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International Journal For Vitamin and... Jun 2024A healthy and balanced diet is an important factor to assure a good functioning of the central and peripheral nervous system. Retinoid X receptor (RXR)-mediated... (Review)
Review
A healthy and balanced diet is an important factor to assure a good functioning of the central and peripheral nervous system. Retinoid X receptor (RXR)-mediated signaling was identified as an important mechanism of transmitting major diet-dependent physiological and nutritional signaling such as the control of myelination and dopamine signalling. Recently, vitamin A5/X, mainly present in vegetables as provitamin A5/X, was identified as a new concept of a vitamin which functions as the nutritional precursor for enabling RXR-mediated signaling. The active form of vitamin A5/X, 9--13,14-dehydroretinoic acid (9CDHRA), induces RXR-activation, thereby acting as the central switch for enabling various heterodimer-RXR-signaling cascades involving various partner heterodimers like the fatty acid and eicosanoid receptors/peroxisome proliferator-activated receptors (PPARs), the cholesterol receptors/liver X receptors (LXRs), the vitamin D receptor (VDR), and the vitamin A(1) receptors/retinoic acid receptors (RARs). Thus, nutritional supply of vitamin A5/X might be a general nutritional-dependent switch for enabling this large cascade of hormonal signaling pathways and thus appears important to guarantee an overall organism homeostasis. RXR-mediated signaling was shown to be dependent on vitamin A5/X with direct effects for beneficial physiological and neuro-protective functions mediated systemically or directly in the brain. In summary, through control of dopamine signaling, amyloid β-clearance, neuro-protection and neuro-inflammation, the vitamin A5/X - RXR - RAR - vitamin A(1)-signaling might be "one of" or even "the" critical factor(s) necessary for good mental health, healthy brain aging, as well as for preventing drug addiction and prevention of a large array of nervous system diseases. Likewise, vitamin A5/X - RXR - non-RAR-dependent signaling relevant for myelination/re-myelination and phagocytosis/brain cleanup will contribute to such regulations too. In this review we discuss the basic scientific background, logical connections and nutritional/pharmacological expert recommendations for the nervous system especially considering the ageing brain.
Topics: Humans; Retinoid X Receptors; Diet; Signal Transduction; Mental Health; Animals
PubMed: 38904956
DOI: 10.1024/0300-9831/a000808 -
Current Findings and Potential Mechanisms of KarXT (Xanomeline-Trospium) in Schizophrenia Treatment.Clinical Drug Investigation Jun 2024Standard schizophrenia treatment involves antipsychotic medications that target D2 dopamine receptors. However, these drugs have limitations in addressing all symptoms... (Review)
Review
Standard schizophrenia treatment involves antipsychotic medications that target D2 dopamine receptors. However, these drugs have limitations in addressing all symptoms and can lead to adverse effects such as motor impairments, metabolic effects, sedation, sexual dysfunction, cognitive impairment, and tardive dyskinesia. Recently, KarXT has emerged as a novel drug for schizophrenia. KarXT combines xanomeline, a muscarinic receptor M1 and M4 agonist, with trospium, a nonselective antimuscarinic agent. Of note, xanomeline can readily cross blood-brain barrier (BBB) and, thus, enter into the brain, thereby stimulating muscarinic receptors (M1 and M4). By doing so, xanomeline has been shown to target negative symptoms and potentially improve positive symptoms. Trospium, on the other hand, is not able to cross BBB, thereby not affecting M1 and M4 receptors; instead, it acts as an antimuscarinic agent and, hence, diminishes peripheral activity of muscarinic receptors to minimize side effects probably stemming from xanomeline in other organs. Accordingly, ongoing clinical trials investigating KarXT's efficacy in schizophrenia have demonstrated positive outcomes, including significant improvements in the Positive and Negative Syndrome Scale (PANSS) total score and cognitive function compared with placebo. These findings emphasize the potential of KarXT as a promising treatment for schizophrenia, providing symptom relief while minimizing side effects associated with xanomeline monotherapy. Despite such promising evidence, further research is needed to confirm the efficacy, safety, and tolerability of KarXT in managing schizophrenia. This review article explores the current findings and potential mechanisms of KarXT in the treatment of schizophrenia.
PubMed: 38904739
DOI: 10.1007/s40261-024-01377-9 -
Cerebral Cortex (New York, N.Y. : 1991) Jun 2024Serotonin (5-HT) regulates working memory within the prefrontal cortex network, which is crucial for understanding obsessive-compulsive disorder. However, the mechanisms...
Serotonin (5-HT) regulates working memory within the prefrontal cortex network, which is crucial for understanding obsessive-compulsive disorder. However, the mechanisms how network dynamics and serotonin interact in obsessive-compulsive disorder remain elusive. Here, we incorporate 5-HT receptors (5-HT1A, 5-HT2A) and dopamine receptors into a multistable prefrontal cortex network model, replicating the experimentally observed inverted U-curve phenomenon. We show how the two 5-HT receptors antagonize neuronal activity and modulate network multistability. Reduced binding of 5-HT1A receptors increases global firing, while reduced binding of 5-HT2A receptors deepens attractors. The obtained results suggest reward-dependent synaptic plasticity mechanisms may attenuate 5-HT related network impairments. Integrating serotonin-mediated dopamine release into circuit, we observe that decreased serotonin concentration triggers the network into a deep attractor state, expanding the domain of attraction of stable nodes with high firing rate, potentially causing aberrant reverse learning. This suggests a hypothesis wherein elevated dopamine concentrations in obsessive-compulsive disorder might result from primary deficits in serotonin levels. Findings of this work underscore the pivotal role of serotonergic dysregulation in modulating synaptic plasticity through dopamine pathways, potentially contributing to learned obsessions. Interestingly, serotonin reuptake inhibitors and antidopaminergic potentiators can counteract the over-stable state of high-firing stable points, providing new insights into obsessive-compulsive disorder treatment.
Topics: Prefrontal Cortex; Obsessive-Compulsive Disorder; Serotonin; Humans; Dopamine; Models, Neurological; Receptors, Dopamine; Nerve Net; Computer Simulation; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Neuronal Plasticity; Receptor, Serotonin, 5-HT1A
PubMed: 38904079
DOI: 10.1093/cercor/bhae258 -
Frontiers in Neuroscience 2024Dopamine (DA) plays a pivotal role in reward processing, cognitive functions, and emotional regulation. The prefrontal cortex (PFC) is a critical brain region for these...
Dopamine (DA) plays a pivotal role in reward processing, cognitive functions, and emotional regulation. The prefrontal cortex (PFC) is a critical brain region for these processes. Parvalbumin-positive (PV+) neurons are one of the major classes of inhibitory GABAergic neurons in the cortex, they modulate the activity of neighboring neurons, influencing various brain functions. While DA receptor expression exhibits age-related changes, the age-related changes of these receptors in PV+ neurons, especially in the PFC, remain unclear. To address this, we investigated the expression of DA D1 (D1R) and D2 (D2R) receptors in PV+ neurons within the orbitofrontal (OFC) and prelimbic (PrL) cortices at different postnatal ages (P28, P42, P56, and P365). We found that the expression of D1R and D2R in PV+ neurons showed both age- and region-related changes. PV+ neurons in the OFC expressed a higher abundance of D1 than those in the PrL, and those neurons in the OFC also showed higher co-expression of D1R and D2R than those in the PrL. In the OFC and PrL, D1R in PV+ neurons increased from P28 and reached a plateau at P42, then receded to express at P365. Meanwhile, D2R did not show significant age-related changes between the two regions except at P56. These results showed dopamine receptors in the prefrontal cortex exhibit age- and region-specific changes, which may contribute to the difference of these brain regions in reward-related brain functions.
PubMed: 38903598
DOI: 10.3389/fnins.2024.1364067 -
Psychiatry Research Jun 2024The risk of fatal choking for people with schizophrenia and associations with antipsychotic medication are largely unknown. Therefore, we calculated the choking-related...
The risk of fatal choking for people with schizophrenia and associations with antipsychotic medication are largely unknown. Therefore, we calculated the choking-related standardized mortality ratio for schizophrenia relative to the general population (SMR). We also computed adjusted hazard ratios (aHR) of choking-related mortality for antipsychotics in a nationwide cohort of patients with schizophrenia (N = 59,916). SMR was 20.5 (95 % confidence interval (CI)=17.1-23.9). The aHR was 1.74 (95 %CI=1.19-2.55) for strong dopamine 2-antagonists. For other antipsychotics, CIs included 1. Importantly, aHRs were particularly high for high dose categories of strong dopamine D2 receptor (D2R) antagonists. In conclusion, a schizophrenia diagnosis is associated with a 20-fold risk of death due to choking. This risk is elevated during use of strong D2R antagonist antipsychotics, particularly when prescribed in high dosages.
PubMed: 38901365
DOI: 10.1016/j.psychres.2024.116012 -
Journal of Pharmaceutical and... Jun 2024Traditional Chinese medicines (TCMs) are popular in clinic because of their safety and efficacy. They contain abundant natural active compounds, which are important...
Traditional Chinese medicines (TCMs) are popular in clinic because of their safety and efficacy. They contain abundant natural active compounds, which are important sources of new drug discovery. However, how to efficiently identify active compounds from complex ingredients remains a challenge. In this study, a method combining UHPLC-MS/MS characterization and in silico screening was developed to discover compounds with dopamine D2 receptor (D2R) activity in Stephania epigaea (S. epigaea). By combining the compounds identified in S. epigaea by UHPLC-MS/MS with reported compounds, a virtual library of 80 compounds was constructed for in silico screening. Potentially active compounds were chosen based on screening scores and subsequently tested for in vitro activity on a transfected cell line CHO-K1-D2 model using label-free cellular phenotypic assay. Three D2R agonists and five D2R antagonists were identified. (-)-Asimilobine, N-nornuciferine and (-)-roemerine were reported for the first time as D2R agonists, with EC values of 0.35 ± 0.04 μM, 1.37 ± 0.10 μM and 0.82 ± 0.22 μM, respectively. Their target specificity was validated by desensitization and antagonism assay. (-)-Isocorypalmine, (-)-tetrahydropalmatine, (-)-discretine, (+)-corydaline and (-)-roemeroline showed strong antagonistic activity on D2R with IC values of 92 ± 9.9 nM, 1.73 ± 0.13 μM, 0.34 ± 0.02 μM, 2.09 ± 0.22 μM and 0.85 ± 0.08 μM, respectively. Their kinetic binding profiles were characterized using co-stimulation assay and they were both D2R competitive antagonists. We docked these ligands with human D2R crystal structure and analyzed the structure-activity relationship of aporphine-type D2R agonists and protoberberine-type D2R antagonists. These results would help to elucidate the mechanism of action of S. epigaea for its analgesic and sedative efficacy and benefit for D2R drug design. This study demonstrated the potential of integrating UHPLC-MS/MS with in silico and in vitro screening for accelerating the discovery of active compounds from TCMs.
PubMed: 38901158
DOI: 10.1016/j.jpba.2024.116289 -
Journal of Clinical PsychopharmacologyDeutetrabenazine is approved for adults with tardive dyskinesia (TD). Data based on underlying psychiatric condition and baseline dopamine receptor antagonist (DRA) use...
Deutetrabenazine Provides Long-Term Benefit for Tardive Dyskinesia Regardless of Underlying Condition and Dopamine Receptor Antagonist Use: A Post Hoc Analysis of the 3-Year, Open-Label Extension Study.
BACKGROUND
Deutetrabenazine is approved for adults with tardive dyskinesia (TD). Data based on underlying psychiatric condition and baseline dopamine receptor antagonist (DRA) use are limited.
METHODS
Patients with TD who completed parent studies ARM-TD or AIM-TD were eligible for the 3-year, open-label extension study (RIM-TD; NCT02198794). In RIM-TD, deutetrabenazine was titrated based on dyskinesia control and tolerability. In this post hoc analysis of RIM-TD, total motor Abnormal Involuntary Movement Scale (AIMS) score and adverse events (AEs) were analyzed by underlying condition and DRA use at parent study baseline.
RESULTS
Of 343 patients enrolled in RIM-TD, 336 were included in the analysis by underlying condition, and 337 were included in the analysis by DRA use. One hundred eighty-nine of 205 (92%) patients with psychotic disorders (schizophrenia/schizoaffective disorder) and 65 of 131 (50%) with mood and other disorders (depression/bipolar disorder/other) were receiving a DRA. Mean (SE) deutetrabenazine doses at week 145 were 40.4 (1.13), 38.5 (1.21), 39.9 (1.00), and 38.5 (1.48) mg/d for patients with psychotic disorders, those with mood and other disorders, and those receiving DRAs or not, respectively. Mean (SD) changes in total motor AIMS score from this study baseline to week 145 were -6.3 (4.53), -7.1 (4.92), -6.1 (4.42), and -7.5 (5.19). Exposure-adjusted incidence rates (number of AEs/patient-years) of AEs were similar across groups: any (1.02, 1.71, 1.08, 1.97), serious (0.10, 0.12, 0.10, 0.12), and leading to discontinuation (0.07, 0.05, 0.06, 0.05).
CONCLUSIONS
Long-term deutetrabenazine provided clinically meaningful improvements in TD-related movements, with a favorable benefit-risk profile, regardless of underlying condition or DRA use.
Topics: Humans; Tardive Dyskinesia; Male; Female; Tetrabenazine; Middle Aged; Adult; Dopamine Antagonists; Psychotic Disorders; Aged; Antipsychotic Agents; Schizophrenia; Treatment Outcome
PubMed: 38901008
DOI: 10.1097/JCP.0000000000001885 -
Expert Opinion on Pharmacotherapy Jun 2024Adrenergic neurotransmitter reuptake inhibitors are gaining attention in treatment for attention-deficit hyperactivity disorder (ADHD). Due to their effects on... (Review)
Review
INTRODUCTION
Adrenergic neurotransmitter reuptake inhibitors are gaining attention in treatment for attention-deficit hyperactivity disorder (ADHD). Due to their effects on norepinephrine, dopamine, and serotonin neurotransmission, they benefit both ADHD and comorbid disorders and have some other advantages including longer duration of action and fewer adverse effects compared to stimulants. There is continued interest in these agents with novel mechanisms of action in treatment of ADHD.
AREAS COVERED
The authors conducted a PubMed literature search using the following key words: 'ADHD' AND 'adrenergic reuptake inhibitors' OR 'nonstimulants' OR 'atomoxetine' OR 'Viloxazine' OR 'Dasotraline' OR 'Centanafadine' OR 'PDC-1421' OR 'Reboxetine' OR 'Edivoxetine' OR 'Bupropion' OR 'Venlafaxine' OR 'Duloxetine.' They reviewed FDA fact sheets of available medications for safety/tolerability studies and reviewed published clinical studies of these medications for treatment of ADHD.
EXPERT OPINION
Adrenergic neurotransmitter reuptake inhibitors fit the diverse needs of children and adolescents with ADHD with 1) poor tolerability to stimulants (e.g. due to growth suppression, insomnia, rebound irritability, co-morbid depression, anxiety and tic disorders, substance abuse or diversion concerns), 2) cardiac risks, and/or 3) need for extended duration of action. Their differences in receptor affinities and modulating effects support the unique benefits of individual agents.
Topics: Humans; Attention Deficit Disorder with Hyperactivity; Child; Adolescent; Adrenergic Uptake Inhibitors; Central Nervous System Stimulants; Animals; Neurotransmitter Uptake Inhibitors
PubMed: 38900676
DOI: 10.1080/14656566.2024.2369197 -
MSystems Jun 2024Platinum-based chemotherapy failure represents a significant challenge in the management of ovarian cancer (OC) and contributes to disease recurrence and poor prognosis....
Platinum-based chemotherapy failure represents a significant challenge in the management of ovarian cancer (OC) and contributes to disease recurrence and poor prognosis. Recent studies have shed light on the involvement of the gut microbiota in modulating anticancer treatments. However, the precise underlying mechanisms, by which gut microbiota regulates the response to platinum-based therapy, remain unclear. Here, we investigated the role of gut microbiota on the anticancer response of cisplatin and its underlying mechanisms. Our results demonstrate a substantial improvement in the anticancer efficacy of cisplatin following antibiotic-induced perturbation of the gut microbiota in OC-bearing mice. 16S rRNA sequencing showed a pronounced alteration in the composition of the gut microbiome in the cecum contents following exposure to cisplatin. Through metabolomic analysis, we identified distinct metabolic profiles in the antibiotic-treated group, with a notable enrichment of the gut-derived metabolite 3-methylxanthine in antibiotic-treated mice. Next, we employed a strategy combining transcriptome analysis and chemical-protein interaction network databases. We identified metabolites that shared structural similarity with 3-methylxanthine, which interacted with genes enriched in cancer-related pathways. It is identified that 3-methylxanthinesignificantly enhances the effectiveness of cisplatin by promoting apoptosis both and . Importantly, through integrative multiomics analyses, we elucidated the mechanistic basis of this enhanced apoptosis, revealing a dopamine receptor D1-dependent pathway mediated by 3-methylxanthine. This study elucidated the mechanism by which gut-derived metabolite 3-methylxanthine mediated cisplatin-induced apoptosis. Our findings highlight the potential translational significance of 3-methylxanthine as a promising adjuvant in conjunction with cisplatin, aiming to improve treatment outcomes for OC patients.IMPORTANCEThe precise correlation between the gut microbiota and the anticancer effect of cisplatin in OC remains inadequately understood. Our investigation has revealed that manipulation of the gut microbiota via the administration of antibiotics amplifies the efficacy of cisplatin through the facilitation of apoptosis in OC-bearing mice. Metabolomic analysis has demonstrated that the cecum content from antibiotic-treated mice exhibits an increase in the levels of 3-methylxanthine, which has been shown to potentially enhance the therapeutic effectiveness of cisplatin by an integrated multiomic analysis. This enhancement appears to be attributable to the promotion of cisplatin-induced apoptosis, with 3-methylxanthine potentially exerting its influence via the dopamine receptor D1-dependent pathway. These findings significantly contribute to our comprehension of the impact of the gut microbiota on the anticancer therapy in OC. Notably, the involvement of 3-methylxanthine suggests its prospective utility as a supplementary component for augmenting treatment outcomes in patients afflicted with ovarian cancer.
PubMed: 38899930
DOI: 10.1128/msystems.01301-23 -
Addiction Biology Jun 2024The association of impaired dopaminergic neurotransmission with the development and maintenance of alcohol use disorder is well known. More specifically, reduced...
Correlation of striatal dopamine D2/3 receptor availability with GABA level in the anterior cingulate cortex in healthy controls but not in alcohol-dependent subjects and individuals at high risk: A multimodal magnetic resonance spectroscopy and positron emission tomography study.
BACKGROUND
The association of impaired dopaminergic neurotransmission with the development and maintenance of alcohol use disorder is well known. More specifically, reduced dopamine D2/3 receptors in the striatum of subjects with alcohol dependence (AD) compared to healthy controls have been found in previous studies. Furthermore, alterations of gamma-aminobutyric acid (GABA) and glutamate (Glu) levels in the anterior cingulate cortex (ACC) of AD subjects have been documented in several studies. However, the interaction between cortical Glu levels and striatal dopamine D2/3 receptors has not been investigated in AD thus far.
METHODS
This study investigated dopamine D2/3 receptor availability via 18F-fallypride positron emission tomography (PET) and GABA as well as Glu levels via magnetic resonance spectroscopy (MRS) in 19 detoxified AD subjects, 18 healthy controls (low risk, LR) controls and 19 individuals at high risk (HR) for developing AD, carefully matched for sex, age and smoking status.
RESULTS
We found a significant negative correlation between GABA levels in the ACC and dopamine D2/3 receptor availability in the associative striatum of LR but not in AD or HR individuals. Contrary to our expectations, we did not observe a correlation between Glu concentrations in the ACC and striatal D2/3 receptor availability.
CONCLUSIONS
The results may reflect potential regulatory cortical mechanisms on mesolimbic dopamine receptors and their disruption in AD and individuals at high risk, mirroring complex neurotransmitter interactions associated with the pathogenesis of addiction. This is the first study combining 18F-fallypride PET and MRS in AD subjects and individuals at high risk.
Topics: Humans; Positron-Emission Tomography; Gyrus Cinguli; Male; Alcoholism; Receptors, Dopamine D2; Adult; Female; Receptors, Dopamine D3; gamma-Aminobutyric Acid; Magnetic Resonance Spectroscopy; Middle Aged; Corpus Striatum; Case-Control Studies; Glutamic Acid; Benzamides
PubMed: 38899357
DOI: 10.1111/adb.13424