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Frontiers in Oncology 2022[This corrects the article DOI: 10.3389/fonc.2021.697950.].
[This corrects the article DOI: 10.3389/fonc.2021.697950.].
PubMed: 35356217
DOI: 10.3389/fonc.2022.880458 -
Cureus Feb 2022Tourette's Syndrome (TS), in which patients have sudden, repeated, involuntary twitches and movements, called tics, is a condition of the nervous system. They can be... (Review)
Review
Tourette's Syndrome (TS), in which patients have sudden, repeated, involuntary twitches and movements, called tics, is a condition of the nervous system. They can be motor, vocal, simple, or complex tics. It can be physically, emotionally, mentally, and socially distressing and challenging for those suffering from it. Usually, it is accompanied by various comorbidities like attention-deficit hyperactivity disorder, obsessive-compulsive disorder, and sleep disorders. A variety of environmental and genetic factors are also associated with tics in TS like the first-degree relatives are more at risk of developing TS.TS is heterogeneous with complicated patterns of inheritance and phenotypic manifestations. There is a strong association between common single nucleotide polymorphisms (SNP, s) in the SLITRK1 gene and TS. Environmental factors like prenatal, postnatal, and perinatal factors directly influence tics in TS. These factors are low birth weight, intrauterine growth retardation (IGR), and various infections. The treatment of TS can be broadly classified into non-pharmacological and pharmacological treatment. Non-pharmacological therapy includes various behavioural interventions that can be helpful in situations when patients are tolerant of medical treatments. Psychoeducation and counselling play an essential role in the treatment of TS. It is vital to give a proper understanding to the patient and their family about the disease. Cognitive-behavioral intervention for tics, cognitive-behavioral therapy, exposure and response prevention, relaxation techniques, deep brain stimulation, and habit reversal training are the commonly used therapies for tics. These therapies have shown good efficacy because it improves the Yale Global Tic Severity Scale score (YGTSS) significantly. And they show effectiveness in patients who are irresponsive to medical treatment. The main lines of medical treatment are antipsychotics and alpha agonists. Typical (haloperidol, pimozide) or atypical (aripiprazole, risperidone, olanzapine) Antipsychotics differ in their side effects, efficacy, and tolerance in different age groups of children. Haloperidol was the first drug approved by the Food and Drug Administration for tics, but later on, new developments and improvements were made as far as drug therapy is concerned. The alpha-agonist most commonly used is clonidine which is also available in the form of adhesive patches. Another alpha agonist which is also widely used is guanfacine. Botulinum toxin and baclofen have also shown efficacy in dealing with tics in TS with other comorbidities. We will review in this article all the main lines of treatment and their effectiveness in TS.
PubMed: 35345730
DOI: 10.7759/cureus.22449 -
Frontiers in Behavioral Neuroscience 2022Rats work very hard for intracranial self-stimulation (ICSS) and tradeoff effort or time allocation for intensity and frequency parameters producing a sigmoidal function...
Rats work very hard for intracranial self-stimulation (ICSS) and tradeoff effort or time allocation for intensity and frequency parameters producing a sigmoidal function of the subjective reward magnitude of ICSS. Previous studies using electrical intracranial stimuli (ICS) as a discriminative cue focused on estimating detection thresholds or on the discrimination between intensities. To our knowledge, there is no direct comparison of the reinforcer tradeoff functions with the discriminative functions. Rats were trained to press and hold the lever for ICSS using the maximum reinforcing intensity below motor alterations or avoidance behavior. First, rats were trained to hold the lever for 1 s; after stability, they undergo trials where intensity or frequency was decreased on 0.1 log step. Thereafter, they undergo further training with a hold of 2 and later of 4 s to determine tradeoff with intensity or frequency. The same rats were trained on a discrimination task where the previously used ICSS signaled a lever where a 1 s hold response was followed by a reinforcing ICSS; on randomly alternating trials, a -0.6 log ICS signaled an alternate lever where a similar hold response led to a reinforcer. After mastering discrimination, generalization tests were carried out with varying intensity or frequency. Rats completed training with 2 and later 4 s hold response. After the completion of each task, the rats had different doses of a pimozide challenge while their intensity and hold-down requirement were varied. With regards to the rats' tradeoff response time allocation as a function of intensity or frequency, sigmoid functions were displaced to the right when long responses were required. Rats that learned the discrimination task attained a discrimination index of 90-98%. Discrimination accuracy decreased slightly with the increase of hold requirement, but generalization gradients were not displaced to the right as a function of the response requirement. Pimozide induced a dose-dependent displacement of the time-allocation gradients, but it did not affect the generalization gradients. It is concluded that rats integrate response requirements as part of the reinforcement tradeoff function, but the response cost is not integrated into the discriminative function of ICSS.
PubMed: 35264936
DOI: 10.3389/fnbeh.2022.799015 -
Frontiers in Pharmacology 2021Repurposing of currently available drugs is a valuable strategy to tackle the consequences of COVID-19. Recently, several studies have investigated the effect of...
Repurposing of currently available drugs is a valuable strategy to tackle the consequences of COVID-19. Recently, several studies have investigated the effect of psychoactive drugs on SARS-CoV-2 in cell culture models as well as in clinical practice. Our aim was to expand these studies and test some of these compounds against newly emerged variants. Several antidepressants and antipsychotic drugs with different primary mechanisms of action were tested in ACE2/TMPRSS2-expressing human embryonic kidney cells against the infection by SARS-CoV-2 spike protein-dependent pseudoviruses. Some of these compounds were also tested in human lung epithelial cell line, Calu-1, against the first wave (B.1) lineage of SARS-CoV-2 and the variants of concern, B.1.1.7, B.1.351, and B.1.617.2. Several clinically used antidepressants, including fluoxetine, citalopram, reboxetine, imipramine, as well as antipsychotic compounds chlorpromazine, flupenthixol, and pimozide inhibited the infection by pseudotyped viruses with minimal effects on cell viability. The antiviral action of several of these drugs was verified in Calu-1 cells against the B.1 lineage of SARS-CoV-2. By contrast, the anticonvulsant carbamazepine, and novel antidepressants ketamine, known as anesthetic at high doses, and its derivatives as well as MAO and phosphodiesterase inhibitors phenelzine and rolipram, respectively, showed no activity in the pseudovirus model. Furthermore, fluoxetine remained effective against pseudoviruses with common receptor binding domain mutations, N501Y, K417N, and E484K, as well as B.1.1.7 (alpha), B.1.351 (beta), and B.1.617.2 (delta) variants of SARS-CoV-2. Our study confirms previous data and extends information on the repurposing of these drugs to counteract SARS-CoV-2 infection including different variants of concern, however, extensive clinical studies must be performed to confirm our findings.
PubMed: 35126106
DOI: 10.3389/fphar.2021.755600 -
Cancers Jan 2022Glioblastoma (GBM) is a devastating disease and the most common primary brain malignancy of adults with a median survival barely exceeding one year. Recent findings...
Glioblastoma (GBM) is a devastating disease and the most common primary brain malignancy of adults with a median survival barely exceeding one year. Recent findings suggest that the antipsychotic drug pimozide triggers an autophagy-dependent, lysosomal type of cell death in GBM cells with possible implications for GBM therapy. One oncoprotein that is often overactivated in these tumors and associated with a particularly dismal prognosis is Signal Transducer and Activator of Transcription 3 (STAT3). Here, we used isogenic human and murine GBM knockout cell lines, advanced fluorescence microscopy, transcriptomic analysis and FACS-based assessment of cell viability to show that STAT3 has an underappreciated, context-dependent role in drug-induced cell death. Specifically, we demonstrate that depletion of STAT3 significantly enhances cell survival after treatment with Pimozide, suggesting that STAT3 confers a particular vulnerability to GBM. Furthermore, we show that active STAT3 has no major influence on the early steps of the autophagy pathway, but exacerbates drug-induced lysosomal membrane permeabilization (LMP) and release of cathepsins into the cytosol. Collectively, our findings support the concept of exploiting the pro-death functions of autophagy and LMP for GBM therapy and to further determine whether STAT3 can be employed as a treatment predictor for highly apoptosis-resistant, but autophagy-proficient cancers.
PubMed: 35053502
DOI: 10.3390/cancers14020339 -
European Child & Adolescent Psychiatry Mar 2022In 2011, the European Society for the Study of Tourette Syndrome (ESSTS) published the first European guidelines for Tourette Syndrome (TS). We now present an update of... (Review)
Review
In 2011, the European Society for the Study of Tourette Syndrome (ESSTS) published the first European guidelines for Tourette Syndrome (TS). We now present an update of the part on pharmacological treatment, based on a review of new literature with special attention to other evidence-based guidelines, meta-analyses, and randomized double-blinded studies. Moreover, our revision took into consideration results of a recent survey on treatment preferences conducted among ESSTS experts. The first preference should be given to psychoeducation and to behavioral approaches, as it strengthens the patients' self-regulatory control and thus his/her autonomy. Because behavioral approaches are not effective, available, or feasible in all patients, in a substantial number of patients pharmacological treatment is indicated, alone or in combination with behavioral therapy. The largest amount of evidence supports the use of dopamine blocking agents, preferably aripiprazole because of a more favorable profile of adverse events than first- and second-generation antipsychotics. Other agents that can be considered include tiapride, risperidone, and especially in case of co-existing attention deficit hyperactivity disorder (ADHD), clonidine and guanfacine. This view is supported by the results of our survey on medication preference among members of ESSTS, in which aripiprazole was indicated as the drug of first choice both in children and adults. In treatment resistant cases, treatment with agents with either a limited evidence base or risk of extrapyramidal adverse effects might be considered, including pimozide, haloperidol, topiramate, cannabis-based agents, and botulinum toxin injections. Overall, treatment of TS should be individualized, and decisions based on the patient's needs and preferences, presence of co-existing conditions, latest scientific findings as well as on the physician's preferences, experience, and local regulatory requirements.
Topics: Adult; Attention Deficit Disorder with Hyperactivity; Child; Female; Guanfacine; Humans; Male; Risperidone; Tic Disorders; Tourette Syndrome
PubMed: 34757514
DOI: 10.1007/s00787-021-01899-z -
Scientific Reports Oct 2021The persistent increase of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) infections negatively impacts Tuberculosis treatment outcomes. Host-directed...
The persistent increase of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) infections negatively impacts Tuberculosis treatment outcomes. Host-directed therapies (HDT) pose an complementing strategy, particularly since Mtb is highly successful in evading host-defense by manipulating host-signaling pathways. Here, we screened a library containing autophagy-modulating compounds for their ability to inhibit intracellular Mtb-bacteria. Several active compounds were identified, including two drugs of the diphenylbutylpiperidine-class, Fluspirilene and Pimozide, commonly used as antipsychotics. Both molecules inhibited intracellular Mtb in pro- as well as anti-inflammatory primary human macrophages in a host-directed manner and synergized with conventional anti-bacterials. Importantly, these inhibitory effects extended to MDR-Mtb strains and the unrelated intracellular pathogen, Salmonella enterica serovar Typhimurium (Stm). Mechanistically Fluspirilene and Pimozide were shown to regulate autophagy and alter the lysosomal response, partly correlating with increased bacterial localization to autophago(lyso)somes. Pimozide's and Fluspirilene's efficacy was inhibited by antioxidants, suggesting involvement of the oxidative-stress response in Mtb growth control. Furthermore, Fluspirilene and especially Pimozide counteracted Mtb-induced STAT5 phosphorylation, thereby reducing Mtb phagosome-localized CISH that promotes phagosomal acidification. In conclusion, two approved antipsychotic drugs, Pimozide and Fluspirilene, constitute highly promising and rapidly translatable candidates for HDT against Mtb and Stm and act by modulating the autophagic/lysosomal response by multiple mechanisms.
Topics: Anti-Bacterial Agents; Antipsychotic Agents; Antitubercular Agents; Autophagy; Cell Line; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Repositioning; High-Throughput Screening Assays; Humans; Lysosomes; Microbial Sensitivity Tests; Models, Biological; Mycobacterium tuberculosis; Phagosomes; Pimozide; Salmonella Infections; Salmonella enterica; Small Molecule Libraries; Tuberculosis
PubMed: 34608194
DOI: 10.1038/s41598-021-98980-z -
Prostate Cancer and Prostatic Diseases Mar 2023The taxane cabazitaxel (CBZ) is a promising treatment for docetaxel-resistant castration-resistant prostate cancer (CRPC). However, the survival benefit with CBZ for...
BACKGROUND
The taxane cabazitaxel (CBZ) is a promising treatment for docetaxel-resistant castration-resistant prostate cancer (CRPC). However, the survival benefit with CBZ for patients with CRPC is limited. This study used screening tests for candidate drugs targeting CBZ-resistant-related gene expression and identified pimozide as a potential candidate for overcoming CBZ resistance in CRPC.
METHODS
We established CBZ-resistant cell lines, DU145CR and PC3CR by incubating DU145 cells and PC3 cells with gradually increasing concentrations of CBZ. We performed in silico drug screening for candidate drugs that could reprogram the gene expression signature of a CBZ-resistant prostate cancer cells using a Connectivity Map. The in vivo effect of the drug combination was tested in xenograft mice models.
RESULTS
We identified pimozide as a promising candidate drug for CBZ-resistant CRPC. Pimozide had a significant antitumor effect on DU145CR cells. Moreover, combination treatment with pimozide and CBZ had a synergic effect for DU145CR cells in vitro and in vivo. Microarray analysis identified AURKB and KIF20A as potential targets of pimozide in CBZ-resistant CRPC. DU145CR had significantly higher AURKB and KIF20A expression compared with a non-CBZ-resistant cell line. Inhibition of AURKB and KIF20A had an antitumor effect in DU145CR xenograft tumors. Higher expression of AURKB and KIF20A was a poor prognostic factor of TGCA prostate cancer cohort. CBZ-resistant prostate cancer tissues in our institution had higher AURKB and KIF20A expression.
CONCLUSIONS
Pimozide appears to be a promising drug to overcome CBZ resistance in CRPC by targeting AURKB and KIF20A.
Topics: Male; Humans; Animals; Mice; Antineoplastic Agents; Prostatic Neoplasms, Castration-Resistant; Drug Resistance, Neoplasm; Pimozide; Early Detection of Cancer; Taxoids; Cell Line, Tumor
PubMed: 34593983
DOI: 10.1038/s41391-021-00426-0 -
Behavioural Brain Research Jan 2022Tremor is one of the motor symptoms of Parkinson's disease (PD), present also in neuroleptic-induced parkinsonism. Tremulous Jaw Movements (TJMs) are suggested to be a...
Tremor is one of the motor symptoms of Parkinson's disease (PD), present also in neuroleptic-induced parkinsonism. Tremulous Jaw Movements (TJMs) are suggested to be a well-validated rodent model of PD resting tremor. TJMs can be induced by typical antipsychotics and are known to be reduced by different drugs, including adenosine A receptor antagonists. The aim of the present study was to search for brain structures involved in the tremorolytic action of SCH58261, a selective A receptor antagonist, in TJMs induced by subchronic pimozide. Besides TJMs, we evaluated in the same animals the expression of zif-268 mRNA (neuronal responsiveness marker), and mRNA levels for glutamic acid decarboxylase 65-kDa isoform (GAD65) and vesicular glutamate transporters 1 and 2 (vGluT1/2) in selected brain structures, as markers of GABAergic and glutamatergic neurons, respectively. We found that SCH58261 reduced the pimozide-induced TJMs. Pimozide increased the zif-268 mRNA level in the striatum, nucleus accumbens (NAc) core, and substantia nigra pars reticulata (SNr). Additionally, it increased GAD65 mRNA in the striatum and SNr, and vGluT2 mRNA levels in the subthalamic nucleus (STN). A positive correlation between zif-268, GAD65 and vGluT2 mRNAs and TJMs was found. SCH58261 reversed the pimozide-increased zif-268 mRNA in the striatum and NAc core and GAD65 mRNA in the striatum and SNr. In contrast, SCH58261 did not influence vGluT2 mRNA in STN. The present study suggests an importance of the striato-subthalamo-nigro-thalamic circuit in neuroleptic-induced TJMs. The tremorolytic effect of A receptor blockade seems to involve this circuit bypassing, however, STN.
Topics: Animals; Antipsychotic Agents; Brain; Corpus Striatum; Dopamine Antagonists; Early Growth Response Protein 1; Glutamate Decarboxylase; Jaw; Male; Movement; Parkinson Disease, Secondary; Pimozide; Pyrimidines; RNA, Messenger; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A2A; Subthalamic Nucleus; Tremor; Triazoles
PubMed: 34536428
DOI: 10.1016/j.bbr.2021.113585 -
International Journal of Molecular... Aug 2021Protein-protein interactions between G protein-coupled receptors (GPCRs) can augment their functionality and increase the repertoire of signaling pathways they regulate....
Protein-protein interactions between G protein-coupled receptors (GPCRs) can augment their functionality and increase the repertoire of signaling pathways they regulate. New therapeutics designed to modulate such interactions may allow for targeting of a specific GPCR activity, thus reducing potential for side effects. Dopamine receptor (DR) heteromers are promising candidates for targeted therapy of neurological conditions such as Parkinson's disease since current treatments can have severe side effects. To facilitate development of such therapies, it is necessary to identify the various DR binding partners. We report here a new interaction partner for DRD and DRD, the orphan receptor G protein-coupled receptor 143 (GPR143), an atypical GPCR that plays multiple roles in pigment cells and is expressed in several regions of the brain. We previously demonstrated that the DRD/ DRD antagonist pimozide also modulates GPR143 activity. Using confocal microscopy and two FRET methods, we observed that the DRs and GPR143 colocalize and interact at intracellular membranes. Furthermore, co-expression of wildtype GPR143 resulted in a 57% and 67% decrease in DRD and DRD activity, respectively, as determined by β-Arrestin recruitment assay. GPR143-DR dimerization may negatively modulate DR activity by changing affinity for dopamine or delaying delivery of the DRs to the plasma membrane.
Topics: Dopamine; Eye Proteins; Humans; Membrane Glycoproteins; Mutation; Protein Binding; Protein Interaction Domains and Motifs; Receptors, Dopamine D2; Receptors, Dopamine D3; Signal Transduction; beta-Arrestins
PubMed: 34361094
DOI: 10.3390/ijms22158328