Tubulin s-palmitoylation involves the thioesterification of a cysteine residue in tubulin with palmitate. The palmitate moiety is produced by the fatty acid synthesis pathway, which is rate-limited by acetyl-CoA carboxylase (ACC). While it is known that ACC is phosphorylated at serine 79 (pSer79) by AMPK and accumulates at the spindle pole (SP) during mitosis, a functional role for tubulin palmitoylation during mitosis has not been identified. In this study, we found that modulating pSer79-ACC level at the SP using AMPK agonist and inhibitor induced spindle defects. Loss of ACC function induced spindle abnormalities in cell lines and in germ cells of the Drosophila germarium, and palmitic acid (PA) rescued the spindle defects in the cell line treated transiently with the ACC inhibitor, TOFA. Furthermore, inhibition of protein palmitoylating or depalmitoylating enzymes also induced spindle defects. Together, these data suggested that precisely regulated cellular palmitate level and protein palmitoylation may be required for accurate spindle assembly. We then showed that tubulin was largely palmitoylated in interphase cells but less palmitoylated in mitotic cells. TOFA treatment diminished tubulin palmitoylation at doses that disrupt microtubule (MT) instability and cause spindle defects. Moreover, spindle MTs comprised of α-tubulins mutated at the reported palmitoylation site exhibited disrupted dynamic instability. We also found that TOFA enhanced the MT-targeting drug-induced spindle abnormalities and cytotoxicity. Thus, our study reveals that precise regulation of ACC during mitosis impacts tubulin palmitoylation to delicately control MT dynamic instability and spindle assembly, thereby safeguarding nuclear and cell division.

KPNA1 is a mediator of nucleocytoplasmic transport that is abundantly expressed in the mammalian brain and regulates neuronal differentiation and synaptic function. De novo mutations in Kpna1 have been identified using genome-wide association studies in humans with schizophrenia; however, it remains unclear how KPNA1 contributes to schizophrenia pathogenesis. Recent studies have suggested a complex combination of genetic and environmental factors that are closely related to psychiatric disorders. Here, we found that subchronic administration of phencyclidine, a psychotropic drug, induced vulnerability and behavioral abnormalities consistent with the symptoms of schizophrenia in Kpna1-deficient mice. Microarray assessment revealed that the expression levels of dopamine d1/d2 receptors, an RNA editing enzyme, and a cytoplasmic dynein component were significantly altered in the nucleus accumbens brain region in a gene-environment (G × E) interaction-dependent manner. Our findings demonstrate that Kpna1-deficient mice may be useful as a G × E interaction mouse model for psychiatric disorders and for further investigation into the pathogenesis of such diseases and disorders.

Arrhythmogenic cardiomyopathy (AC) is an inherited disorder characterized by progressive loss of the ventricular myocardium causing life-threatening ventricular arrhythmias, syncope and sudden cardiac death in young and athletes. About 40% of AC cases carry one or more mutations in genes encoding for desmosomal proteins, including Desmoplakin (Dsp). We present here the first stable Dsp knock-out (KO) zebrafish line able to model cardiac alterations and cell signalling dysregulation, characteristic of the AC disease, on which environmental factors and candidate drugs can be tested. Our stable Dsp knock-out (KO) zebrafish line was characterized by cardiac alterations, oedema and bradycardia at larval stages. Histological analysis of mutated adult hearts showed reduced contractile structures and abnormal shape of the ventricle, with thinning of the myocardial layer, vessels dilation and presence of adipocytes within the myocardium. Moreover, TEM analysis revealed "pale", disorganized and delocalized desmosomes. Intensive physical training protocol caused a global worsening of the cardiac phenotype, accelerating the progression of the disease. Of note, we detected a decrease of Wnt/β-catenin signalling, recently associated with AC pathogenesis, as well as Hippo/YAP-TAZ and TGF-β pathway dysregulation. Pharmacological treatment of mutated larvae with SB216763, a Wnt/β-catenin agonist, rescued pathway expression and cardiac abnormalities, stabilizing the heart rhythm. Overall, our Dsp KO zebrafish line recapitulates many AC features observed in human patients, pointing at zebrafish as a suitable system for in vivo analysis of environmental modulators, such as the physical exercise, and the screening of pathway-targeted drugs, especially related to the Wnt/β-catenin signalling cascade.

Systemic lupus erythematosus (SLE) is a heterogeneous disease with unpredictable patterns of activity. Patients with similar activity levels may have different prognosis and molecular abnormalities. In this study, we aimed to measure the main differences in drug-induced gene expression signatures across SLE patients and to evaluate the potential for clinical data to build a machine learning classifier able to predict the SLE subset for individual patients. SLE transcriptomic data from two cohorts were compared with drug-induced gene signatures from the CLUE database to compute a connectivity score that reflects the capability of a drug to revert the patient signatures. Patient stratification based on drug connectivity scores revealed robust clusters of SLE patients identical to the clusters previously obtained through longitudinal gene expression data, implying that differential treatment depends on the cluster to which patients belongs. The best drug candidates found, mTOR inhibitors or those reducing oxidative stress, showed stronger cluster specificity. We report that drug patterns for reverting disease gene expression follow the cell-specificity of the disease clusters. We used 2 cohorts to train and test a logistic regression model that we employed to classify patients from 3 independent cohorts into the SLE subsets and provide a clinically useful model to predict subset assignment and drug efficacy.

Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is a rare genetic disease characterized by low HDL-C levels, low plasma cholesterol esterification, and the formation of Lipoprotein-X (Lp-X), an abnormal cholesterol-rich lipoprotein particle. LCAT deficiency causes corneal opacities, normochromic normocytic anemia, and progressive renal disease due to Lp-X deposition in the glomeruli. Recombinant LCAT is being investigated as a potential therapy for this disorder. Several hepatic disorders, namely primary biliary cirrhosis, primary sclerosing cholangitis, cholestatic liver disease, and chronic alcoholism also develop Lp-X, which may contribute to the complications of these disorders. We aimed to test the hypothesis that an increase in plasma LCAT could prevent the formation of Lp-X in other diseases besides FLD. We generated a murine model of intrahepatic cholestasis in LCAT-deficient (KO), wild type (WT), and LCAT-transgenic (Tg) mice by gavaging mice with alpha-naphthylisothiocyanate (ANIT), a drug well known to induce intrahepatic cholestasis. Three days after the treatment, all mice developed hyperbilirubinemia and elevated liver function markers (ALT, AST, Alkaline Phosphatase). The presence of high levels of LCAT in the LCAT-Tg mice, however, prevented the formation of Lp-X and other plasma lipid abnormalities in WT and LCAT-KO mice. In addition, we demonstrated that multiple injections of recombinant human LCAT can prevent significant accumulation of Lp-X after ANIT treatment in WT mice. In summary, LCAT can protect against the formation of Lp-X in a murine model of cholestasis and thus recombinant LCAT could be a potential therapy to prevent the formation of Lp-X in other diseases besides FLD.

Zebrafish is an elegant vertebrate employed to model the pathological etiologies of human maladies such as cardiac diseases. Persistent physiological stresses can induce abnormalities in heart functions such as cardiac hypertrophy (CH), which can lead to morbidity and mortality. In the present study, using zebrafish as a study model, efficacy of the traditional Indian Ayurveda medicine "Yogendra Ras" (YDR) was validated in ameliorating drug-induced cardiac hypertrophy. YDR was prepared using traditionally described methods and composed of nano- and micron-sized metal particles. Elemental composition analysis of YDR showed the presence of mainly Au, Sn, and Hg. Cardiac hypertrophy was induced in the zebrafish following a pretreatment with erythromycin (ERY), and the onset and reconciliation of disease by YDR were determined using a treadmill electrocardiogram, heart anatomy analysis, C-reactive protein release, and platelet aggregation time-analysis. YDR treatment of CH-induced zebrafish showed comparable results with the Standard-of-care drug, verapamil, tested in parallel. Under in-vitro conditions, treatment of isoproterenol (ISP)-stimulated murine cardiomyocytes (H9C2) with YDR resulted in the suppression of drug-stimulated biomarkers of oxidative stress: COX-2, NOX-2, NOX-4, ANF, troponin-I, -T, and cardiolipin. Taken together, zebrafish showed a strong disposition as a model for studying the efficacy of Ayurvedic medicines towards drug-induced cardiopathies. YDR provided strong evidence for its capability in modulating drug-induced CH through the restoration of redox homeostasis and exhibited potential as a viable complementary therapy.

Flutamide, a widely used nonsteroidal anti-androgen, but not its bioisostere bicalutamide, has been associated with idiosyncratic drug-induced liver injury. Although the susceptibility factors are unknown, mitochondrial injury has emerged as a putative hazard of flutamide. To explore the role of mitochondrial sensitization in flutamide hepatotoxicity, we determined the effects of superimposed drug stress in a murine model of underlying mitochondrial abnormalities. Male wild-type or heterozygous Sod2(+/-) mice were injected intraperitoneously with flutamide (0, 30 or 100 mg/kg/day) for 28 days. A kinetic pilot study revealed that flutamide (100 mg/kg/day) caused approximately 10-fold greater exposure than the reported therapeutic mean plasma levels. Mutant (5/10), but not wild-type, mice in the high-dose group exhibited small foci of hepatocellular necrosis and an increased number of apoptotic hepatocytes. Hepatic GSSG/GSH, protein carbonyl levels, and serum lactate levels were significantly increased, suggesting oxidant stress and mitochondrial dysfunction. Measurement of mitochondrial superoxide in cultured hepatocytes demonstrated that mitochondria were a significant source of flutamide-enhanced oxidant stress. Indeed, mitochondria isolated from flutamide-treated Sod2(+/-) mice exhibited decreased aconitase activity as compared to vehicle controls. A transcriptomics analysis using MitoChips revealed that flutamide-treated Sod2(+/-) mice exhibited a selective decrease in the expression of all complexes I and III subunits encoded by mitochondrial DNA. In contrast, Sod2(+/-) mice receiving bicalutamide (50 mg/kg/day) did not reveal any hepatic changes. These results are compatible with our concept that flutamide targets hepatic mitochondria and exerts oxidant stress that can lead to overt hepatic injury in the presence of an underlying mitochondrial abnormality.

Background: Glecaprevir/pibrentasvir (G/P; 300 mg/120 mg) is a new direct-acting antiviral (DAA) that exhibits anti-hepatitis C virus (HCV) pan-genotype (GT) activity for 8, 12, or 16 weeks. However, the U.S. Food and Drug Administration have received reports that using G/P causes moderate to severe liver impairment. In some cases, isolated hyperbilirubinemia and jaundice have been reported without concomitant evidence of increased transaminase levels or other hepatic decompensation events. Objective: This study aimed to analyze the incidence of drug-induced liver injury of G/P for chronic hepatitis C virus.Materials and methods: We searched databases from the inception of each database until March 2021. Data were pooled using a random-effects model. The Cochrane Risk of Bias Tool (RoB 2.0) and the OpenMeta [Analyst] software were performed for quality assessment and quantitative studies, respectively. The primary outcome was grade 3 level of drug-induced liver injury (DILI). Results: The nine studies included in the meta-analysis involved a total of 7,650 participants, and the overall sustained virologic response rate was above 95%. The most frequent drug-related laboratory abnormalities in DILI involved total bilirubin, alanine aminotransferase, aspartate aminotransferase, and hemoglobin, but these abnormalities were minimal. The cirrhosis-without cirrhosis incidence risk ratio (IRR) was 2.724 (95% confidence interval: 1.182-6.276) in the grade 3 hyperbilirubinemia subgroup analysis. No significant differences were found within the other subgroups, in HCV GTs, and in treatment duration.Conclusions: DILI was found to occur frequently with G/P treatment. Hyperbilirubinemia occurred most frequently, especially, in patients with cirrhosis. However, G/P is still the primary therapy of choice for CKD and end-stage renal disease (ESRD) patients due to a superior safety rate.

The etiology of schizophrenia is unknown, but neurodevelopmental disturbances, myelin- and oligodendrocyte abnormalities and synaptic dysfunction have been suggested as pathophysiological factors in this severe psychiatric disorder. Cholesterol is an essential component of myelin and has proved important for synapse formation. Recently, we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element-binding protein (SREBP) transcription factors. We here compare the action of chlorpromazine, haloperidol, clozapine, olanzapine, risperidone and ziprasidone on SREBP activation and SREBP-controlled gene expression (ACAT2, HMGCR, HMGCS1, FDPS, SC5DL, DHCR7, LDLR, FASN and SCD1) in four CNS-relevant human cell lines.

Epilepsy is a disorder characterized by recurrent seizures that affects 1% of the population. However, the neurochemical alterations observed in epilepsy are not fully understood. There are different animal models of epilepsy, such as genetic or drug induced. In the present study, we utilize Wistar Audiogenic Rats (WAR), a murine strain that develops seizures in response to high intensity audio stimulation, in order to investigate abnormalities in glutamatergic and GABAergic systems.

Background: Xiao-Yao-San (XYS) is a traditional Chinese prescription that regulates gastrointestinal function, improves mental and psychological abnormalities, and enhances liver function. However, the underlying mechanism of XYS for relieving anti-tuberculosis (AT) drug-induced liver injury is not clear. Objective: The current study examined whether XYS alleviated the symptoms of AT drug-induced liver injury in mice via the mitochondrial oxidative stress pathway. Methods: BALB/c male mice were randomly divided into four groups of 12 animals, including a control group, a model group, a 0.32 g/kg XYS group, and a 0.64 g/kg XYS group. The effect of XYS on the degree of liver injury was observed using haematoxylin and eosin staining (HE) and oil red O staining of pathological sections, biochemical parameters, and reactive oxygen species (ROS) levels. The protein expression of mitochondrial synthesis-related proteins and ferroptosis-related proteins was examined using Western blotting. Results: XYS improved the pathological changes in liver tissue and reduced the level of oxidative stress in liver-injured mice. XYS increased the expression of mitochondrial synthesis-related proteins and reversed the expression of ferroptosis-related proteins. Knockdown of G-rich RNA sequence binding factor 1 (Grsf1) expression with Grsf1 shRNA blocked the protective effects of XYS in liver injury. Conclusion: Our findings suggest that XYS alleviates AT drug-induced liver injury by mediating Grsf1 in the mitochondrial oxidative stress pathway.

Growing evidences suggest the presence of several similarities in the molecular mechanisms underlying the neurodegenerative diseases and metabolic abnormalities. Adults who develop Metabolic Syndrome (MS) are at a higher risk of developing Alzheimer's disease (AD). Pharmacological agents, like dipeptidyl peptidase-4 (DPP-4) inhibitors that increase the levels of glucagon like peptide 1 (GLP-1) and ameliorate symptoms of MS, have become an auspicious candidate as disease modifying agents in the treatment of AD. The present study investigates the beneficial effects of Vildagliptin, a DPP-4 inhibitor in counteracting cognitive decline in different models of dementia targeting the AKT, JAK/STAT signaling pathways and hippocampal Klotho expression, to judge the neuroprotective, anti-apoptotic and anti-inflammatory effects of the drug. Cognitive decline was induced by either administration of high fat high sugar (HFHS) diet for 45 days alone, or with oral administration of AlCl3 (100 mg/kg/day) for 60 days. Rats were orally administered Vildagliptin (10 mg/kg) for 60 days along with AlCl3 administration. Vildagliptin treatment improved spatial memory and activities in morris water maze (MWM) test and open field test respectively. Results revealed an increase of both hippocampal klotho and Bcl-2 expressions along with an increase in both AKT and ERK1/2 phosphorylation. In contrast, Vildagliptin treatment decreased hippocampal contents of inflammatory, apoptotic and oxidative stress biomarkers as TNF-α, caspase-3 and FOXO1 along with restoring metabolic abnormalities. A significant decrease in BAX expressions with JAK2/STAT3 inhibition was observed. These findings demonstrate that the neuroprotective role of vildagliptin is possibly via modulating Klotho protein together with AKT pathway.

To investigate the timing, incidence, clinical presentation, pharmacokinetics and pharmacogenetic predictors for antiretroviral and anti-tuberculosis drug induced liver injury (DILI) in HIV patients with or without TB co-infection.

Fragile X syndrome (FXS) is characterized by immature dendritic spine architectures and cognitive impairment. 7, 8-Dihydroxyflavone (7, 8-DHF) has recently been identified as a high affinity tropomyosin receptor kinase B (TrkB) agonist. The purpose of this paper was to examine the utility of 7, 8-DHF as an effective pharmacotherapeutic agent that targets dendritic pathology and cognitive impairments in FXS mutant. We synthesized pharmacologic, behavioral, and biochemical approaches to examine the effects of 7, 8-DHF on spatial and fear memory functions, and morphological spine abnormalities in fragile X mental retardation 1 (Fmr1) gene knock-out mice. The study found that 4 weeks of treatment with 7, 8-DHF improved spatial and fear memory, and ameliorated morphological spine abnormalities including the number and elongation of spines in the hippocampus and amygdala. Further mechanism analysis revealed that 7, 8-DHF enhanced the expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) GluA1 receptor, but reduced the normal levels of GluA2 at the synapses in Fmr1. Potentially related to drug-induced changes in AMPA receptor subunits, 7, 8-DHF at the synapses led to phosphorylation of specific serine sites on subunits Ser818 and Ser813 of GluA1, and Ser880 of GluA2, as well as phosphorylation of TrkB, calcium/calmodulin-dependent protein kinase II, and protein kinase C. However, 7, 8-DHF neither affected behavioral performance nor increased TrkB phosphorylation in WT mice, which suggested that it had FXS-specific correcting effect. Altogether, these results demonstrated that 7, 8-DHF improved learning and memory, and reduced abnormalities in spine morphology, thus providing a potential pharmacotherapeutic strategy for FXS.

Torsades de Pointes (TdP) is a type of ventricular arrhythmia which could be observed as an unwanted drug-induced cardiac side effect, and it is associated with repolarization abnormalities in single cells. The pharmacological evaluations of TdP risk in previous years mainly focused on the hERG channel due to its vital role in the repolarization of cardiomyocytes. However, only considering drug effects on hERG led to false positive predictions since the drug action on other ion channels can also have crucial regulatory effects on repolarization. To address the limitation of only evaluating hERG, the Comprehensive in Vitro Proarrhythmia Assay initiative has proposed to systematically integrate drug effects on multiple ion channels into in silico drug trial to improve TdP risk assessment. It is not clear how many ion channels are sufficient for reliable TdP risk predictions, and whether differences in IC50 and Hill coefficient values from independent sources can lead to divergent in silico prediction outcomes. The rationale of this work is to investigate the above two questions using a computationally efficient population of human ventricular cells optimized to favor repolarization abnormality. Our blinded results based on two independent data sources confirm that simulations with the optimized population of human ventricular cell models enable efficient in silico drug screening, and also provide direct observation and mechanistic analysis of repolarization abnormality. Our results show that 1) the minimum set of ion channels required for reliable TdP risk predictions are Nav1.5 (peak), Cav1.2, and hERG; 2) for drugs with multiple ion channel blockage effects, moderate IC50 variations combined with variable Hill coefficients can affect the accuracy of in silico predictions.

The preclinical identification of drug-induced cardiotoxicity and its translation into human risk are still major challenges in pharmaceutical drug discovery. The ICH S7B Guideline and Q&A on Clinical and Nonclinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential promotes human in silico drug trials as a novel tool for proarrhythmia risk assessment. To facilitate the use of in silico data in regulatory submissions, explanatory control compounds should be tested and documented to demonstrate consistency between predictions and the historic validation data. This study aims to quantify drug-induced electrophysiological effects on in silico cardiac human Purkinje cells, to compare them with existing in vitro rabbit data, and to assess their accuracy for clinical pro-arrhythmic risk predictions. The effects of 14 reference compounds were quantified in simulations with a population of in silico human cardiac Purkinje models. For each drug dose, five electrophysiological biomarkers were quantified at three pacing frequencies, and results compared with available in vitro experiments and clinical proarrhythmia reports. Three key results were obtained: 1) In silico, repolarization abnormalities in human Purkinje simulations predicted drug-induced arrhythmia for all risky compounds, showing higher predicted accuracy than rabbit experiments; 2) Drug-induced electrophysiological changes observed in human-based simulations showed a high degree of consistency with in vitro rabbit recordings at all pacing frequencies, and depolarization velocity and action potential duration were the most consistent biomarkers; 3) discrepancies observed for dofetilide, sotalol and terfenadine are mainly caused by species differences between humans and rabbit. Taken together, this study demonstrates higher accuracy of in silico methods compared to in vitro animal models for pro-arrhythmic risk prediction, as well as a high degree of consistency with in vitro experiments commonly used in safety pharmacology, supporting the potential for industrial and regulatory adoption of in silico trials for proarrhythmia prediction.

Background: In the absence of SARS-CoV-2 specific antiviral treatments, various repurposed pharmaceutical approaches are under investigation for the treatment of COVID-19. Antiviral drugs considered for this condition include atazanavir, remdesivir, lopinavir-ritonavir, and favipiravir. Whilst the combination of lopinavir and ritonavir has been previously linked to prolongation of the QTc interval on the ECG and risk of torsades de pointes arrhythmia, less is known in this regard about atazanavir, remdesivir, and favipiravir. Unwanted abnormalities of drug-induced QTc prolongation by diverse drugs are commonly mediated by a single cardiac anti-target, the hERG potassium channel. This computational modeling study was undertaken in order to explore the ability of these five drugs to interact with known determinants of drug binding to the hERG channel pore. Methods: Atazanavir, remdesivir, ritonavir, lopinavir and favipiravir were docked to in silico models of the pore domain of hERG, derived from cryo-EM structures of hERG and the closely related EAG channel. Results: Atazanavir was readily accommodated in the open hERG channel pore in proximity to the S6 Y652 and F656 residues, consistent with published experimental data implicating these aromatic residues in atazanavir binding to the channel. Lopinavir, ritonavir, and remdesivir were also accommodated in the open channel, making contacts in a model-dependent fashion with S6 aromatic residues and with residues at the base of the selectivity filter/pore helix. The ability of remdesivir (at 30 μM) to inhibit the channel was confirmed using patch-clamp recording. None of these four drugs could be accommodated in the closed channel structure. Favipiravir, a much smaller molecule, was able to fit within the closed channel and could adopt multiple binding poses in the open channel, but with few simultaneous interactions with key binding residues. Only favipiravir and remdesivir showed the potential to interact with lateral pockets below the selectivity filter of the channel. Conclusions: All the antiviral drugs studied here can, in principle, interact with components of the hERG potassium channel canonical binding site, but are likely to differ in their ability to access lateral binding pockets. Favipiravir's small size and relatively paucity of simultaneous interactions may confer reduced hERG liability compared to the other drugs. Experimental structure-function studies are now warranted to validate these observations.

Olanzapine is one of the most effective medicines available for stabilizing schizophrenia spectrum disorders. However, it has been reported to show the greatest propensity for inducing body weight gain and producing metabolic side effects, which cause a great burden in patients with psychiatric disorders. Since the gut microbiota has a profound impact on the initiation and development of metabolic diseases, we conducted a longitudinal study to explore its role in olanzapine-induced obesity and metabolic abnormalities. Female Sprague-Dawley rats were treated with different doses of olanzapine, and metabolic and inflammatory markers were measured. Olanzapine significantly induced body weight gain (up to a 2.1-fold change), which was accompanied by hepatic inflammation and increased plasma triglyceride levels (up to a 2.9-fold change), as well as gut microbiota dysbiosis. Subsequently, fuzzy c-means clustering was used to characterize three clusters of longitudinal trajectories for microbial fluctuations: (i) genera continuing to increase, (ii) genera continuing to decrease, and (iii) genera temporarily changing. Among them, Enterorhabdus (r = 0.38), Parasutterella (r = 0.43), and Prevotellaceae UCG-001 (r = 0.52) positively correlated with body weight gain. In addition, two MetaCyc metabolic pathways were identified as associated with olanzapine-induced body weight gain, including the superpathway of glucose and xylose degradation and the superpathway of l-threonine biosynthesis. In conclusion, we demonstrate that olanzapine can directly alter the gut microbiota and rapidly induce dysbiosis, which is significantly associated with body weight gain. This may suggest gut microbiota targets in future studies on metabolic abnormalities caused by olanzapine. IMPORTANCE Olanzapine is one of the most effective second-generation antipsychotics for stabilizing schizophrenia spectrum disorders. However, olanzapine has multiple drug-induced metabolic side effects, including weight gain. This study provides insight to the gut microbiota target in olanzapine-induced obesity. Specifically, we explored the longitudinal gut microbiota trajectories of female Sprague-Dawley rats undergoing olanzapine treatment. We showed that olanzapine treatment causes a dynamic alteration of gut microbiota diversity. Additionally, we identified three genera, Parasutterella, Enterorhabdus, and Prevotellaceae UCG-001, that may play an important role in olanzapine-induced obesity. In this case, the supply or removal of specific elements of the gut microbiota may represent a promising avenue for treatment of olanzapine-related metabolic side effects.

Objectives. Doxapram hydrochloride is a respiratory stimulant that has an inhibitory effect on myocardial IK1 potassium channels and is thought to increase membrane instability and excitability in myocardial cells. We examined the arrhythmogenic effects of doxapram hydrochloride in a rat model of halothane adrenaline-induced arrhythmia. Methods. Thirteen female Wistar rats (12-14 weeks old) were used in the study. Animals were anesthetized with inhalation of halothane to permit observation of the effects of doxapram hydrochloride on halothane adrenaline-induced arrhythmia. Time-dependent changes in ECG repolarization characteristics (QT, QTc, JTp, JT, and Tp-e intervals) were studied. Results. Doxapram hydrochloride itself did not induce arrhythmia but did induce bidirectional ventricular tachycardia after addition of adrenaline. Conclusion. Drug-induced impairment of intracellular Ca(2+) regulation caused BVT in the absence of genetic abnormalities in proteins in the sarcoplasmic reticulum.

The present investigation was undertaken to study the effect of proglumide, a cholecystokinin (CCK) receptor antagonist, on iminodipropionitrile (IDPN)-induced excitation, chorea, and circling (ECC) syndrome in rats. The animals were exposed to IDPN in the dose of 100 mg/kg/day IP for 9 days. Proglumide (PG) was administered IP daily 1 h before IDPN in the doses of 250, 500, and 750 mg/kg body weight in three different groups of rats. The animals were observed daily for neurobehavioral abnormalities including dyskinetic head movements, circling, tail hanging, air righting reflex, locomotor activity, and contact inhibition of the righting reflex. After behavioral studies, blood and brain samples were collected for the analysis of malondialdehyde (MDA), conjugated dienes, vitamin E, and glutathione peroxidase (GSH-Px). The temporal bones were also collected for inner ear histopathology. Our results showed that proglumide significantly and dose-dependently exacerbated the incidence and the severity of IDPN-induced ECC syndrome during the treatment period as well as up to 3 weeks of postdosing. Administration of IDPN produced a significant increase in MDA and conjugated dienes and a decrease in vitamin E and GSH-Px, suggesting the role of oxygen-derived free radicals (ODFR) in IDPN-induced neurotoxicity. Concomitant treatment with proglumide potentiated IDPN-induced oxidative stress. The histopathology of the inner ear showed significantly high degeneration of sensory hair cells in the crista ampullaris of the rats treated with IDPN plus proglumide compared to IDPN-alone-treated animals. Further studies are warranted to determine the role of CCK in nitrile toxicity and drug-induced dyskinesia.