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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 -
Journal of Neuroinflammation Apr 2024Parkinson's disease (PD) is a neurodegenerative disorder that is characterized by the presence of proteinaceous alpha-synuclein (α-syn) inclusions (Lewy bodies),...
BACKGROUND
Parkinson's disease (PD) is a neurodegenerative disorder that is characterized by the presence of proteinaceous alpha-synuclein (α-syn) inclusions (Lewy bodies), markers of neuroinflammation and the progressive loss of nigrostriatal dopamine (DA) neurons. These pathological features can be recapitulated in vivo using the α-syn preformed fibril (PFF) model of synucleinopathy. We have previously determined that microglia proximal to PFF-induced nigral α-syn inclusions increase in soma size, upregulate major-histocompatibility complex-II (MHC-II) expression, and increase expression of a suite of inflammation-associated transcripts. This microglial response is observed months prior to degeneration, suggesting that microglia reacting to α-syn inclusion may contribute to neurodegeneration and could represent a potential target for novel therapeutics. The goal of this study was to determine whether colony stimulating factor-1 receptor (CSF1R)-mediated microglial depletion impacts the magnitude of α-syn aggregation, nigrostriatal degeneration, or the response of microglial in the context of the α-syn PFF model.
METHODS
Male Fischer 344 rats were injected intrastriatally with either α-syn PFFs or saline. Rats were continuously administered Pexidartinib (PLX3397B, 600 mg/kg), a CSF1R inhibitor, to deplete microglia for a period of either 2 or 6 months.
RESULTS
CSF1R inhibition resulted in significant depletion (~ 43%) of ionized calcium-binding adapter molecule 1 immunoreactive (Iba-1ir) microglia within the SNpc. However, CSF1R inhibition did not impact the increase in microglial number, soma size, number of MHC-II immunoreactive microglia or microglial expression of Cd74, Cxcl10, Rt-1a2, Grn, Csf1r, Tyrobp, and Fcer1g associated with phosphorylated α-syn (pSyn) nigral inclusions. Further, accumulation of pSyn and degeneration of nigral neurons was not impacted by CSF1R inhibition. Paradoxically, long term CSF1R inhibition resulted in increased soma size of remaining Iba-1ir microglia in both control and PFF rats, as well as expression of MHC-II in extranigral regions.
CONCLUSIONS
Collectively, our results suggest that CSF1R inhibition does not impact the microglial response to nigral pSyn inclusions and that CSF1R inhibition is not a viable disease-modifying strategy for PD.
Topics: Animals; Microglia; alpha-Synuclein; Rats; Male; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; Rats, Inbred F344; Pyrroles; Aminopyridines; Inclusion Bodies; Substantia Nigra; Disease Models, Animal
PubMed: 38664840
DOI: 10.1186/s12974-024-03108-5 -
Frontiers in Neuroscience 2024Dopamine D3 receptor (D3R) ligands have been studied for the possible treatment of neurological and neuropsychiatric disorders. However, selective D3R radioligands for...
INTRODUCTION
Dopamine D3 receptor (D3R) ligands have been studied for the possible treatment of neurological and neuropsychiatric disorders. However, selective D3R radioligands for binding studies have been challenging to identify due to the high structural similarity between the D2R and D3R. In a prior study, we reported a new conformationally-flexible benzamide scaffold having a high affinity for D3R and excellent selectivity vs. D2R. In the current study, we characterized the binding properties of a new radioiodinated ligand, [I]HY-3-24.
METHODS
binding studies were conducted in cell lines expressing D3 receptors, rat striatal homogenates, and rat and non-human primate (NHP) brain tissues to measure regional brain distribution of this radioligand.
RESULTS
HY-3-24 showed high potency at D3R ( = 0.67 ± 0.11 nM, IC = 1.5 ± 0.58 nM) compared to other D2-like dopamine receptor subtypes (D2R = 86.7 ± 11.9 nM and D4R > 1,000). The (0.34 ± 0.22 nM) and B (38.91 ± 2.39 fmol/mg) values of [I]HY-3-24 were determined. binding studies in rat striatal homogenates using selective D2R and D3R antagonists confirmed the D3R selectivity of [I]HY-3-24. Autoradiography results demonstrated that [I]HY-3-24 specifically binds to D3Rs in the nucleus accumbens, islands of Calleja, and caudate putamen in rat and NHP brain sections.
CONCLUSION
These results suggest that [I]HY-3-24 appears to be a novel radioligand that exhibits high affinity binding at D3R, with low binding to other D2-like dopamine receptors. It is anticipated that [I]HY-3-24 can be used as the specific D3R radioligand.
PubMed: 38655111
DOI: 10.3389/fnins.2024.1380009 -
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 -
Molecular Pharmaceutics May 2024The main purpose of our studies is to demonstrate that commercially available mesoporous silica (MS) can be used to control the physical state of aripiprazole (ARP). The...
The main purpose of our studies is to demonstrate that commercially available mesoporous silica (MS) can be used to control the physical state of aripiprazole (ARP). The investigations performed utilizing differential scanning calorimetry and broadband dielectric spectroscopy reveal that silica can play different roles depending on its concentration in the system with amorphous ARP. At low MS content, it activates recrystallization of the active pharmaceutical ingredient and supports forming the III polymorphic form of ARP. At intermediate MS content (between ca. 27 and 65 wt %), MS works as a recrystallization inhibitor of ARP. At these concentrations, the formation of III polymorphic form is no longer favorable; therefore, it is possible to use this additive to obtain ARP in either IV or X polymorphic form. At the same time, employing MS in concentrations >65 wt % amorphous form of ARP with high physical stability can be obtained. Finally, regardless of the polymorphic form it crystallizes into, each composite is characterized by the same temperature dependence of relaxation times in the supercooled and glassy states.
Topics: Aripiprazole; Silicon Dioxide; Calorimetry, Differential Scanning; Porosity; Crystallization; Dielectric Spectroscopy; X-Ray Diffraction
PubMed: 38644570
DOI: 10.1021/acs.molpharmaceut.3c01095 -
Biomedicine & Pharmacotherapy =... May 2024Depression ranks as the fourth most prevalent global disease, with suicide incidents occurring at a younger age. Sulpiride (SUL), an atypical antidepressant drug acting...
Depression ranks as the fourth most prevalent global disease, with suicide incidents occurring at a younger age. Sulpiride (SUL), an atypical antidepressant drug acting as a dopamine D2 receptor antagonist and possessing anti-inflammatory properties, exhibits limited ability to penetrate the blood brain barrier (BBB). This weak penetration hampers its inhibitory effect on prolactin release in the pituitary gland, consequently leading to hyperprolactinemia. In order to enhance the central nervous system efficacy of sulpiride and reduce serum prolactin levels, we covalently linked sulpiride to VPALR derived from the nuclear DNA repair protein ku70. In vivo study on depressive mice using intraperitoneal injection of VPALR-SUL demonstrated a significant increase in struggle time and total distance compared to those treated with only sulpiride while also reducing serum prolactin concentration. The pharmacokinetic study results showed that VPALR-SUL prolonged half-life and increased bioavailability. In conclusion, VPALR-SUL exhibited potential for enhancing sulpiride transport across the BBB, augmenting its antidepressant effects, and reducing serum prolactin levels. This study laid a foundation for improving sulpiride delivery and developing novel antidepressants.
Topics: Animals; Prolactin; Sulpiride; Antidepressive Agents; Mice; Male; Cell-Penetrating Peptides; Depression; Blood-Brain Barrier; Biological Availability
PubMed: 38642503
DOI: 10.1016/j.biopha.2024.116610 -
Journal of Mother and Child Feb 2024Domperidone is a commonly prescribed galactagogue used off-label for lactation insufficiency. Prescriber unfamiliarity or safety concerns can lead to therapeutic delay...
BACKGROUND
Domperidone is a commonly prescribed galactagogue used off-label for lactation insufficiency. Prescriber unfamiliarity or safety concerns can lead to therapeutic delay and potential early breastfeeding discontinuation. To facilitate access, the study site pharmacy department developed a Structured Administration and Supply Arrangement (SASA) for International Board-Certified Lactation Consultants (IBCLC) to screen and initiate domperidone using a checklist.
MATERIAL
To validate a domperidone screening tool via analysis of its use and compliance, together with a staff satisfaction survey.
METHODS
Records were extracted from the REDCap® database for women with documented domperidone supply between 06/05/2022 and 27/01/2023 and reviewed with medical records. A staff survey was distributed assessing compliance and attitudes towards the SASA.
RESULTS
Records of supply revealed that 34% (17/50) of patients were referred to a physician, revealing a discrepancy between database documentation and checklists, as no referrals were documented. Overall staff satisfaction with the SASA was rated 4.6 out of 5. 77.7% (7/9) felt confident counselling and supplying domperidone with the SASA in place. 88.9% (8/9) felt confident using the checklist to identify the appropriateness of therapy and referral to a physician.
CONCLUSIONS
The system in place allows the IBCLCs to initiate and supply domperidone in a timely manner to breastfeeding mothers with lactation insufficiency. The support tools, including domperidone SASA, REDCap® documentation database and the checklist domperidone as a Galactagogue Checklist, can be greatly appreciated by the LCs. Continued discussion with IBCLCs to refine and improve the SASA and associated education package will result in more consistent compliance.
Topics: Female; Humans; Domperidone; Galactogogues; Consultants; Outpatients; Lactation; Pharmacy
PubMed: 38639101
DOI: 10.34763/jmotherandchild.20242801.d-23-00093 -
PloS One 2024Obesity leads to insulin resistance (IR) and type 2 diabetes. In humans, low levels of the hormone prolactin (PRL) correlate with IR, adipose tissue (AT) dysfunction,...
Obesity leads to insulin resistance (IR) and type 2 diabetes. In humans, low levels of the hormone prolactin (PRL) correlate with IR, adipose tissue (AT) dysfunction, and increased prevalence of T2D. In obese rats, PRL treatment promotes insulin sensitivity and reduces visceral AT adipocyte hypertrophy. Here, we tested whether elevating PRL levels with the prokinetic and antipsychotic drug sulpiride, an antagonist of dopamine D2 receptors, improves metabolism in high fat diet (HFD)-induced obese male mice. Sulpiride treatment (30 days) reduced hyperglycemia, IR, and the serum and pancreatic levels of triglycerides in obese mice, reduced visceral and subcutaneous AT adipocyte hypertrophy, normalized markers of visceral AT function (PRL receptor, Glut4, insulin receptor and Hif-1α), and increased glycogen stores in skeletal muscle. However, the effects of sulpiride reducing hyperglycemia were also observed in obese prolactin receptor null mice. We conclude that sulpiride reduces obesity-induced hyperglycemia by mechanisms that are independent of prolactin/prolactin receptor activity. These findings support the therapeutic potential of sulpiride against metabolic dysfunction in obesity.
Topics: Humans; Mice; Male; Rats; Animals; Insulin Resistance; Mice, Obese; Dopamine D2 Receptor Antagonists; Prolactin; Receptors, Prolactin; Diabetes Mellitus, Type 2; Sulpiride; Obesity; Diet, High-Fat; Hyperglycemia; Hypertrophy; Insulin
PubMed: 38635745
DOI: 10.1371/journal.pone.0301496 -
Wellcome Open Research 2023There is an urgent need to develop more effective and safer antipsychotics beyond dopamine 2 receptor antagonists. An emerging and promising approach is TAAR1 agonism....
BACKGROUND
There is an urgent need to develop more effective and safer antipsychotics beyond dopamine 2 receptor antagonists. An emerging and promising approach is TAAR1 agonism. Therefore, we will conduct a living systematic review and meta-analysis to synthesize and triangulate the evidence from preclinical animal experiments and clinical studies on the efficacy, safety, and underlying mechanism of action of TAAR1 agonism for psychosis.
METHODS
Independent searches will be conducted in multiple electronic databases to identify clinical and animal experimental studies comparing TAAR1 agonists with licensed antipsychotics or other control conditions in individuals with psychosis or animal models for psychosis, respectively. The primary outcomes will be overall psychotic symptoms and their behavioural proxies in animals. Secondary outcomes will include side effects and neurobiological measures. Two independent reviewers will conduct study selection, data extraction using predefined forms, and risk of bias assessment using suitable tools based on the study design. Ontologies will be developed to facilitate study identification and data extraction. Data from clinical and animal studies will be synthesized separately using random-effects meta-analysis if appropriate, or synthesis without meta-analysis. Study characteristics will be investigated as potential sources of heterogeneity. Confidence in the evidence for each outcome and source of evidence will be evaluated, considering the summary of the association, potential concerns regarding internal and external validity, and reporting biases. When multiple sources of evidence are available for an outcome, an overall conclusion will be drawn in a triangulation meeting involving a multidisciplinary team of experts. We plan trimonthly updates of the review, and any modifications in the protocol will be documented. The review will be co-produced by multiple stakeholders aiming to produce impactful and relevant results and bridge the gap between preclinical and clinical research on psychosis.
PROTOCOL REGISTRATION
PROSPERO-ID: CRD42023451628.
PubMed: 38634067
DOI: 10.12688/wellcomeopenres.19866.1 -
Journal of Medical Case Reports Apr 2024Significant elevation of creatine kinase levels (above three digits) and leucocytosis in the absence of muscle rigidity, tremors, or autonomic dysfunction can pose a...
BACKGROUND
Significant elevation of creatine kinase levels (above three digits) and leucocytosis in the absence of muscle rigidity, tremors, or autonomic dysfunction can pose a real challenge in the context of antipsychotic treatment as an early herald of neuroleptic malignant syndrome.
CASE PRESENTATION
We present here two cases of adult male patients of Black British heritage, ages 51 years and 28 years, respectively. Both received a diagnosis of schizoaffective disorder and presented with massive increase of creatine kinase blood level after aripiprazole depot administration, one with pernicious increase associated with silent neuroleptic malignant syndrome, and the second with asymptomatic benign enzyme elevation.
CONCLUSION
Though aripiprazole use is less likely to cause neuroleptic malignant syndrome, on rare occasions it can produce massive symptomatic or asymptomatic increase in serum creatine kinase enzyme levels, raising the need for close monitoring, especially at the initial doses of the drug.
Topics: Adult; Humans; Male; Aripiprazole; Neuroleptic Malignant Syndrome; Antipsychotic Agents; Psychotic Disorders; Creatine Kinase
PubMed: 38632633
DOI: 10.1186/s13256-024-04508-0