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International Journal of Molecular... Apr 2024In Parkinson's disease (PD), along with typical motor dysfunction, abnormal breathing is present; the cause of which is not well understood. The study aimed to analyze...
In Parkinson's disease (PD), along with typical motor dysfunction, abnormal breathing is present; the cause of which is not well understood. The study aimed to analyze the effects of stimulation of the serotonergic system with 5-HT and 5-HT agonists in a model of PD induced by injection of 6-hydroxydopamine (6-OHDA). To model PD, bilateral injection of 6-OHDA into both striata was performed in male Wistar rats. Respiratory disturbances in response to 7% hypercapnia (CO in O) in the plethysmographic chamber before and after stimulation of the serotonergic system and the incidence of apnea were studied in awake rats 5 weeks after 6-OHDA or vehicle injection. Administration of 6-OHDA reduced the concentration of serotonin (5-HT), dopamine (DA) and norepinephrine (NA) in the striatum and the level of 5-HT in the brainstem of treated rats, which have been associated with decreased basal ventilation, impaired respiratory response to 7% CO and increased incidence of apnea compared to Sham-operated rats. Intraperitoneal (i.p.) injection of the 5-HTR agonist 8-OH-DPAT and 5-HTR agonist NBOH-2C-CN increased breathing during normocapnia and hypercapnia in both groups of rats. However, it restored reactivity to hypercapnia in 6-OHDA group to the level present in Sham rats. Another 5-HTR agonist TCB-2 was only effective in increasing normocapnic ventilation in 6-OHDA rats. Both the serotonergic agonists 8-OH-DPAT and NBOH-2C-CN had stronger stimulatory effects on respiration in PD rats, compensating for deficits in basal ventilation and hypercapnic respiration. We conclude that serotonergic stimulation may have a positive effect on respiratory impairments that occur in PD.
Topics: Animals; Male; Rats; Disease Models, Animal; Dopamine; Hypercapnia; Norepinephrine; Oxidopamine; Parkinson Disease; Rats, Wistar; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Respiration; Serotonin; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Agonists
PubMed: 38673988
DOI: 10.3390/ijms25084403 -
PloS One 2024To report the first and largest systematic review and meta-analysis of randomized controlled trials (RCT) to evaluate the efficacy and safety of aripiprazole or... (Meta-Analysis)
Meta-Analysis
Efficacy and safety of aripiprazole or bupropion augmentation and switching in patients with treatment-resistant depression or major depressive disorder: A systematic review and meta-analysis of randomized controlled trials.
OBJECTIVES
To report the first and largest systematic review and meta-analysis of randomized controlled trials (RCT) to evaluate the efficacy and safety of aripiprazole or bupropion augmentation and switching in patients with treatment-resistant depression (TRD) or major depressive disorder(MDD).
METHODS
We conducted a systematic literature retrieval via PubMed, Embase, Web of Science, and Cochrane until April 2023 for RCT, which evaluated the efficacy and safety of aripiprazole or bupropion augmentation and switching for patients with TRD or MDD. Outcomes measured were changes in the Montgomery-Asberg Depression Rating Scale (MADRS), response and remission rate, and serious adverse events.
RESULTS
Five RCTs, including 4480 patients, were included for meta-analysis. Among them, two RCTs were rated as "high risk" in three aspects (allocation concealment, blinding of participants and personnel and blinding of outcome assessment) because of the non-blind method, and the quality evaluation of the remaining works of literature was "low risk". Augmentation treatment with Aripiprazole (A-ARI) was associated with a significant higher response rate compared with augmentation treatment with bupropion (A-BUP) (RR: 1.15; 95% CI: 1.05, 1.25; P = 0.0007; I2 = 23%). Besides, A-ARI had a significant higher remission rate compared with switching to bupropion (S-BUP) (RR: 1.22; 95% CI: 1.00, 1.49; P = 0.05; I2 = 59%) and A-BUP had a significant higher remission rate compared with S-BUP (RR: 1.20; 95% CI: 1.06, 1.36; P = 0.0004; I2 = 0%). In addition, there was no significant difference in remission rate(RR: 1.05; 95% CI: 0.94, 1.17; P = 0.42; I2 = 33%), improvement of MADRS(WMD: -2.07; 95% CI: -5.84, 1.70; P = 0.28; I2 = 70%) between A-ARI and A-BUP. No significant difference was observed in adverse events and serious adverse events among the three treatment strategies.
CONCLUSIONS
A-ARI may be a better comprehensive antidepressant treatment strategy than A-BUP or S-BUP for patients with TRD or MDD. More large-scale, multi-center, double-blind RCTs are needed to further evaluated the efficacy and safety of aripiprazole or bupropion augmentation and switching treatment strategies.
Topics: Aripiprazole; Bupropion; Humans; Depressive Disorder, Major; Randomized Controlled Trials as Topic; Depressive Disorder, Treatment-Resistant; Treatment Outcome; Drug Therapy, Combination
PubMed: 38669232
DOI: 10.1371/journal.pone.0299020 -
Biology Mar 2024Gliomas have displayed significant challenges in oncology due to their high degree of invasiveness, recurrence, and resistance to treatment strategies. In this work, the...
Gliomas have displayed significant challenges in oncology due to their high degree of invasiveness, recurrence, and resistance to treatment strategies. In this work, the key hub genes mainly associated with different grades of glioma, which were represented by pilocytic astrocytoma (PA), oligodendroglioma (OG), anaplastic astrocytoma (AA), and glioblastoma multiforme (GBM), were identified through weighted gene co-expression network analysis (WGCNA) of microarray datasets retrieved from the Gene Expression Omnibus (GEO) database. Through this, four highly correlated modules were observed to be present across the PA (GSE50161), OG (GSE4290), AA (GSE43378), and GBM (GSE36245) datasets. The functional annotation and pathway enrichment analysis done through the Database for Annotation, Visualization, and Integrated Discovery (DAVID) showed that the modules and hub genes identified were mainly involved in signal transduction, transcription regulation, and protein binding, which collectively deregulate several signaling pathways, mainly PI3K/Akt and metabolic pathways. The involvement of several hub genes primarily linked to other signaling pathways, including the cAMP, MAPK/ERK, Wnt/β-catenin, and calcium signaling pathways, indicates potential interconnectivity and influence on the PI3K/Akt pathway and, subsequently, glioma severity. The Drug Repurposing Encyclopedia (DRE) was used to screen for potential drugs based on the up- and downregulated hub genes, wherein the synthetic progestin hormones norgestimate and ethisterone were the top drug candidates. This shows the potential neuroprotective effect of progesterone against glioma due to its influence on EGFR expression and other signaling pathways. Aside from these, several experimental and approved drug candidates were also identified, which include an adrenergic receptor antagonist, a PPAR-γ receptor agonist, a CDK inhibitor, a sodium channel blocker, a bradykinin receptor antagonist, and a dopamine receptor agonist, which further highlights the gene network as a potential therapeutic avenue for glioma.
PubMed: 38666818
DOI: 10.3390/biology13040206 -
European Journal of Pharmaceutics and... Jun 2024Carbidopa and levodopa remain the established therapeutic standard for managing Parkinson's disease. Nevertheless, their oral administration is hindered by rapid...
Carbidopa and levodopa remain the established therapeutic standard for managing Parkinson's disease. Nevertheless, their oral administration is hindered by rapid enzymatic degradation and gastrointestinal issues, limiting their efficacy, and necessitating alternative delivery methods. This work presents a novel strategy employing dissolving microarray patches (MAPs) loaded with carbidopa and levodopa, formulated with Tween® 80 to improve their transdermal delivery. The fabricated MAPs demonstrated an acceptable mechanical strength, resisting pressures equivalent to manual human thumb application (32 N) onto the skin. Additionally, these MAPs exhibited an insertion depth of up to 650 µm into excised neonatal porcine skin. Ex vivo dermatokinetic studies could achieve delivery efficiencies of approximately 53.35 % for levodopa and 40.14 % for carbidopa over 24 h, demonstrating their significant potential in drug delivery. Biocompatibility assessments conducted on human dermal fibroblast cells corroborated acceptable cytocompatibility, confirming the suitability of these MAPs for dermal application. In conclusion, dissolving MAPs incorporating carbidopa and levodopa represent a promising alternative for improving the therapeutic management of Parkinson's disease.
Topics: Carbidopa; Levodopa; Parkinson Disease; Animals; Swine; Humans; Administration, Cutaneous; Antiparkinson Agents; Transdermal Patch; Skin; Drug Delivery Systems; Fibroblasts; Skin Absorption; Drug Combinations
PubMed: 38663522
DOI: 10.1016/j.ejpb.2024.114304 -
BioRxiv : the Preprint Server For... Apr 2024The dopamine D1 receptor (D1R) has fundamental roles in voluntary movement and memory and is a validated drug target for neurodegenerative and neuropsychiatric...
The dopamine D1 receptor (D1R) has fundamental roles in voluntary movement and memory and is a validated drug target for neurodegenerative and neuropsychiatric disorders. However, previously developed D1R selective agonists possess a catechol moiety which displays poor pharmacokinetic properties. The first selective non-catechol D1R agonists were recently discovered and unexpectedly many of these ligands showed G protein biased signaling. Here, we investigate both catechol and non-catechol D1R agonists to validate potential biased signaling and examine if this impacts agonist-induced D1R endocytosis. We determined that most, but not all, non-catechol agonists display G protein biased signaling at the D1R and have reduced or absent Beta-arrestin recruitment. A notable exception was compound (Cmpd) 19, a non-catechol agonist with full efficacy at both D1R-G protein or D1R Beta-arrestin pathways. In addition, the catechol ligand A-77636 was a highly potent, super agonist for D1R Beta-arrestin activity. When examined for agonist-induced D1R endocytosis, balanced agonists SKF-81297 and Cmpd 19 induced robust D1R endocytosis while the G protein biased agonists did not. The Beta-arrestin super agonist, A-77636, showed significantly increased D1R endocytosis. Moreover, Beta-arrestin recruitment efficacy of tested agonists strongly correlated with total D1R endocytosis. Taken together, these results indicate the degree of D1R signaling functional selectivity profoundly impacts D1R endocytosis regardless of pharmacophore. The range of functional selectivity of these D1R agonists will provide valuable tools to further investigate D1R signaling, trafficking and therapeutic potential.
PubMed: 38659786
DOI: 10.1101/2024.04.15.589637 -
Pituitary Jun 2024Prolactinomas are common tumours that significantly reduce quality-of-life (QOL) due to sellar mass effect, secondary hypogonadism, and the peripheral effects of...
BACKGROUND
Prolactinomas are common tumours that significantly reduce quality-of-life (QOL) due to sellar mass effect, secondary hypogonadism, and the peripheral effects of prolactin. Understanding the factors that influence QOL would provide insights into therapeutic targets to optimise patient outcomes and improve wellbeing in prolactinoma.
METHODS
A systematic review was performed in accordance with the PRISMA statement. Studies that reported patient QoL using validated metrics were included. Bias and methodological rigour were assessed using the MINORS criteria.
RESULTS
A total of 18 studies were identified studies were available for review, comprising 877 patients. Most were small cross-sectional studies at high risk of bias. Prolactinoma exhibit worse QOL than healthy controls, particularly mental and psychosocial wellbeing. QOL is also worse than patients with non-functional adenomas, but better than those with Cushing's disease and acromegaly. QOL correlates with prolactin levels, and approaches population baseline with prolonged biochemical control. Dopamine agonists and surgery both improve overall QOL, however improvements are more rapid with surgery.
CONCLUSION
Poor quality of life in prolactinoma is multifactorial, related to biochemical control, side effects of therapy, and sellar mass effect. Targeting persistent symptoms, reducing healthcare costs, and reducing side-effects of therapy are avenues to improving QOL in patients with prolactinoma.
Topics: Prolactinoma; Humans; Quality of Life; Pituitary Neoplasms; Dopamine Agonists
PubMed: 38656635
DOI: 10.1007/s11102-024-01392-1 -
Journal of Psychopharmacology (Oxford,... Jun 2024A major effort of the pharmaceutical industry has been to identify and market drug treatments that are effective in ameliorating the symptoms of psychotic illness but... (Review)
Review
A major effort of the pharmaceutical industry has been to identify and market drug treatments that are effective in ameliorating the symptoms of psychotic illness but without the limitations of the current treatments acting at dopamine D2 receptors. These limitations include the induction of a range of adverse effects, the inadequate treatment response of a substantial proportion of people with schizophrenia, and the generally poor response to negative and cognitive features of the disease. Recently introduced drug treatments have gone some way to avoiding the first of these, with a reduced propensity for weight gain, cardiovascular risk and extrapyramidal motor effects. Despite claims of some small improvements in negative symptoms, these drugs have not demonstrated substantial increases in efficacy. Of the drugs currently in development as antipsychotic agents, several are misleadingly described as having novel 'non-dopaminergic' mechanisms that may offer improvements in addressing the limitations of adverse effects and efficacy. It will be argued, using the trace amine-associated receptor 1 agonist as an example, that several of these new drugs still act primarily through modulation of dopaminergic neurotransmission and, in not addressing the primary pathology of schizophrenia, are therefore unlikely to have the much-needed improvements in efficacy required to address the unmet need associated with resistance to current treatments.
Topics: Humans; Antipsychotic Agents; Receptors, Dopamine D2; Schizophrenia; Animals; Receptors, G-Protein-Coupled
PubMed: 38654553
DOI: 10.1177/02698811241249415 -
Pediatric Neurology Jun 2024In Lesch-Nyhan disease (LND), early dopamine deficiency is thought to contribute to dystonia and self-injury, gradually developing over the first years of life. Previous...
BACKGROUND
In Lesch-Nyhan disease (LND), early dopamine deficiency is thought to contribute to dystonia and self-injury, gradually developing over the first years of life. Previous attempts to restore dopamine levels in older patients have been unsuccessful. Based on the hypothesis that very early dopamine replacement can prevent full phenotypic development, we treated three patients with LND from infancy with levodopa.
METHODS
Levodopa/carbidopa (4:1) was started at age 11 to 13 months, aiming at escalating to 5 to 6 mg/kg levodopa per day. Follow-up focused on dystonia severity and whether self-injury occurred. In addition, the literature was reviewed to delineate the age at onset of self-injury for all reported cases to date.
RESULTS
During long-term follow-up, self-injury appears to have been prevented in two patients (now aged 14 and 15.5 years), as their HPRT1 gene mutations had been invariably associated with self-injury before. Future self-injury is unlikely, as only 1.1% of 264 published cases had self-injury onset later in life than these patients' current ages. The third patient started self-injury at age 1.5 years, while on a substantially lower levodopa dose. A clear effect of levodopa on dystonia could not be determined.
CONCLUSIONS
Our observations suggest that levodopa, given early enough and sufficiently dosed, might be able to prevent self-injury in LND. Therefore, levodopa could be considered in patients with LND as early as possible, at least before the self-injury appears. Further research is needed to establish very early levodopa as an effective treatment strategy in LND, and to optimize timing and dosing.
Topics: Humans; Levodopa; Lesch-Nyhan Syndrome; Self-Injurious Behavior; Adolescent; Male; Female; Infant; Carbidopa; Dopamine Agents; Drug Combinations
PubMed: 38653184
DOI: 10.1016/j.pediatrneurol.2024.03.020 -
Addiction & Health Feb 2024The likelihood of substance dependency in offspring is increased in cases when there is a family history of drug or alcohol use. Mothering is limited by maternal... (Review)
Review
The likelihood of substance dependency in offspring is increased in cases when there is a family history of drug or alcohol use. Mothering is limited by maternal addiction because of the separation. Maternal separation (MS) leads to the development of behavioural and neuropsychiatric issues in the future. Despite the importance of this issue, empirical investigations of the influences of maternal substance use and separation on substance use problems in offspring are limited, and studies that consider both effects are rare. This study aims to review a few studies on the mechanisms, treatments, genetics, epigenetics, molecular and psychological alterations, and neuroanatomical regions involved in the dependence of offspring who underwent maternal addiction and separation. The PubMed database was used. A total of 95 articles were found, including the most related ones in the review. The brain's lateral paragigantocellularis (LPGi), nucleus accumbens (NAc), caudate-putamen (CPu), prefrontal cortex (PFC), and hippocampus, can be affected by MS. Dopamine receptor subtype genes, alcohol biomarker minor allele, and preproenkephalin mRNA may be affected by alcohol or substance use disorders. After early-life adversity, histone acetylation in the hippocampus may be linked to brain-derived neurotrophic factor (BDNF) gene epigenetics and glucocorticoid receptors (GRs). The adverse early-life experiences differ in offspring›s genders and rewire the brain›s dopamine and endocannabinoid circuits, making offspring more susceptible to dependence. Related psychological factors rooted in early-life stress (ELS) and parental substance use disorder (SUD). Treatments include antidepressants, histone deacetylase inhibitors, lamotrigine, ketamine, choline, modafinil, methadone, dopamine, cannabinoid 1 receptor agonists/antagonists, vitamins, oxytocin, tetrahydrocannabinol, SR141716A, and dronabinol. Finally, the study emphasizes the need for multifaceted strategies to prevent these outcomes.
PubMed: 38651025
DOI: 10.34172/ahj.2024.1478