Effects Of Chlorpromazine Research Articles

Immunomodulatory properties of splenocytes treated with chlorpromazine in experimental aggression

Aggressive behavior is considered to be as one of the central symptoms of many neuropsychiatric disorders. It is a serious medical and biological problem associated both with high frequency and severity of manifestations and lack of selective correction means. The purpose of this study was to evaluate the functional phenotype of immune cells treated with chlorpromazine in aggressive animals in vitro, as well as the effect of transplantation of these cells on syngeneic aggressive recipient’s immune cells functional activity. Aggressive behavior was formed in active mice as a result of repeated experience of victories in agonistic interactions with animals with a submissive partner. Further, aggressive animals were isolated into individual cells and used as donors and recipients of immune cells. Immune cells were obtained under sterile conditions from suspension of spleen cells precultured with chlorpromazine. The level of spontaneous and mitogen-induced cell proliferation was assessed using a standard method of radioactive label incorporation. The quantitative content of cytokines in samples of treated with chlorpromazine cell cultures supernatant was determined by enzyme immunoassay using appropriate test systems. Further aggressive syngeneic recipients were intravenously injected with splenocytes precultured with chlorpromazine. The control group of animals was injected with splenocytes precultured under similar conditions, without the chlorpromazine addition. The recipients were assessed for the spleen cells proliferative activity and the intensity of humoral and cellular immune response using standard methods, by the number of antibody-forming spleen cells and severity of a delayed-type hypersensitivity reaction in response to T-dependent antigen introduction. It was found that treatment with chlorpromazine in vitro suppressed mitogen-stimulated proliferation of splenocytes in aggressive mice, without changing of spontaneous proliferation. It was also accompanied by some cytokines production decrease: IL-6, IL-2 and IFNã. When studying the humoral and cellular immune response intensity in aggressive recipients after transplantation of donor’s syngeneic splenocytes treated with chlorpromazine, a decrease in the intensity of humoral immune response was recorded. Transplantation of donor’s splenocytes treated with chlorpromazine was also accompanied by a decrease in spontaneous and mitogen-stimulated proliferation of splenocytes from aggressive recipients. Thus, the obtained data indicate the inhibitory effect of chlorpromazine on immune cell’s functional activity in aggressive mice, as well as the positive immunomodulatory effect of chlorpromazine-treated immune cells transplantation at aggressive behavior in experimental animals.

Electrochemical oxidation of Fe (II) using chlorpromazine drug at boron-doped diamond electrode: application to in vivo mechanism study interaction of chlorpromazine on hemoglobin iron and evaluation of some biomolecules

In this study, the electrochemical properties of aqueous chlorpromazine hydrochloride (CPZ) in the presence of Fe (II) were investigated by cyclic voltammetry at a boron-doped diamond (BDD) electrode. The results showed that an EC′ reaction mechanism occurs, where electrochemically generated CPZ species (cation radical) are reduced by Fe (II) back to the parent CPZ, and Fe (II) is oxidized to Fe (III). The detection limit, sensitivity, and dynamic concentration ranges were 2.8 μM, 0.0188 μA μM−1 and 10–166 μM. Based on the electrochemical results, the interaction of chlorpromazine (CPZ), a widely used antipsychotic tranquillizer, with the allosteric protein, hemoglobin, has been studied. First, four groups of six female rats weighing 400–450 g were selected. The rats were injected with different concentrations of chlorpromazine over a 3-week period, and the concentrations of hemoglobin, methemoglobin, red blood cells (RBCs), and hematocrit (HCT) were analyzed in the blood of each rat. After injection of different concentrations of the drug, the amount of hemoglobin) as a source of Fe (II)) decreased, but the amount of methemoglobin (as a source of Fe (III) increased. In addition, UV spectroscopic measurements in the range of 200–700 nm indicate the conversion of hemoglobin to methemoglobin in chlorpromazine-treated rats compared to the normal sample, and there was a direct relationship between the increasing methemoglobin concentration of chlorpromazine. Furthermore, the amount of RBC and HCT was measured. The results showed that RBC (21.05%–56.52%) and HCT (10.04%–53.19%) decreased. Finally, this study demonstrates a new mechanism for the effects of CPZ on hemoglobin iron in rat blood based on electrochemical results.

Central effects of peripherally administrated immune cells modulated by a psychoactive substance in aggression

IntroductionIt is known that the formation of aggressive behavior is accompanied by neurodegenerative and neuroinflammatory changes. Immune cells have a regulatory effect on the central nervous system functions, including regulation of behavior.ObjectivesWe first demonstrated that ex vivo chlorpromazine - modulated immune cells have a positive aggressive behavior editing effect. The aim of the study was to investigate the influence of the indicated cells on some central mechanisms underlying the development of aggressive reactions.Methods(CBAxC57Bl/6) F1 aggressive male mice, developed in conditions of chronic social stress, were undergoing the transplantation of syngeneic spleen lymphocytes with ex vivo chlorpromazine-modulated functional activity. In recipients the immunohistochemical analysis was performed assessing the expression of the microglial marker Iba1. The levels of brain-derived neurotrophic factor (Bdnf ) and cytokines was assessed by ELISA. For histological examination Nissl staining was applied.ResultsAggressive behavior editing after the chlorpromazine-modulated immune cells transplantation registered against the background of some structural and functional changes in the brain. It was found an increase in the density of pyramidal neurons in CA1 and CA3 hippocampal regions and augmented level of Bdnf. The decreased expression of microglial activation marker Iba1, accompanied with decreased levels of pro-inflammatory cytokines (IL-1β, IL-2, IL-6, INF-γ) and increased anti-inflammatory (IL-4) cytokine was found. Visualization of functionally active lymphocytes pre-treated with chlorpromazine in the brain parenchyma of aggressive recipients suggests a direct effect of injected lymphocytes on CNS.ConclusionsThe effect of chlorpromazine - modulated immune cells that edits aggressive behavior is realized by stimulating neurogenesis, neuroplasticity and reducing neuroinflammation.Disclosure of InterestNone Declared

Abstract 4713: Chlorpromazine affects glioblastoma bioenergetics by interfering with pyruvate kinase M2: A route for drug repurposing in glioblastoma

Abstract Glioblastoma, the most common and deadly brain tumor, remains a critical unmet medical need due to the limited effectiveness of current treatments. Drug repurposing has recently emerged as a promising strategy to improve glioblastoma outcomes. Antipsychotic drugs, with their established safety profile and potential to disrupt tumor-neuron interactions, have drawn particular attention. Among these, chlorpromazine, a well-tolerated medication included in the 2021 WHO Model List of Essential Medicines, holds promise due to its therapeutic effects in psychiatric disorders stemming from its non-specific interference with various CNS neurotransmitter receptors. Our recent studies have demonstrated chlorpromazine's ability to inhibit several molecular and cellular processes in glioblastoma cells, suggesting its potential as a novel treatment option for this challenging disease.To elucidate chlorpromazine's mechanism of action as a potential anticancer drug, we employed two proteomics approaches: Reverse-Phase Protein microArrays to evaluate its impact on signal transduction pathways and Activity-Based Protein Profiling followed by mass spectrometry to identify novel molecular targets.Our data revealed that chlorpromazine significantly modulates major signal transduction pathways and implicates pyruvate kinase (PK) M2 as a drug target. PKM2, a PK variant characteristic of many cancers, plays a crucial role in orchestrating metabolic alterations, exemplified by the Warburg effect – the high glucose consumption and lactate production by cancer cells even under oxygen-rich conditions. PKM2 functions as a tetramer in the glycolytic pathway, while its dimeric form acquires nuclear localization, protein kinase activity, and interacts with various transcription factors, contributing to its pro-tumorigenic activity.Consistent with its ability to target PKM2, chlorpromazine promoted PKM2 tetramerization in glioblastoma cells, leading to significant alterations in glioblastoma energy metabolism. Notably, RPE-1 non-cancer neuroepithelial cells showed a reduced response to the drug. Additionally, silencing PKM2 diminished the effects of chlorpromazine. 3D modeling revealed that chlorpromazine interacts with the PKM2 tetramer at the same site involved in binding other small-molecule activators that stabilize the PKM2 tetramer.These findings suggest that chlorpromazine counteracts the Warburg effect and, consequently, malignancy in glioblastoma cells, while sparing non-cancerous RPE-1 cells. This preclinical evidence supports the rationale behind our recently completed multicenter Phase II clinical trial investigating the role of chlorpromazine in glioblastoma treatment. The study is registered as EudraCT #2019-001988-75 and ClinicalTrials.gov Identifier #NCT0422444. Citation Format: Claudia Abbruzzese, Silvia Matteoni, Paola Matarrese, Michele Signore, Barbara Ascione, Elisabetta Iessi, Aymone Gurtner, Andrea Sacconi, Andrea Pace, Veronica Villani, Andrea Polo, Susan Costantini, Alfredo Budillon, Gennaro Ciliberto, Marco G. Paggi. Chlorpromazine affects glioblastoma bioenergetics by interfering with pyruvate kinase M2: A route for drug repurposing in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4713.

The cytotoxic effects of prazosin, chlorpromazine, and haloperidol on hepatocellular carcinoma and immortalized non-tumor liver cells.

Liver cancer annually accounts for over 800,000 cases and 700,000 deaths worldwide. Hepatocellular carcinoma is responsible for over 80% of liver cancer cases. Due to ineffective treatment options and limited surgical interventions, hepatocellular carcinoma is notoriously difficult to treat. Nonetheless, drugs utilized for other medical conditions, such as the antihypertensive medication prazosin, the neuroleptic medication chlorpromazine, and the neuroleptic medication haloperidol, have gained attention for their potential anti-cancer effects. Therefore, this study used these medications for investigating toxicity to hepatocellular carcinoma while testing the adverse effects on a noncancerous liver cell line model THLE-2. After treatment, an XTT cell viability assay, cell apoptosis assay, reactive oxygen species (ROS) assay, apoptotic proteome profile, and western blot were performed. We calculated IC50 values for chlorpromazine and prazosin to have a molar range of 35-65µM. Our main findings suggest the capability of both of these treatments to reduce cell viability and generate oxidative stress in HepG2 and THLE-2 cells (p value < 0.05). Haloperidol, however, failed to demonstrate any reduction in cell viability revealing no antitumor effect up to 100µM. Based on our findings, a mechanism of cell death was not able to be established due to lack of cleaved caspase-3 expression. Capable of bypassing many aspects of the lengthy, costly, and difficult cancer drug approval process, chlorpromazine and prazosin deserve further investigation for use in conjunction with traditional chemotherapeutics.

Effect of Neurotropic and Immunotropic Drugs on Leukocyte Elastase Activity In Vitro.

Leukocyte elastase is a marker of inflammation. Previously, a relationship was found between the severity of mental disorders in patients and elastase-like activity of blood plasma. The effect of various neurotropic drugs on leukocyte elastase activity was analyzed in an in vitro experiment. We revealed an inhibitory effect of the benzodiazepine tranquilizers diazepam and bromodihydrochlorophenylbenzodiazepine and immunomodulators aminodihydrophthalazinedione and diclofenac on the plasma elastase-like activity of healthy donors and pure human neutrophil elastase. The antipsychotics chlorpromazine and alimemazine, as well as the nootropic vinpocetine increased elastase-like activity in a dose-dependent manner. The activating effect of chlorpromazine and vinpocetine, but not alimemazine, was reproduced in neutrophil elastase. We hypothesized that these drugs can affect the development of inflammatory reactions in the complex therapy of mental disorders.

Chlorpromazine-Induced Neurological Symptoms Mimicking Stroke in an Elderly Patient with Intractable Hiccups: A Case Report

Background: Chlorpromazine, a widely utilized antipsychotic medication, has been recognized for its efficacy in treating intractable hiccups through its antagonistic action on histamine H1, dopamine D2, and muscarinic M1 receptors. Despite its therapeutic benefits, there is a spectrum of potential side effects, including neurological symptoms such as drug-induced stuttering, which poses diagnostic challenges and may lead to unnecessary investigations. Objective: This case study aims to explore the paradoxical effect of chlorpromazine, which, while effectively treating an 80-year-old male patient's intractable hiccups, induced slurred speech and drowsiness, symptoms that resolved upon cessation of the drug. Methods: A comprehensive evaluation was conducted, involving the patient's clinical presentation, treatment regimen, and the temporal relationship between medication administration and symptom onset. Investigations included a complete blood count, C-reactive protein, liver function tests, COVID-19 antigen test, cardiac workup, and brain MRI. Treatment response and side effects were meticulously documented, with follow-up to assess the resolution of symptoms. Results: Following the administration of chlorpromazine (50mg orally), the patient's hiccups ceased, but he subsequently developed slurred speech and drowsiness. These symptoms were not present upon initial examination and resolved completely following the discontinuation of chlorpromazine. The brain MRI conducted to explore potential neurological causes was found to be insignificant, reinforcing the diagnosis of drug-induced neurological symptoms. Conclusion: While chlorpromazine remains a valuable treatment for intractable hiccups, healthcare providers must be vigilant about its potential to induce neurological symptoms. This case highlights the importance of recognizing drug-induced side effects to avoid unnecessary diagnostic procedures and emphasizes the need for ongoing research into the mechanisms underlying such adverse reactions.

Probable effects of polypharmacy and equivalent doses of psychotropic drugs on prevalence of adverse drug events among psychiatric inpatients in a general hospital in Japan.

In psychiatry, polypharmacy or high psychotropic drug doses increase adverse drug event (ADE) prevalence. However, the full relationship between polypharmacy and ADEs is unclear, and few studies have evaluated dose equivalents for psychotropic drugs for ADEs. Thus, we conducted a retrospective analysis to clarify the effects of polypharmacy and chlorpromazine (CP)-, diazepam (DAP)-, and imipramine- equivalent doses on all ADEs in inpatients. Psychiatric inpatients in a Japanese hospital from April 1, 2016 to March 31, 2018, were enrolled. ADE severity and causality were assessed. Multiple logistic regression analyses were performed to evaluate ADE risk factors. Among 462 patients analyzed, out of 471 patients enrolled, 145 (31.4%) experienced ADEs. The causality assessment determined that "possible" was 96.5%. The most common ADEs were nervous system disorders (35%). Multiple logistic regression analyses indicated an increase in ADE prevalence with the number of drugs used (≥5; p=0.026); CP-equivalent dose (p=0.048); and endocrine, nutritional, and metabolic disorders (p=0.045). DAP-equivalent dose; infectious and parasitic diseases; and injury, poisoning, and consequences of other external causes decreased ADE prevalence (p=0.047, 0.022, and 0.021, respectively). Avoiding polypharmacy in psychiatric inpatients and adjusting drug regimens to safe equivalent doses could reduce ADEs during hospitalization.

Chlorpromazine affects glioblastoma bioenergetics by interfering with pyruvate kinase M2

Glioblastoma (GBM) is the most frequent and lethal brain tumor, whose therapeutic outcome - only partially effective with current schemes - places this disease among the unmet medical needs, and effective therapeutic approaches are urgently required. In our attempts to identify repositionable drugs in glioblastoma therapy, we identified the neuroleptic drug chlorpromazine (CPZ) as a very promising compound. Here we aimed to further unveil the mode of action of this drug. We performed a supervised recognition of the signal transduction pathways potentially influenced by CPZ via Reverse-Phase Protein microArrays (RPPA) and carried out an Activity-Based Protein Profiling (ABPP) followed by Mass Spectrometry (MS) analysis to possibly identify cellular factors targeted by the drug. Indeed, the glycolytic enzyme PKM2 was identified as one of the major targets of CPZ. Furthermore, using the Seahorse platform, we analyzed the bioenergetics changes induced by the drug. Consistent with the ability of CPZ to target PKM2, we detected relevant changes in GBM energy metabolism, possibly attributable to the drug’s ability to inhibit the oncogenic properties of PKM2. RPE-1 non-cancer neuroepithelial cells appeared less responsive to the drug. PKM2 silencing reduced the effects of CPZ. 3D modeling showed that CPZ interacts with PKM2 tetramer in the same region involved in binding other known activators. The effect of CPZ can be epitomized as an inhibition of the Warburg effect and thus malignancy in GBM cells, while sparing RPE-1 cells. These preclinical data enforce the rationale that allowed us to investigate the role of CPZ in GBM treatment in a recent multicenter Phase II clinical trial.

Cholesterol and Ceramide Facilitate Membrane Fusion Mediated by the Fusion Peptide of the SARS-CoV-2 Spike Protein.

SARS-CoV-2 entry into host cells is mediated by the Spike (S) protein of the viral envelope. The S protein is composed of two subunits: S1 that induces binding to the host cell via its interaction with the ACE2 receptor of the cell surface and S2 that triggers fusion between viral and cellular membranes. Fusion by S2 depends on its heptad repeat domains that bring membranes close together and its fusion peptide (FP) that interacts with and perturbs the membrane structure to trigger fusion. Recent studies have suggested that cholesterol and ceramide lipids from the cell surface may facilitate SARS-CoV-2 entry into host cells, but their exact mode of action remains unknown. We have used a combination of in vitro liposome-liposome and in situ cell-cell fusion assays to study the lipid determinants of S-mediated membrane fusion. Our findings reveal that both cholesterol and ceramide lipids facilitate fusion, suggesting that targeting these lipids could be effective against SARS-CoV-2. As a proof of concept, we examined the effect of chlorpromazine (CPZ), an antipsychotic drug known to perturb membrane structure. Our results show that CPZ effectively inhibits S-mediated membrane fusion, thereby potentially impeding SARS-CoV-2 entry into the host cell.

Morphological changes in the liver of rats after administration of chlorpromazine, depending on the dose and duration of administration

Chlorpromazine (CPZ) remains a widely used drug in psychiatric practice today. The drug has a hepatotoxic effect, but the possible mechanisms of this side effect have not yet been fully elucidated. The aim of the study was to determine morphological changes in rat liver tissue under chronic toxic effects of chlorpromazine, depending on the dose and duration of its administration. The study was conducted on 60 sexually mature male rats. CPP was administered intragastrically at different doses (3.5, 7.0, 14.0 and 21.0 mg/kg) for 30 and 60 days. The material was fixed in a 10 % solution of neutral formalin (pH 7.2-7.4) for 24-48 hours, then passed through alcohols of increasing concentration and embedded in paraffin. Serial sections (6-7 µm thick) were prepared from the paraffin blocks and stained with hematoxylin-eosin and picrofuchsin by Van Gieson to determine the degree of fibrotic changes in liver tissue, as well as with Giemsa III to detect fatty degeneration of hepatocytes. The microscopic structure of the hepatic parenchyma was studied using an OLIMPUS BX41 light microscope at 100, 200 and 400x magnification. Morphometric parameters of structural changes were determined using an ocular grid and Image Tulsa 3.6 software. The data were statistically processed by descriptive statistics using the Microsoft Office Excel 2010 spreadsheet processor. When CPZ was administered in different doses and duration, pathological changes of varying severity developed in the liver tissue of rats. In the liver tissue, signs of intracellular and intra-tubular cholestasis are found mainly in the central lobes, accompanied by focal desquamation and proliferation of the biliary epithelium, formation of small-focal, less frequently zonal necrosis of hepatocytes, inflammatory infiltration of portal tracts with its spread to the interlobular stroma and parenchyma. Mitotically active binucleated hepatocytes are the key to the reparative process. Periductal fibrosis develops in the portal sections, marginal proliferation of the bile ducts, hepatocytes with signs of granular and/or fatty dystrophy are noted. In the central veins and vessels of the portal areas, moderate initial sclerotic changes were found, signs of their capillarisation in sinusoids, and the endothelium of the vessels had focal destructive changes. In all portal zones, proliferation of bile ducts and formation of bile pseudo-ducts were observed. Thus, the analysis of the morphometric study data showed that within 60 days of CPZ administration there is a significant increase in the relative volume of connective tissue and stromal-parenchymal index due to a significant decrease in the volume of hepatocytes.

The Acute Effect of Chlorpromazine on Body Temperature in Intensive Care Unit Patients

Aim: Hypothermia is a rare complication of antipsychotic drugs but serious outcomes including death may result. In this study, we aimed to investigate body temperature alterations in acute phase of chlorpromazine treatment, the relationship of inflammatory indicators and risk factors for hypothermic effect in intensive care unit (ICU) patients.&#x0D; Materials and methods: 63 intensive care patients who needed sedative treatment due to agitation were divided into two groups as Group 1 (n = 30) with temperatures ≤ 38°C, and Group 2 (n = 33) with temperatures &gt; 38°C according to baseline body temperatures. Also, recurrent measurements for 12 hours were made at specific intervals following 25 mg intravenous chlorpromazine. &#x0D; Results: In Group 1, decrease in body temperatures was significant from 4th to 12th hours (p &lt; 0.01), while in Group 2, significant decreases in body temperatures at all measurement hours were observed (p &lt; 0.01). Temperature changes (delta temperature) observed at specific measurement intervals were significantly higher in Group 2 compared to Group 1. That difference was statistically significant at all intervals except for ΔTemperature B-6 (p &lt; 0.05). The odds of hypothermic effects by chlorpromazine were 16%, 46%, 3%, and 18% for Acute Physiology and Chronic Health Evaluation II, procalcitonin, C-reactive protein, and white blood cells, respectively. &#x0D; Conclusion: Chlorpromazine treatment applied for agitation in ICU patients was associated with acute hypothermic effect. Severity of disease and comorbidities might increase risk of hypothermia, and inflammatory biomarkers might be predictors of adverse drug reaction.

Inhibitory Effects of Antipsychotic Chlorpromazine on the Survival, Reproduction and Population Growth Other Than Neurotransmitters of Zooplankton in Light of Global Warming.

Global warming and environmental pollution have created a unique combination of abiotic and biotic stresses to zooplankton. However, little information is available on the effects of antipsychotic drugs commonly used to treat psychosis, such as chlorpromazine (CPZ), on non-target aquatic organisms in light of global warming. This study investigated how dopamine concentrations (DAC), acute toxicity and chronic toxicity of Brachionus calyciflorus changed in response to CPZ and gradually increasing temperatures. The results showed that the concentration range of rotifer DAC was 1.06~2.51 ng/g. At 18, 25 and 32 °C, the 24 h LC50 was 1.795, 1.242 and 0.833 mg/L, respectively. Compared to the control, exposure to CPZ significantly decreased life expectancy at hatching, the net reproduction rate, generation time, population growth rate and dopamine concentration of B. calyciflorus in all three temperatures (p < 0.05). The toxicity of CPZ to rotifers was increased by high temperature. These findings indicated that CPZ is highly toxic to rotifers, displaying high ecological risks to aquatic ecosystems.

J Guy Edwards, FRCPsych, FRCP, FRCGP (Hon), DPM, HonMFPH, Founding Editor of Human Psychopharmacology.

J Guy Edwards, FRCPsych, FRCP, FRCGP (Hon), DPM, HonMFPH, Founding Editor of Human Psychopharmacology.

Hematological, biochemical, and biometric changes in Clarias gariepinus exposed to antipsychotic drug chlorpromazine.

Chlorpromazine (CPZ) is a neuroleptic and antipsychotic medication for individuals suffering from schizophrenia and other medical conditions. This study investigated the effects of CPZ on the hematological, biochemical, and biometric characteristics in juvenile Clarias gariepinus. The fish were exposed to 0.53, 1.06, and 2.11 mgL-1 CPZ for 15days after which they were withdrawn from the toxicant and allowed to recover for 5days. Blood were sampled from the fish on days 1, 5, 10, 15, and during the 5-day recovery for hematological and biochemical analysis, and thereafter, the fish were sacrificed for the morphometric analysis. While the values of the white blood cells significantly increased in the exposed fish, the hemoglobin, red blood cells, and packed cell volume decreased. Compared with the control, there were no significant differences in the values of the blood derivatives in the exposed fish. The values of protein and glucose reduced, but those of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase were significantly elevated. Though there was no significant difference in the condition factor, a significant increase in hepatosomatic index occurred on day 15 at 5.28mg/L CPZ. After the 5-day withdrawal from the drug, most of the studied parameters returned to the control values. The present study indicated that CPZ is toxic to fish and should be used with utmost care to guard against toxicological effect on non-target organisms.

Differing Prevalence and Correlates of Metabolic Syndromes Between Chlorpromazine and Clozapine: A 10-year Retrospective Study of a Male Chinese Cohort.

Antipsychotics are known to be associated with metabolic syndromes (MetS). Chlorpromazine (CPZ) and Clozapine (CLZ) are currently the most commonly used antipsychotics in low-income districts of China. However, potential differences in the long-term effects of CPZ and CLZ on MetS in schizophrenia inpatients are not well understood. Here, we aimed to identify any MetS profile differences between long-term schizophrenia patients who were prescribed either CPZ or CLZ at a primary psychiatric hospital. We recruited a total of 204 male schizophrenia patients who received either CPZ or CLZ. We measured their weight, height, body mass index (BMI), waist circumference (WC), diastolic blood pressure (DBP), and systolic blood pressure (SBP), as well as their biochemical indicators, including fasting blood glucose (FBS), triglycerides (TG), cholesterol (TC), high-density lipoprotein cholesterol (HDL-c) and low-density lipoprotein cholesterol (LDL-c). The MetS prevalence in the CPZ and CLZ groups was 31% and 37.5%, respectively. The CLZ group had significantly higher DBP levels and a higher incidence of dyslipidemia (HDL-c) but lower HDL-c and TC levels than the CPZ group. We also determined that smoking history, BMI, and duration of hospitalisation were risk factors for the development of MetS. Moreover, we found that CPZ and CLZ were correlated with the same risk for developing MetS and that BMI was a vital risk factor of MetS for both the CPZ and CLZ groups. Long-term CPZ and CLZ prescriptions were associated with similar profiles for developing MetS of schizophrenia patients.

Testing the Protective Effects of Sulfobutylether-Βeta-Cyclodextrin (SBECD) and Sugammadex against Chlorpromazine-Induced Acute Toxicity in SH-SY5Y Cell Line and in NMRI Mice.

Chlorpromazine (CPZ) is an antipsychotic drug which can cause several adverse effects and drug poisoning. Recent studies demonstrated that CPZ forms highly stable complexes with certain cyclodextrins (CDs) such as sulfobutylether-β-CD (SBECD) and sugammadex (SGD). Since there is no available antidote in CPZ intoxication, and considering the good tolerability of these CDs even if when administered parenterally, we aimed to investigate the protective effects of SBECD and SGD against CPZ-induced acute toxicity employing in vitro (SH-SY5Y neuroblastoma cells) and in vivo (zebrafish embryo) models. Our major findings and conclusions are the following: (1) both SBECD and SGD strongly relieved the cytotoxic effects of CPZ in SH-SY5Y cells. (2) SGD co-treatment did not affect or increase the CPZ-induced 24 h mortality in NMRI mice, while SBECD caused a protective effect in a dose-dependent fashion. (3) The binding constants of ligand–CD complexes and/or the in vitro protective effects of CDs can help to estimate the in vivo suitability of CDs as antidotes; however, some other factors can overwrite these predictions.

The Impact of the Antipsychotic Medication Chlorpromazine on Cytotoxicity through Ca2+ Signaling Pathway in Glial Cell Models.

Chlorpromazine, an antipsychotic medication, is conventionally applied to cope with the psychotic disorder such as schizophrenia. In cellular studies, chlorpromazine exerts many different actions through calcium ion (Ca2+) signaling, but the underlying pathways are elusive. This study explored the effect of chlorpromazine on viability, Ca2+ signaling pathway and their relationship in glial cell models (GBM 8401 human glioblastoma cell line and Gibco® Human Astrocyte (GHA)). First, chlorpromazine between 10 and 40 μM induced cytotoxicity in GBM 8401 cells but not in GHA cells. Second, in terms of Ca2+ homeostasis, chlorpromazine (10-30 μM) increased intracellular Ca2+concentrations ([Ca2+]i)rises in GBM 8401 cells but not in GHA cells. Ca2+ removal reduced the signal by approximately 55%. Furthermore, chelation of cytosolic Ca2+ with BAPTA-AM reduced chlorpromazine (10-40μM)-induced cytotoxicity in GBM 8401 cells. Third, in Ca2+-containing medium of GBM 8401 cells, chlorpromazine-induced Ca2+ entry was inhibited by the modulators of store-operated Ca2+ channel (2-APB and SKF96365). Lastly, in Ca2+-free medium of GBM 8401 cells, treatment with the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin completely inhibited chlorpromazine-increased [Ca2+]i rises. Conversely, treatment with chlorpromazine abolished thapsigargin-increased [Ca2+]i rises. Inhibition of phospholipase C (PLC) with U73122 abolished chlorpromazine-increased [Ca2+]i rises. Together, in GBM 8401 cells but not in GHA cells, chlorpromazine increased [Ca2+]i rises by Ca2+ influx via store-operated Ca2+ entry and PLC-dependent Ca2+ release from the endoplasmic reticulum. Moreover, the Ca2+ chelator BAPTA-AM inhibited cytotoxicity in chlorpromazine-treated GBM 8401 cells. Therefore, Ca2+ signaling was involved in chlorpromazine-induced cytotoxicity in GBM 8401 cells.

Abstract TP1: Chlorpromazine And Promethazine Inhibits Oxidative Stress After Ischemic Stroke

Background: Excess reactive oxygen species (ROS) generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) promotes apoptotic cell death following ischemic/reperfusion injury. Effect of chlorpromazine and promethazine (C+P) on brain activity was reported to induce neuroprotection. The current study was designed to evaluate the inhibitory function of C+P on oxidative injury after stroke. Methods: Adult male Sprague-Dawley rats were subjected to 2 h middle cerebral artery occlusion (MCAO) followed by 6 or 24 h of reperfusion. At the onset of reperfusion, rats received C+P, or apocynin (NOX inhibitor), or rottlerin [protein kinase C (PKC) δ inhibitor]. Brain damage was evaluated using infarct volumes and neurological deficits as well as apoptotic cell death (TUNEL). The enzymatic activity of NOX and ROS production as well as protein expressions of NOX subunits (gp91 phox , p67 phox , p47 phox , and p22 phox ), phosphorylation of PKC δ (p-PKC δ)/PKC δ and manganese superoxide dismutase (MnSOD) was examined. Neural SHSY5Y cells were used under 2 h of oxygen-glucose deprivation (OGD) followed by reoxygenation for 6 and 24 h with or without C+P treatment. ROS and protein levels of NOX subunits, p-PKC δ/PKC δ and MnSOD were detected. Moreover, measurement of PKC δ membrane translocation and detection of the interaction of p47 phox and PKC δ through co-immunoprecipitation were performed. Results: C+P reduced cerebral infarct volumes, neurological deficits, and apoptotic cell death in the ischemic rats, as well observed in the presence of NOX and PKC δ inhibitors. ROS production, NOX activity, expression of NOX subunits, p-PKC δ/PKC δ and MnSOD were significantly reduced by C+P. In ischemic rats administered with NOX and PKC δ inhibitors, ROS, activity of NOX and the NOX subunits protein levels were all decreased. In the OGD/R model, C+P decreased ROS and protein levels of NOX subunits, p-PKC δ/PKC δ and MnSOD. Furthermore, C+P reduced the PKC δ membrane translocation and the interaction of p47 phox and PKC δ. Conclusion: C+P treatments confers neuroprotection in severe stroke by suppressing oxidative stress and ROS production. PKC δ/NOX/MnSOD may be the vital regulators and the potential targets for an efficacious therapy following ischemic stroke.

Repurposed antipsychotic chlorpromazine inhibits colorectal cancer and pulmonary metastasis by inducing G2/M cell cycle arrest, apoptosis, and autophagy.

Despite efforts in developing effective therapeutic strategies, colorectal cancer (CRC) remains one of the most prevalent and lethal neoplasms. Repurposing approved drugs is an alluring strategy for developing anticancer agents. Some antipsychotic drugs, including chlorpromazine (CPZ), possess anticancer activities. However, the pharmacological effects of CPZ on CRC have not been clearly established. MTT assay, flow cytometry, western blotting analysis, subcutaneous mice tumor, and tail-vein-injection established lung metastasis model were used to investigate the anticancer effects of CPZ on CRC and the underlying mechanism. We found that CPZ effectively suppressed CRC by inducing G2/M cell cycle arrest and apoptosis. Cell cycle arrest was associated with decreased activities of the cdc2/cyclin B1 complex, including suppressed expression of cyclin B1, cdc2 and cdc25c, and elevated expression levels of phosphorylated cdc2 (Tyr15). Moreover, CPZ suppressed mitochondrial membrane potential and elevated reactive oxygen species levels in cancer cells, implying that it induces mitochondria-dependent intrinsic apoptosis. CPZ blocked the autophagic flux and induced cytotoxic autophagy in CRC cells. In addition, CPZ suppressed tumor growth in two subcutaneous mouse models without causing obvious side effects. Analysis of the abundance of immune cells in the tumor microenvironment revealed that CPZ did not have an effect on their proportions. Furthermore, it significantly suppressed the lung metastasis of CT26 cells and prolonged mice survival. These findings indicated that repurposing CPZ is a novel treatment strategy for CRC patients.