Combinatorial targeting of glutamine metabolism and lysosomal-based lipid metabolism effectively suppresses glioblastoma.

Antipsychotic drugs have been shown to have antitumor effects but have had limited potency in the clinic. Here, we unveil that pimozide inhibits lysosome hydrolytic function to suppress fatty acid and cholesterol release in glioblastoma (GBM), the most lethal brain tumor. Unexpectedly, GBM develops resistance to pimozide by boosting glutamine consumption and lipogenesis. These elevations are driven by SREBP-1, which we find upregulates the expression of ASCT2, a key glutamine transporter. Glutamine, in turn, intensifies SREBP-1 activation through the release of ammonia, creating a feedforward loop that amplifies both glutamine metabolism and lipid synthesis, leading to drug resistance. Disrupting this loop via pharmacological targeting of ASCT2 or glutaminase, in combination with pimozide, induces remarkable mitochondrial damage and oxidative stress, leading to GBM cell death in vitro and in vivo. Our findings underscore the promising therapeutic potential of effectively targeting GBM by combining glutamine metabolism inhibition with lysosome suppression.

An update on pharmacotherapy for trigeminal neuralgia.

INTRODUCTION: Trigeminal neuralgia is a rare condition that can be effectively treated by carbamazepine or oxcarbazepine but these older drugs are associated with dose-dependent and potentially treatment-limiting adverse effects. Third-generation anticonvulsants, new calcitonin gene-related peptide blockers for migraine, and older drugs such as ketamine and cannabinoids may be promising adjuvants or monotherapeutic options. AREAS COVERED: The new drugs, their presumed mechanisms of action, safety and efficacy are discussed herein. There is a paucity of robust clinical evidence in support of these drugs for trigeminal neuralgia. New migraine agents are considered as well although migraines and trigeminal neuralgia are distinct, albeit similar, conditions. No new drugs have been released to market in recent years with the specific indication of trigeminal neuralgia. EXPERT OPINION: In real-world clinical practice, about half of trigeminal neuralgia patients take more than one agent for prevention and combination therapy may be the optimal approach. Combination therapy might allow for lower doses of carbamazepine or oxcarbazepine, thus reducing the number and severity of potential adverse events but the potential for pharmacokinetic drug-drug interactions must be considered. Drug therapy for trigeminal neuralgia involves acute or abortive treatments, often administered in hospital versus long-term preventive therapy, usually involving oral agents.

Trigeminal neuralgia is a relatively rare condition that usually affects one side of the face below the eye around the cheekbone. The cause of trigeminal neuralgia is sometimes a damaged nerve or a nerve that has lost part of its outer protective sheath (myelin). However, trigeminal neuralgia may have other neurological causes as well. Pain can be triggered by touch, pressure, or chewing and it tends to occur in very painful brief attacks followed by pauses with little or no pain. There are two types of drug treatment for trigeminal neuralgia: drugs to stop an ongoing attack (which are often administered in an emergency room or hospital intravenously) and drugs that are taken orally over the long term to reduce or prevent attacks.The two most effective drugs for trigeminal neuralgia are carbamazepine and oxcarbazepine, which are actually drugs to prevent seizures. They are effective in reducing the pain intensity and number of attacks of trigeminal neuralgia but they have side effects. In fact, these side effects can be so severe that people stop taking the drugs.Many new drugs have come to market recently that may work for trigeminal neuralgia, although none was specifically developed for this use. The newest generation of anti-seizure medications including eslicarbazepine, lacosamide, levetiracetam, and retigabine, may be just as effective as the older carbamazepine and oxcarbazepine drugs with fewer side effects. Clinical studies are needed to test them in trigeminal neuralgia patients but their mechanisms of action suggest that they might work well.There are some new drugs developed for migraine headache that inhibit a substance in the body called CGRP. Migraine headaches and trigeminal neuralgia have some of the same symptoms but they are different conditions but both involve too much CGRP.Other new drugs include lasmiditan, pimozide (used for Tourette syndrome), tizanidine (muscle relaxant), lamotrigine and vixotrigine (anti-seizure drugs) may also be beneficial. It may be that people with trigeminal neuralgia will have to take combination therapy, the use of two or more drugs with different mechanisms of action. Older drugs like ketamine and cannabinoids are also being considered as possible add-on agents for therapy for trigeminal neuralgia.

Targeting OXCT1-mediated ketone metabolism reprograms macrophages to promote antitumor immunity via CD8+ T cells in hepatocellular carcinoma.

BACKGROUND & AIMS: The liver is the main organ of ketogenesis, while ketones are mainly metabolized in peripheral tissues via the critical enzyme 3-oxoacid CoA-transferase 1 (OXCT1). We previously found that ketolysis is reactivated in hepatocellular carcinoma (HCC) cells through OXCT1 expression to promote tumor progression; however, whether OXCT1 regulates antitumor immunity remains unclear. METHODS: To investigate the expression pattern of OXCT1 in HCC in vivo, we conducted multiplex immunohistochemistry experiments on human HCC specimens. To explore the role of OXCT1 in mouse HCC tumor-associated macrophages (TAMs), we generated LysMcreOXCT1f/f (OXCT1 conditional knockout in macrophages) mice. RESULTS: Here, we found that inhibiting OXCT1 expression in tumor-associated macrophages reduced CD8+ T-cell exhaustion through the succinate-H3K4me3-Arg1 axis. Initially, we found that OXCT1 was highly expressed in liver macrophages under steady state and that OXCT expression was further increased in TAMs. OXCT1 deficiency in macrophages suppressed tumor growth by reprogramming TAMs toward an antitumor phenotype, reducing CD8+ T-cell exhaustion and increasing CD8+ T-cell cytotoxicity. Mechanistically, high OXCT1 expression induced the accumulation of succinate, a byproduct of ketolysis, in TAMs, which promoted Arg1 transcription by increasing the H3K4me3 level in the Arg1 promoter. In addition, pimozide, an inhibitor of OXCT1, suppressed Arg1 expression as well as TAM polarization toward the protumor phenotype, leading to decreased CD8+ T-cell exhaustion and slower tumor growth. Finally, high expression of OXCT1 in macrophages was positively associated with poor survival in patients with HCC. CONCLUSIONS: In conclusion, our results demonstrate that OXCT1 epigenetically suppresses antitumor immunity, suggesting that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer. IMPACT AND IMPLICATIONS: The intricate metabolism of liver macrophages plays a critical role in shaping hepatocellular carcinoma progression and immune modulation. Targeting macrophage metabolism to counteract immune suppression presents a promising avenue for hepatocellular carcinoma treatment. Herein, we found that the ketogenesis gene OXCT1 was highly expressed in tumor-associated macrophages (TAMs) and promoted tumor growth by reprogramming TAMs toward a protumor phenotype. Pharmacological targeting or genetic downregulation of OXCT1 in TAMs enhances antitumor immunity and slows tumor growth. Our results suggest that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer.

Ponatinib and STAT5 Inhibitor Pimozide Combined Synergistic Treatment Applications Potentially Overcome Drug Resistance via Regulating the Cytokine Expressional Network in Chronic Myeloid Leukemia Cells.

Chronic myeloid leukemia (CML) is a clonal myeloproliferative hematological disease characterized by the chimeric breakpoint-cluster region/Abelson kinase1 (BCR::ABL1) oncoprotein; playing a pivotal role in CML molecular pathology, diagnosis, treatment, and possible resistance arising from the success and tolerance of tyrosine kinase inhibitor (TKI)-based therapy. The transcription factor STAT5 constitutive signaling, which is influenced by the cytokine signaling network, triggers BCR::ABL1-based CML pathogenesis and is also relevant to acquired TKI resistance. The unsuccessful therapeutic approaches targeting BCR::ABL1, in particular third-line therapy with ponatinib, still need to be further developed with alternative combination strategies to overcome drug resistance. As treatment with the STAT5 inhibitor pimozide in combination with ponatinib resulted in an efficient and synergistic therapeutic approach in TKI-resistant CML cells, this study focused on identifying the underlying amplification of ponatinib response mechanisms by determining different cytokine expression profiles in parental and ponatinib-resistant CML cells, in vitro. The results showed that expression of interleukin (IL) 1B, IL9, and IL12A-B was increased by 2-fold, while IL18 was downregulated by 2-fold in the ponatinib-resistant cells compared to sensitive ones. Importantly, ponatinib treatment upregulated the expression of 21 of the 23 interferon and IL genes in the ponatinib-resistant cells, while treatment with pimozide or a combination dose resulted in a reduction in the expression of 19 different cytokine genes, such as for example, inflammatory cytokines, IL1A-B and IL6 or cytokine genes associated with supporting tumor progression, leukemia stem cell growth or poor survival, such as IL3, IL8, IL9, IL10, IL12, or IL15. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis results showed that the genes were mainly enriched in the regulation of receptor signaling through the Janus kinase/signal transducer and activator of transcription pathway, cytokine-cytokine receptor interaction, and hematopoietic cell lineage. Protein-protein interaction analysis showed that IL2, IL6, IL15, IFNG, and others appeared in the top lists of pathways, indicating their high centrality and importance in the network. Therefore, pimozide could be a promising agent to support TKI therapies in ponatinib resistance. This research would help to clarify the role of cytokines in ponatinib resistance and advance the development of new therapeutics to utilize the STAT5 inhibitor pimozide in combination with TKIs.

The antipsychotic drug pimozide promotes apoptosis through the RAF/ERK pathway and enhances autophagy in breast cancer cells.

The antipsychotic drug pimozide has been demonstrated to inhibit cancer. However, the precise anti-cancer mechanism of pimozide remains unclear. The purpose of this study was to investigate the effects of pimozide on human MCF-7 and MDA-MB-231 breast cancer cell lines, and the potential involvement in the RAF/ERK signaling. The effects of pimozide on cells were examined by 4,5-dimethylthiazol-2-yl-3,5-diphenylformazan, wound healing, colony formation, transwell assays, and caspase activity assay. Flow cytometry and acridine orange and ethidium bromide staining were performed to assess changes in cells. Transmission electron microscopy and monodansylcadaverine staining were used to observe autophagosomes. The cyclic adenosine monophosphate was evaluated using the FRET system. Immunohistochemistry, immunofluorescence, RNA interference, and western blot investigated the expression of proteins. Mechanistically, we focus on the RAF1/ERK signaling. We detected pimozide was docked to RAF1 by Schrodinger software. Pimozide down-regulated the phosphorylation of RAF1, ERK 1/2, Bcl-2, and Bcl-xl, up-regulated Bax, and cleaved caspase-9 to induce apoptosis. Pimozide might promote autophagy by up-regulating cAMP. The enhancement of autophagy increased the conversion of LC3-I to LC3-II and down-regulated p62 expression. But mTOR signaling was not involved in promoting autophagy. The knockdown of RAF1 expression induced autophagy and apoptosis in breast cancer cells, consistent with the results of pimozide or sorafenib alone. Blocked autophagy by chloroquine resulted in the impairment of pimozide-induced apoptosis. These data showed that pimozide inhibits breast cancer by regulating the RAF/ERK signaling pathway and might activate cAMP-induced autophagy to promote apoptosis and it may be a potential drug for breast cancer treatment.

A new hope for early T cell precursor acute lymphoblastic leukemia therapy based on STAT5+ leukemic stem cell targeting.

Leukemia stem cells are known to drive tumor progression, drug resistance, microenvironmental shift, and relapse, which would make them a perfect therapeutic target. However, their phenotypic and functional similarity to their normal counterparts leaves limited road maps for their selective elimination. Tremblay et al. recently unraveled the fundamental role of overactivated pSTAT5 as a functional marker of early T cell precursor acute lymphoblastic leukemia stem cells driving leukemic progression and highlighted its potential use as a therapeutic target to prevent fatal outcomes.

Deletion of the CYP2D6 gene as a likely explanation for the serious side effects of the antipsychotic drug pimozide: a case report.

CYP2D6 analysis prior to the prescription of pimozide is required above a certain dose by the Food and Drug Administration in order to detect individuals with the poor metabolizer status. This precautionary measure aims to prevent the occurrence of serious adverse drug reactions. This study presents a case of a patient diagnosed with schizophrenia spectrum disorder. The patient suffered re-admission in the psychiatry ward because of severe secondary symptoms due to the antipsychotic drug pimozide, previously prescribed on a first admission. In order to assess the patient's medication profile, real-time PCR was performed to analyze the main genes responsible for its metabolization, namely, CYP2D6 and CYP3A4. The pharmacogenetic study revealed that the patient is a poor metabolizer for CYP2D6, presenting deletion of both copies of the gene (diplotype *5/*5). Fortunately, the symptomatology disappeared after the withdrawal of the responsible drug. In conclusion, abiding by the pharmacogenetic clinical practice guidelines and the pharmacogenetic analysis of CYP2D6 when prescribing pimozide would have probably saved the patient from the consequences of severe side effects and the health system expenditure. There is an important need for more training in the pharmacogenetic field for specialists in psychiatry.

Antimicrobial effect of pimozide by targeting ROS-mediated killing in Staphylococcus aureus.

In spite of the higher nosocomial and community-acquired infections caused by Staphylococcus aureus, emerging drug resistance is a leading cause of increased mortality and morbidity associated with the overuse of antimicrobials. It is an emergent need to find out new molecules to combat such infections. In the present study, we analyzed the antibacterial effect of pimozide (PMZ) against gram-positive and gram-negative bacterial strains, including methicillin-sensitive (MSSA) and methicillin-resistant (MRSA) S. aureus. The growth of MSSA and MRSA was completely inhibited at concentrations of 12.5 and 100 µg/mL, respectively, which is referred to as 1× minimum inhibitory concentration (MIC). The cell viability was completely eliminated within 90 min of PMZ treatment (2× MIC) through reactive oxygen species (ROS)-mediated killing without affecting cell membrane permeability. It suppressed α-hemolysin production and biofilm formation of different S. aureus strains by almost 50% at 1× MIC concentration, and was found to detach matured biofilm. PMZ treatment effectively eliminates S. aureus infection in Caenorhabditis elegans and improves its survival by 90% and is found safe to use with no hemolytic effect on human and chicken blood tissues. Taken together, it is concluded that PMZ may turn out to be an effective antibacterial for treating bacterial infections including MSSA and MRSA.

Pimozide Increases a Delayed Rectifier K+ Conductance in Chicken Embryo Vestibular Hair Cells.

Pimozide is a conventional antipsychotic drug largely used in the therapy for schizophrenia and Tourette's syndrome. Pimozide is assumed to inhibit synaptic transmission at the CNS by acting as a dopaminergic D2 receptor antagonist. Moreover, pimozide has been shown to block voltage-gated Ca2+ and K+ channels in different cells. Despite its widespread clinical use, pimozide can cause several adverse effects, including extrapyramidal symptoms and cardiac arrhythmias. Dizziness and loss of balance are among the most common side effects of pimozide. By using the patch-clamp whole-cell technique, we investigated the effect of pimozide [3 µM] on K+ channels expressed by chicken embryo vestibular type-II hair cells. We found that pimozide slightly blocks a transient outward rectifying A-type K+ current but substantially increases a delayed outward rectifying K+ current. The net result was a significant hyperpolarization of type-II hair cells at rest and a strong reduction of their response to depolarizing stimuli. Our findings are consistent with an inhibitory effect of pimozide on the afferent synaptic transmission by type-II hair cells. Moreover, they provide an additional key to understanding the beneficial/collateral pharmacological effects of pimozide. The finding that pimozide can act as a K+ channel opener provides a new perspective for the use of this drug.

STAT5 inhibitor Pimozide as a probable therapeutic option in overcoming Ponatinib resistance in K562 leukemic cells.

Signal Transducer and Activator of Transcription 5 (STAT5) is a transcription factor that plays a key role in neoplasia, triggered by the fusion oncogene BCR-ABL1; it is not only an essential protein for the pathogenesis of chronic myeloid leukemia (CML), but also its overexpression is associated with drug resistance developed toward various generations of Tyrosine Kinase Inhibitors (TKIs); these are still accepted as gold standard therapeutics for the treatment of CML. In this study, it was investigated whether suppression of STAT5 via a "STAT5 inhibitor" Pimozide resulted in any regain of chemosensitivity to third-generation TKI Ponatinib. Accordingly, the experimental work was designed on both parental CML cell line K562WT and its 1 nM Ponatinib-resistant counterpart, indicated as K562-Pon1. Based on the experimental results, Pimozide was more effective in resistant cells compared to wild-type cells for inducing apoptosis and block cell arrest. Combination therapy of Pimozide and Ponatinib demonstrated that STAT5 was a significant protein for regaining chemosensitivity to Ponatinib when its expression was suppressed both at mRNA and protein level. In conclusion, we consider that STAT5 inhibitor Pimozide can be a good alternative or combination therapy with TKIs for patients suffering from chemotherapeutic drug resistance. Communicated by Ramaswamy H. Sarma.

The inhibitory effects of pimozide, an antipsychotic drug, on voltage-gated K+ channels in rabbit coronary arterial smooth muscle cells.

Pimozide is an antipsychotic drug used to treat chronic psychosis, such as Tourette's syndrome. Despite its widespread clinical use, pimozide can cause unexpected adverse effects, including arrhythmias. However, the adverse effects of pimozide on vascular K+ channels have not yet been determined. Therefore, we investigated the effects of pimozide on voltage-gated K+ (Kv) channels in rabbit coronary arterial smooth muscle cells. Pimozide concentration-dependently inhibited the Kv currents with an IC50 value of 1.78 ± 0.17 µM and a Hill coefficient of 0.90 ± 0.05. The inhibitory effect on the Kv current by pimozide was highly voltage-dependent in the voltage range of Kv channel activation, and additive inhibition of the Kv current by pimozide was observed in the full activation voltage range. The decay rate of inactivation was significantly accelerated by pimozide. Pimozide shifted the inactivation curve to a more negative potential. The recovery time constant from inactivation increased in the presence of pimozide. Furthermore, pimozide-induced inhibition of the Kv current was augmented by applying train pulses. Although pretreatment with the Kv2.1 subtype inhibitor guangxitoxin and the Kv7 subtype inhibitor linopirdine did not alter the degree of pimozide-induced inhibition of the Kv currents, pretreatment with the Kv1.5 channel inhibitor DPO-1 reduced the inhibitory effects of pimozide on Kv currents. Pimozide induced membrane depolarization. We conclude that pimozide inhibits Kv currents in voltage-, time-, and use (state)-dependent manners. Furthermore, the major Kv channel target of pimozide is the Kv1.5 channel.

Seventy Years of Treating Delusional Disorder with Antipsychotics: A Historical Perspective.

For many decades, delusional disorder (DD) has been considered a treatment-resistant disorder, with antipsychotics acknowledged as the best, though imperfect, treatment. It is possible that the discovery of the right drug could turn treatment resistance into treatment response. The goal of this narrative review is to provide a historical perspective of the treatment of DD since the introduction of antipsychotics 70 years ago. The following search terms were used to scan the literature: antipsychotics AND "delusional disorder". Findings were that therapy for DD symptoms has changed over time. Initial reports suggested that the drug of choice was the antipsychotic pimozide, and that this drug was especially effective for the somatic subtype of DD. Subsequent studies demonstrated that other antipsychotics, for instance, risperidone and olanzapine, were also highly effective. Treatment response may vary according to the presence or absence of specific symptoms, such as cognitive defect and depression. Clozapine, partial D2 agonists, and long-acting injectable drugs may be more effective than other drugs, but the evidence is not yet in. Because of the absence of robust evidence, treatment guidelines for the optimal management of DD are not yet available.

Pimozide inhibits the growth of breast cancer cells by alleviating the Warburg effect through the P53 signaling pathway.

The Warburg effect is a promising target for the diagnosis and treatment of cancer, referring to the ability of cancer cells to generate energy through high levels of glycolysis even in the presence of oxygen, allowing them to grow and proliferate rapidly. The antipsychotic Pimozide has strong anti-breast cancer effects both in vivo and in vitro, whether Pimozide has an inhibitory effect on aerobic glycolysis has not been elucidated. In this study, Pimozide inhibited the Warburg effect of breast cancer cells by hindering glucose uptake, ATP level and lactate production; reducing the extracellular acidification rate (ECAR); suppressing the expression of PKM2, a rate-limiting enzyme in glycolysis. Intriguingly, Pimozide was significantly involved in reprogramming glucose metabolism in breast cancer cells through a p53-dependent manner. Mechanistic studies demonstrated Pimozide increased the expression of p53 through inhibition of the PI3K/Akt/MDM2 signaling pathway, which in turn downregulated the expression of PKM2. In sum, our results suggest that Pimozide mediates the p53 signaling pathway through PI3K/AKT/MDM2 to inhibit the Warburg effect and breast cancer growth, and it may be a potential aerobic glycolysis inhibitor for the treatment of breast cancer.

On the Similarity Between the Reinforcing and the Discriminative Properties of Intracranial Self-Stimulation.

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.

Corrigendum: STAT5a Confers Doxorubicin Resistance to Breast Cancer by Regulating ABCB1.

[This corrects the article DOI: 10.3389/fonc.2021.697950.].

STAT3 Enhances Sensitivity of Glioblastoma to Drug-Induced Autophagy-Dependent Cell Death.

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.

Blockade of adenosine A2A receptors inhibits Tremulous Jaw Movements as well as expression of zif-268 and GAD65 mRNAs in brain motor structures.

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 A2A receptor antagonists. The aim of the present study was to search for brain structures involved in the tremorolytic action of SCH58261, a selective A2A 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 A2A receptor blockade seems to involve this circuit bypassing, however, STN.

Treatment of tardive dyskinesia: a review and update for dermatologists managing delusions of parasitosis.

INTRODUCTION: This article introduces to the dermatology provider two medications for the treatment of tardive dyskinesia (TD), which were the first medications approved by the US FDA specifically for the treatment of TD. In addition to describing these two new medications, this article will also provide a focused review of the pathogenesis of TD, as well as non-FDA-approved treatments, which have been tried prior to the advent of these medications. METHODS: A PubMed search was conducted and articles were reviewed by the senior authors and included if they were relevant for dermatologists regarding etiology, symptoms, risk, and treatment of TD. RESULTS: One of the most widely accepted explanations of TD involves the concept of 'dopamine receptor hypersensitivity state.' There are several other less well substantiated proposed pathogenic pathways of TD. The clinical manifestation is characterized by involuntary movements. Prevention includes switching to a 2nd generation agent or using the lowest dose possible for the shortest amount of time. Two new FDA-approved medications for TD are also discussed and reviewed. CONCLUSION: TD now has FDA-approved medications for treatment. Now, there is even more reason for the dermatologist to have increased confidence when treating delusions of parasitosis (DOP) with antipsychotic agents.