic olanzapine treatment resulted deterioration of some parameters in control group, and could restore only few negative signs in model rats.

Muscarinic cannabinoid suppression of excitation, a novel form of coincidence detection.

Δ9-tetrahydrocannabinol (THC), the chief psychoactive ingredient of cannabis, acts in the brain primarily via cannabinoid CB1 receptors. These receptors are implicated in several forms of synaptic plasticity - depolarization-induced suppression of excitation (DSE), metabotropic suppression of excitation (MSE), long term depression (LTD) and activation-dependent desensitization. Cultured autaptic hippocampal neurons express all of these, illustrating the rich functional and temporal heterogeneity of CB1 at a single set of synapses. Here we report that coincident activation of muscarinic acetylcholine receptors and elicitation of DSE in autaptic hippocampal neurons results in a substantial (~40%) and temporally precise inhibition of excitatory transmission lasting ~10minutes. Its induction is blocked by CB1 and muscarinic M3/M5 receptor antagonists and is absent in CB1 receptor knockout neurons. Notably, once it is established, inhibition is reversed by a CB1, but not a muscarinic, antagonist, suggesting that the inhibition occurs via persistent activation of CB1 receptors. We refer to this inhibition as muscarinic cannabinoid suppression of excitation (MCSE). MCSE can be mimicked by coapplication of muscarinic and cannabinoid agonists and requires Ca2+-release from internal stores. As such, MCSE represents a novel and targeted form of coincidence detection - important for many modes of learning and memory -- between cannabinoid and muscarinic signaling systems that elicits a medium-duration depression of synaptic signaling. Given the known roles of muscarinic and cannabinoid receptors in the hippocampus, MCSE may be important in the modulation of hippocampal signaling at the site of septal inputs, with potential implications for learning and memory, epilepsy and addiction.

Modulatory Effects of Muscarinic M1 Receptor Agonist (VU0364572) in the Cellular Response to Cocaine in the Mice Nucleus Accumbens and Prefrontal Cortex

Modulatory Effects of Muscarinic M1 Receptor Agonist (VU0364572) in the Cellular Response to Cocaine in the Mice Nucleus Accumbens and Prefrontal Cortex

Cholinergic neurotransmission in the brain of streptozotocin-induced rat model of sporadic Alzheimer's disease: long-term follow up.

Rats treated intracerebroventricularly with streptozotocin (STZ-icv) develop pathologic features, which resemble those in Alzheimer's disease and have been proposed as a non-transgenic model for sporadic type of the disease (sAD). We aimed to characterize cholinergic transmission in the rat brain as a function of STZ-icv dose and time after the treatment. Acetylcholinesterase (AChE) activity and expression of muscarinic (M1, M4) and nicotinic (α7) receptors, cholin acetyltransferase (ChAT) and glial fibrillary acidic protein (GFAP) were measured in hippocampus (HPC) and parietotemporal cortex (CTX) of STZ-icv and age-matched control rats one week, and one, three, six and nine months after the icv administration of STZ (0.3, 1 and 3mg/kg), respectively. Cholinergic and astroglial changes were found most pronounced with a highest STZ dose in time-dependent manner. The cortex and hippocampus exhibited specific alterations in cholinergic transmission following STZ-icv administration, with either similar or distinct patterns depending on the parameter observed: increased AChE activity in HPC and invariable in CTX; increased M4 and ChAT levels in both regions; substantial cortical M1 level increment and moderate hippocampal M1 decrement; and decreased α7 levels in both regions, with subsequent increase observed only in HPC. Alterations in cerebral cholinergic neurotransmission in STZ-icv rat model were mostly following a threephasic time pattern: acute response (Phase I), complete/partial compensation (Phase II), and reappearance/progression of changes (Phase III). Staging structure of cholinergic changes in STZ-icv rat model might be speculated to partly correlate with cholinergic pathology in clinical AD stages.

Capturing changes in social functioning and positive affect using ecological momentary assessment during a 12-month trial of xanomeline and trospium chloride in schizophrenia.

Experiential negative symptoms (NS) are determinants of disability in schizophrenia (SCZ). Xanomeline/Trospium Chloride (X/T), an M1/M4 muscarinic receptor agonist, is an approved monotherapy for treatment of schizophrenia, including NS. We used remote ecological momentary assessments (EMA) to track changes in indicators of NS during 12months of outpatient treatment with X/T. After discontinuing previous medications, 566 outpatients with SCZ received open-label X/T monotherapy for up to 12months. Participants completed 3 EMA surveys 7days a week, one week a month. Surveys queried whether participants were home vs. away and alone vs with someone, as well as productive and unproductive activities, and moods. Hierarchical linear modeling (HLM) examined temporal changes and the relationships between the indicators of NS. 500 participants answered one or more EMA surveys and 350 met 33% adherence criteria, answering a total of 40,464 surveys, with overall adherence among these participants at 66%. During treatment with X/T, there were significant decreases in surveys at home (p<.001), alone (p<.001), and engaging in unproductive activities (p<.001). There were significant increases in productive activities both home (p<.001) and away (p<.001) and in positive affect (PA) (p<.001). Improvements in PA converged with reduced unproductive activities, particularly when others were present (p<.001). Behavioral indicators of NS improved early and were sustained with X/T treatment. Improvements were multidimensional, shifting toward more time with others, away from home, and engaged in productive activities. These improvements were associated with increases in PA, consistent with previous EMA studies of NS.

Segmental Regulation of Intestinal Motility by Colitis and the Adaptive Immune System in the Mouse Ileum and Colon.

Gastrointestinal motility disturbances are a hallmark of inflammatory bowel disease (IBD); however, their mechanisms remain unclear. This study used a dextran sulfate sodium-induced colitis mouse model, deficient in mature B and T lymphocytes, to assess intestinal motility and the role of the adaptive immune system in health and IBD. In healthy mice, the absence of adaptive lymphocytes reduced acetylcholine (ACh) sensitivity in the ileum. During colitis, it decreases motility by reducing the intensity and frequency of spontaneous contractions while increasing cholinergic responsiveness. In the proximal colon, adaptive immunity deficiency led to increased contractility and reduced ACh sensitivity in homeostasis, whereas colitis reduced contractile capacity. In the mid colon, immune-deficient mice had reduced ACh sensitivity in homeostasis and exacerbated contractile responses during colitis. In the distal colon, adaptive immunity loss reduced contractility in health and cholinergic responsiveness during colitis. These motility alterations were associated with altered acetylcholinesterase and M2/M3 muscarinic receptor expression. Notably, adaptive lymphocyte deficiency resulted in reduced tissue damage and lower tumor necrosis factor-α expression in the colon during colitis, paralleling intestinal motility changes. Overall, the adaptive immune system critically regulates motility and inflammation across different intestinal segments in IBD.

Muscarinic acetylcholine receptor 3 localized to primary endothelial cilia regulates blood pressure and cognition

We previously demonstrated that the inability of primary endothelial cilia to sense fluid shear stress can lead to nitric oxide (NO) deficiency and cause hypertension (HTN). Decreased biosynthesis of NO contributes to cerebral amyloid angiopathy in Alzheimer’s disease (AD) patients through increased deposition of amyloid beta (Aβ). However, the molecular mechanisms underlying the pathogenesis of HTN and AD are incompletely understood. The objective of this study was to examine the pathophysiological roles of vascular primary cilia and muscarinic acetylcholine receptor 3 (CHRM3) in HTN and AD. We discovered, for the first time, that CHRM3 was localized to primary cilia of endothelial and cerebrovascular cells, and that CHRM3 expression was downregulated in cilialess cells. Moreover, CHRM3 activation enhanced cilia length and sensory function in terms of eNOS activation. To further examine the role of vascular CHRM3 in vivo, we showed that endothelial CHRM3 knockout was associated with increased BP and attenuated acetylcholine-mediated vascular relaxation. In addition, endothelial CHRM3 knockout resulted in altered fear behavior. This demonstrates the physiological significance of endothelial CHRM3 signaling and primary cilia-derived NO production as an important mechanism in the control of BP and cognition.

Scaled and Weighted Laplacian Matrices as Functional Descriptors for GPCR Ligands.

The G protein-coupled receptor (GPCR) pharmacology accounts for a significant field in research, clinical studies, and therapeutics. Computer-aided drug discovery is an evolving suite of techniques and methodologies that facilitate accelerated progress in drug discovery and repositioning. However, the structure-activity relationships of molecules targeting GPCRs are highly challenging in many cases since slight structural modifications can lead to drastic changes in biological functionality. Numerous molecular descriptors have been described, many of which successfully characterize the structural and physicochemical features of drug sets. Nonetheless, elucidating the structure-functionality relationships over extensive sets of drugs with multiple structural variations and known biological activity remains challenging in various biological systems. This work presents novel topological descriptors using Laplacian matrices, weighted, and scaled by atomic mass and partial charges. We tested these descriptors on three sets of GPCR ligands: muscarinic, β-adrenergic, and δ-opioid receptor ligands, evaluating their potential as functional descriptors of these receptors.

Protective Effects of Resveratrol Against Perfluorooctanoic Acid-Induced Testicular and Epididymal Toxicity in Adult Rats Exposed During Their Prepubertal Period

The antioxidant properties of resveratrol (RES) against oxidative toxicity induced by testicular toxicants are well documented. The current study aimed to investigate the probable beneficial role of RES on male reproduction in adult rats following prepubertal exposure to perfluorooctanoic acid (PFOA). Healthy rats of the Wistar strain (23 days old) were allocated into four groups. Rats in group I did not receive any treatment, while rats in groups II, III, and IV received RES, PFOA, and RES + PFOA, respectively, between days 23 and 56 and were monitored for up to 90 days. Exposure to PFOA resulted in a significant reduction in spermiogram parameters, testicular 3β- and 17β-HSD activity levels, and circulatory levels of testosterone. A significant elevation in LPx, PCs, H2O2, and O2−, associated with a concomitant reduction in SOD, CAT, GPx, GR, and GSH, was noticed in the testes, as well as region-specific changes in pro- and antioxidants in the epididymides of exposed rats compared to controls. A significant increase in serum FSH and LH, testicular cholesterol levels, and caspase-3 activity was observed in PFOA-exposed rats compared to controls. Histological analysis revealed that the integrity of the testes was deteriorated in PFOA-exposed rats. Transcriptomic profiling of the testes and epididymides revealed 98 and 611 altered genes, respectively. In the testes, apoptosis and glutathione pathways were disrupted, while in the epididymides, glutathione and bile secretion pathways were altered in PFOA-exposed rats. PFOA exposure resulted in the down-regulation in the testes of 17β-HSD, StAR, nfe2l2, ar, Lhcgr, and mRNA levels, associated with the up-regulation of casp3 mRNA, and down-regulation of alpha 1 adrenoceptor, muscarinic choline receptor 3, and androgen receptor in the epididymides of exposed rats compared to the controls. These events might lead to male infertility in PFOA-exposed rats. In contrast, restoration of selected reproductive variables was observed in RES plus PFOA-exposed rats compared to rats exposed to PFOA alone. Taken together, we postulate that prepubertal exposure to PFOA triggered oxidative damage and altered genes in the testes and epididymides, leading to suppressed male reproductive health in adult rats, while RES, with its steroidogenic, antiapoptotic, and antioxidant effects, restored PFOA-induced fertility potential in rats.

Increased nerve density adversely affects outcome in colorectal cancer and denervation suppresses tumor growth

BackgroundThe colon and rectum are highly innervated, with neural components within the tumor microenvironment playing a significant role in colorectal cancer (CRC) progression. While perineural invasion (PNI) is associated with poor prognosis in CRC, the impact of nerve density and diameter on tumor behavior remains unclear. This study aims to evaluate the prognostic value of nerve characteristics in CRC and to verify the impact of nerves on tumor growth.MethodsTissue samples from 129 CRC patients were stained with immunofluorescent markers NF-L and S100B to detect nerves. Nerve diameter and density were measured and normalized. Kaplan-Meier survival analysis and Cox regression models were used to identify prognostic factors. Prognostic models were established using receiver operating characteristic (ROC) curve analysis to assess the predictive value of neural factors. A murine chemical denervation model was employed to disrupt sympathetic nerves using 6-hydroxydopamine, inhibit muscarinic receptor 3 with darifenacin, and ablate sensory neurons with capsaicin.ResultsThe total nerve density was 0.72 ± 0.59/mm², with intratumoral (0.42 ± 0.40/mm²) being significantly lower than extratumoral regions (1.00 ± 0.75/mm²). The average nerve diameter was 28.14 ± 6.04 μm, with no significant difference between intratumoral (28.2 ± 7.65 μm) and extratumoral regions (27.86 ± 6.72 μm). PNI was observed in 65 patients (50.4%). PNI and high normalized nerve density (NND) were associated with shorter overall survival and disease-free survival in CRC patients, with PNI identified as an independent prognostic factor. Patients with PNI exhibit higher NND. Incorporating PNI and NND into ROC curve analysis improved the sensitivity and specificity of survival predictions. In the murine model, chemical denervation of sympathetic, parasympathetic, and sensory nerves significantly reduced rectal tumor volume.ConclusionsPNI and NND are critical factors influencing CRC patient survival and enhance the accuracy of survival prediction models. Moreover, chemical denervation effectively inhibits rectal tumor growth in vivo, highlighting the potential of neural targeting as a therapeutic strategy in CRC.

Frequency of autoantibodies and their associated clinical characteristics and outcomes in patients with dilated cardiomyopathy: A systematic review and meta-analysis.

Dilated cardiomyopathy (DCM) is a prevalent myocardial disorder characterized by impaired cardiac function affecting either the left ventricle or both ventricles. Accumulating evidence suggests that autoimmunity represents a key mechanism implicated in its pathogenesis, as several abundant autoantibodies have been identified in patients with the condition. However, the prevalence of these antibodies (Abs) in patients with DCM compared to that in both healthy controls (HCs) and those with ischemic cardiomyopathy (ICM), as well as their potential association with DCM, remains unclear. This study aimed to elucidate the prevalence of certain autoantibodies in patients with DCM compared to that in HCs and patients with ICM, as well as to evaluate their correlation with clinical characteristics and outcomes. A comprehensive literature search of the PubMed, Web of Science, EMBASE, the Cochrane Library, and Scopus was conducted up to March 26, 2024, and any article that fulfilled our inclusion criteria was reviewed. A meta-analysis was then conducted, using both random- and fixed-effects models. A total of 38 studies met the inclusion criteria and were pulled for this analysis. Significantly higher prevalence rates of autoantibodies targeting the anti-β1 adrenergic receptor (β1-AR; odds ratio [OR] = 4.96, p = 0.000), M2 muscarinic receptor (M2-R; OR = 4.07, p = 0.000), adenine nucleotide translocator (ANT; OR = 21.18, p = 0.001) and myosin (OR = 12.26, p = 0.000) were observed in patients with DCM compared to HCs. Moreover, patients with DCM exhibited a significantly higher frequency of positive ANT Abs (OR = 34.52, p = 0.005) compared to those with ICM. Regarding clinical characteristics and outcomes, seropositivity for β1-AR Abs was found to be significantly correlated with New York Heart Association (NYHA) classification (standardized mean difference [SMD] = 0.78, p = 0.006), left ventricular ejection fraction (LVEF) (SMD = -1.38, p = 0.001), and heartbeat (HB) (SMD = 1.505, p = 0.022). Seropositivity for anti‑calcium channel Abs was significantly associated with sudden cardiac death (SCD; OR = 3.17, p = 0.000) and all-cause mortality (OR = 2.06, p = 0.008), while anti-troponin I (TnI) Abs were associated with atrial fibrillation (OR = 0.21, p = 0.042). In terms of Ab prevalence rates, significant heterogeneity in the frequency of anti-β1-AR Abs between studies investigating DCM and ICM may be partially explained by the detection methods used and the mean ages of the patients. Meta-regression analysis suggested that the patients' ages may partially explain the observed heterogeneity between studies regarding β1-AR Ab seropositivity and HB. However, the heterogeneity observed in the studies comparing the prevalences of Abs in patients with DCM vs HCs and ICM, as well as their associated clinical characteristics, could not be explained by subgroup analyses or demographic factors such as age and sex-nor by cardiac function. Patients with DCM are more likely to have elevated levels of anti- β1-AR, M2-R, ANT and myosin autoantibodies compared to HCs, as well as higher levels of ANT Abs compared to patients with ICM. Anti-β1-AR, calcium channel, and TnI Abs may play an essential role in DCM severity and poor prognosis. This study represents the first comprehensive meta-analysis regarding autoantibody prevalence and DCM and may thus potentially guide the clinical management of such patients. However, further research is warranted to evaluate the accuracy of this presumed role of autoantibodies in DCM, owing to the small number of the studies included and their high degree of heterogeneity.

Strategic Inhibition of CHRM Autoantibodies: Molecular Insights and Therapeutic Potentials in Long COVID.

In addition to the conventional symptoms reported for COVID-19, it is becoming increasingly clear that patients with long COVID are exhibiting new symptoms due to the emergence of autoantibodies against G-protein-coupled receptors, among which human muscarinic cholinergic receptors (CHRMs) have been prominently reported. With a chronic condition such as long COVID, additional symptoms caused by anti-CHRM autoantibodies (AAbs) have proven to be an added burden on these patients. The origins of these AAbs, their interactions with, and effects on the function of neural and non-neural cells within the nervous system have remained unknown. Furthermore, the specific symptom complex to which they contribute has not been clearly understood. In this context, we address these issues here and suggest methods to combat the autoantibodies that contribute to neurological symptoms in long COVID.

A cholinergic spinal pathway for the adaptive control of breathing.

The ability to amplify motor neuron (MN) output is essential for generating high intensity motor actions. This is critical for breathing that must be rapidly adjusted to accommodate changing metabolic demands. While brainstem circuits generate the breathing rhythm, the pathways that directly augment respiratory MN output are not well understood. Here, we mapped first-order inputs to phrenic motor neurons (PMNs), a key respiratory MN population that initiates diaphragm contraction to drive breathing. We identified a predominant spinal input from a distinct subset of genetically-defined V0 C cholinergic interneurons. We found that these interneurons receive phasic excitation from brainstem respiratory centers, augment phrenic output through M2 muscarinic receptors, and are highly activated under a hypercapnia challenge. Specifically silencing cholinergic interneuron neurotransmission impairs the breathing response to hypercapnia. Collectively, our findings identify a novel spinal pathway that amplifies breathing, presenting a potential target for promoting recovery of breathing following spinal cord injury.

Biological Effects of Calceolarioside A as a Natural Compound: Anti-Ovarian Cancer, Anti-Tyrosinase, and Anti-HMG-CoA Reductase Potentials with Molecular Docking and Dynamics Simulation Studies.

One kind of hydroxycinnamic acid is calceolarioside A. Plantago coronopus, Cassinopsis madagascariensis, and other organisms for whom data are available are known to have this naturally occurring compound. IC50 values of Calceolarioside A for ovarian cell lines (NIH-OVCAR-3, ES-2, UACC-1598, Hs832.Tc, TOV-21G, UWB1.289) were 24.42, 13.50, 9.31, 14.90, 20.07, and 16.18µM, respectively. IC50 values were 19.83 and 73.48µM for tyrosinase and HMG-CoA reductase enzymes. The chemical activities of Calceolarioside A against HMG-CoA reductase and tyrosinase were assessed by conducting the molecular docking study, MM/GBSA calculation, and molecular dynamics (MD) simulation. The anticancer activities of this compound were evaluated against some ovarian cancer cells, such as NIH-OVCAR-3, ES-2, UACC-1598, Hs832.Tc, TOV-21G, and UWB1.289 cell lines. The chemical activities of Calceolarioside A against some of the expressed surface receptor proteins (folate receptor, CD44, EGFR, Formyl Peptide Receptor-Like 1, M2 muscarinic receptor, and estrogen receptors) were investigated using computational methods. The results exhibited the interplay among atoms. The compound formed robust associations with both the enzymes and receptors. Calceolarioside A can hinder the functioning of these enzymes and the proliferation of malignant cells.

Control of cortical slow oscillations and epileptiform discharges with photoswitchable type 1 muscarinic ligands

Abstract Acetylcholine and the cholinergic system are crucial to brain function, including functions like consciousness and cognition. Dysregulation of this system is implicated in the pathophysiology of neurological conditions, such as Alzheimer’s disease. For this reason, cholinergic neuromodulation is relevant in both basic neuroscience and clinical neurology. In this study, we used photopharmacology to modulate neuronal activity using the novel selective type-1 muscarinic (M1) photoswitchable drugs: the agonist benzyl quinolone carboxylic acid–azo-iperoxo (BAI) and the antagonist cryptozepine-2. Our aim was to investigate the control over these cholinergic receptors by means of light, to investigate the effects of these drugs on the physiological spontaneous slow waves and on epileptic activity in the cerebral cortex. We first used transfected HEK cell cultures and demonstrated BAI's preferential activation of M1 muscarinic acetylcholine receptors (mAChRs) compared to M2 mAChRs. Next, we found that white light illumination of BAI increased the frequency of spontaneous slow wave activity in brain cortical networks of both active slices and anesthetized mice, through M1-mAChRs activation. Illumination of cryptozepine-2 with UV light effectively suppressed not only the muscarinic-induced increase slow waves frequency, but also muscarinic-induced epileptiform discharges. These findings not only shed light on the role of M1 acetylcholine receptors in the cortical network dynamics but also lay the ground for developing advanced light-based pharmacological therapies. Photopharmacology offers the potential for high precision spatiotemporal control of brain networks with high pharmacological specificity in both healthy and disease conditions.

A retrospective study on potential drug‒drug interactions in patients with severe asthma receiving biological therapy: a single-center experience

BackgroundPrevalence of potential drug-drug interactions (pDDIs) in adult patients with severe asthma on biological therapy and their clinical significance have not been fully addressed, thus the aim of this study was to investigate them.MethodsIn this retrospective observational study, patients who were diagnosed with severe asthma and to whom biological therapy was prescribed between September 2015 and December 2020, were enrolled. The study was conducted at the Department of Allergic and Obstructive Pulmonary Diseases, Clinic for Lung Diseases Jordanovac, Clinical Hospital Center Zagreb. Data on demographic characteristics as well as concomitant medication were collected. The analysis of pDDIs was conducted via Lexicomp® online software. Interactions of significance levels A and B were only recorded, while those of levels C, D and X were further analysed. The collected data was processed via Microsoft Excel 365 software.Results60 adult patients, 60% female and 40% male, with median age of 56.2 years, were enrolled. The incidence of pDDIs was 86.67%. Total number of pDDIs detected was 518, out of which 43.24%, 45%, 4.44% and 7.3% of clinical significance B, C, D and X. Interactions of level C, D and X were recorded in, as follows: 83.33%, 25% and 33.33% patients with an average of 4.66, 1.53 and 1.9 interactions per patient. Only 13.33% of the patients had none of the potential clinically significant DDI. Most drug pairs contained at least one antiasthmatic drug. Muscarinic receptor antagonists, oral corticosteroids, β2 agonists and methylxanthines showed potential of entering into clinically significant DDIs, while leukotriene antagonists and biologicals showed no potential for the above.ConclusionPrevalence of potential drug-drug interactions in patients with severe asthma on biological therapy is high. The majority of identified interactions have moderate to high level of clinical significance. Their identification, prevention and resolution could contribute to optimizing therapy, maximizing its therapeutic effect and avoiding undesirable adverse events.

11C]MK-6884 PET imaging reveals lower M4 muscarinic acetylcholine receptor availability following cocaine self-administration in male rats.

Cocaine Use Disorder (CUD) remains a significant problem in the United States, with high rates of relapse and no present FDA-approved treatment. The acetylcholine neurotransmitter system, specifically through modulation of muscarinic acetylcholine receptor (mAChR) function, has shown promise as a therapeutic target for multiple aspects of CUD. Enhancement of the M4 mAChR subtype via positive allosteric modulation has been shown to inhibit the behavioral and neurochemical effects of cocaine across several rodent models of CUD. However, it is unclear how cocaine exposure affects M4 mAChR expression or distribution. To evaluate the effects of cocaine self-administration on M4 mAChR availability using [11C]MK-6884 in vivo PET imaging in rats that self-administered cocaine (cocaine SA) or sucrose pellets (control). Sprague-Dawley rats self-administered cocaine or sucrose pellets for 15 days under 2-h or 4-h sessions followed by PET imaging with [11C]MK-6884, a radiolabeled M4 selective positive allosteric modulator to determine the effects of cocaine on [11C]MK-6884 standard uptake values with cerebellum as reference (SUVr). Cumulative cocaine intake ranged between 324 and 776mg/kg. Cocaine self-administration was associated with significantly lower [11C]MK-6884 SUVrs in the cortex, hippocampus, and striatum compared to cocaine-naive rats, with a negative correlation between radiotracer SUVrs and cocaine intake in the hippocampus. These results suggest that cocaine self-administration decreases M4 mAChR availability, providing further support for pursuing activation/enhancement of M4 mAChR function as a viable pharmacotherapeutic approach for CUD.

Audio-vestibular dysfunction in rheumatoid arthritis associated secondary Sjogren syndrome, and its correlation to serum level of anticardiolipin and muscarinic type 3 receptors antibodies: a cross-sectional observational study

BackgroundIn secondary Sjogren syndrome (sSS), the presence and extent of hearing and vestibular abnormalities are controversial. Hence, to ascertain if individuals with Rheumatoid arthritis (RA) associated secondary Sjogren syndrome (sSS) had subclinical audio-vestibular impairment as well as to investigate whether serum anticardiolipin and muscarinic receptors type 3 antibodies had a role in its pathogenesis, this cross-sectional study was conducted on 50 RA patients with secondary Sjogren syndrome manifestations and 50 RA patients without such manifestations were included, along with 50 apparently healthy volunteers who were aged, and sex-matched as controls. Full history taking, Otologic examination, Immunologic evaluation, and Audio-vestibular assessment were done for all subjects.ResultsTwenty-five percent of our patients experienced subjective audio-vestibular symptoms. In the audiogram, 30 (60%) of the 50 RA patients with sSS and 5 (10%) of RA patients without sSS had abnormal hearing loss compared to only 4 (8%) of the controls (p ≤ 0.001) with a predominance of high-frequency sensorineural hearing loss. Also, 20% of our patients experienced a higher frequency of head-shaking nystagmus than they did (p ≤ 0.001). 30% had a statistically significant increase in the frequency of abnormal caloric test results as compared to either controls (0%) or RA patients without sSS (0%); p ≤ 0.001 Finally, all audio-vestibular symptoms and tests exhibit a strong positive correlation with muscarinic receptors type 3 and anticardiolipin antibodies.ConclusionThe use of muscarinic receptors type 3 and anticardiolipin antibodies are beneficial for early diagnosis of audio-vestibular dysfunction in RA-associated secondary Sjogren syndrome patients. Therefore, this study is important since it justifies rheumatologists’ screening for inner ear damage in their RA patients especially if associated with secondary Sjogren.

State-dependent modulation of spiny projection neurons controls levodopa-induced dyskinesia in a mouse model of Parkinson's disease.

In the later stages of Parkinson's disease (PD), patients often manifest levodopa-induced dyskinesia (LID), compromising their quality of life. The pathophysiology underlying LID is poorly understood, and treatment options are limited. To move toward filling this treatment gap, the intrinsic and synaptic changes in striatal spiny projection neurons (SPNs) triggered by the sustained elevation of dopamine (DA) during dyskinesia were characterized using electrophysiological, pharmacological, molecular and behavioral approaches. Our studies revealed that the intrinsic excitability and functional corticostriatal connectivity of SPNs in dyskinetic mice oscillate between the on- and off-states of LID in a cell- and state-specific manner. Although triggered by levodopa, these rapid oscillations in SPN properties depended on both dopaminergic and cholinergic signaling. In a mouse PD model, disrupting M1 muscarinic receptor signaling specifically in iSPNs or deleting its downstream signaling partner CalDAG-GEFI blunted the levodopa-induced oscillation in functional connectivity, enhanced the beneficial effects of levodopa and attenuated LID severity.