Investigating the cardiotoxicity of N-n-butyl haloperidol iodide: Inhibition mechanisms on hERG channels.

The human Ether-à-go-go-Related Gene (hERG) encodes a protein responsible for forming the alpha subunit of the IKr channel, which plays a crucial role in cardiac repolarization. The proper functioning of hERG channels is paramount in maintaining a normal cardiac rhythm. Inhibition of these channels can result in the prolongation of the QT interval and potentially life-threatening arrhythmias. Cardiotoxicity is a primary concern in the field of drug development. N-n-Butyl haloperidol iodide (F2), a derivative of haloperidol, has been investigated for its therapeutic potential. However, the impact of this compound on cardiac toxicity, specifically on hERG channels, remains uncertain. This study employs computational and experimental methodologies to examine the inhibitory mechanisms of F2 on hERG channels. Molecular docking and molecular dynamics simulations commonly used techniques in computational biology to predict protein-ligand complexes' binding interactions and stability. In the context of the F2-hERG complex, these methods can provide valuable insights into the potential binding modes and strength of interaction between F2 and the hERG protein. On the other hand, electrophysiological assays are experimental techniques used to characterize the extent and nature of hERG channel inhibition caused by various compounds. By measuring the electrical activity of the hERG channel in response to different stimuli, these assays can provide important information about the functional effects of ligand binding to the channel. The study's key findings indicate that F2 interacts with the hERG channel by forming hydrogen bonding, π-cation interactions, and hydrophobic forces. This interaction leads to the inhibition of hERG currents in a concentration-dependent manner, with an IC50 of 3.75 µM. The results presented in this study demonstrate the potential cardiotoxicity of F2 and underscore the significance of considering hERG channel interactions during its clinical development. This study aims to provide comprehensive insights into the interaction between F2 and hERG, which will may guid us in the safe use of F2 and in the development of new derivatives with high efficiency while low toxicity.

Olanzapine, but not haloperidol, exerts pronounced acute metabolic effects in the methylazoxymethanol rat model.

AIM: Widely used second-generation antipsychotics are associated with adverse metabolic effects, contributing to increased cardiovascular mortality. To develop strategies to prevent or treat adverse metabolic effects, preclinical models have a clear role in uncovering underlying molecular mechanisms. However, with few exceptions, preclinical studies have been performed in healthy animals, neglecting the contribution of dysmetabolic features inherent to psychotic disorders. METHODS: In this study, methylazoxymethanol acetate (MAM) was prenatally administered to pregnant Sprague-Dawley rats at gestational day 17 to induce a well-validated neurodevelopmental model of schizophrenia mimicking its assumed pathogenesis with persistent phenotype. Against this background, the dysmetabolic effects of acute treatment with olanzapine and haloperidol were examined in female rats. RESULTS: Prenatally MAM-exposed animals exhibited several metabolic features, including lipid disturbances. Half of the MAM rats exposed to olanzapine had pronounced serum lipid profile alteration compared to non-MAM controls, interpreted as a reflection of a delicate MAM-induced metabolic balance disrupted by olanzapine. In accordance with the drugs' clinical metabolic profiles, olanzapine-associated dysmetabolic effects were more pronounced than haloperidol-associated dysmetabolic effects in non-MAM rats and rats exposed to MAM. CONCLUSION: Our results demonstrate metabolic vulnerability in female prenatally MAM-exposed rats, indicating that findings from healthy animals likely provide an underestimated impression of metabolic dysfunction associated with antipsychotics. In the context of metabolic disturbances, neurodevelopmental models possess a relevant background, and the search for adequate animal models should receive more attention within the field of experimental psychopharmacology.

Pharmacological and toxicological evaluation of methyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxoide against haloperidol induced Parkinson like symptoms in animal model: In-vitro and in-vivo studies.

In Parkinson's disease (PD), degradation of dopaminergic neurons in substantia nigra causes striatal deficiency of dopamine, which results in tremors, bradykinesia with instability in posture, rigidity and shuffled gait. Prevalence of PD increases with age as from 65 to 85 years. In an attempt to devise targeted safe therapy, nanoparticles of methyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (MBD) (MBDN), were prepared and their acute toxicity and safety was evaluated. Thirty-six healthy albino mice were randomly divided into six groups (n = 6): normal control, diseased control, standard (levodopa/carbidopa (100/25 mg/kg) and the remaining three groups were administered 1.25, 2.5 and 5 mg/kg MBDN during 21 days study. Except control, all mice, were injected haloperidol (1 mg/ kg i.p.) 1-h prior to treatment to induce PD. Acute toxicity test showed, no effect of MBDN on lipid profile, brain, renal and liver function and histoarchitecture of kidney, liver and heart, except decreased (p < 0.05) platelet count. Behavioral studies showed significant improvement (p < 0.001) in motor function and reduction of oxidation status in a MBDN in a dose dependent manner. Thus, the study findings revealed significance of MBDN as a selective MAO-B inhibitor for the improvement of Parkinson's symptoms in animal model.

Antipsychotics Induced Reproductive Toxicity by Stimulating Oxidative Stress: A Comparative in Vivo and in Silico Study.

The pathophysiological mechanism behind the link between antipsychotic drugs and sexual dysfunction is still unknown. The goal of this research is to compare the potential effects of antipsychotics on the male reproductive system. Fifty rats were randomly assigned into the five groups indicated: Control, Haloperidol, Risperidone, Quetiapine and Aripiprazole. Sperm parameters were significantly impaired in all antipsychotics-treated groups. Haloperidol and Risperidone significantly decreased the level of testosterone. All antipsychotics had significantly reduced inhibin B level. A significant reduction was observed in SOD activity in all antipsychotics-treated groups. While GSH levels diminished, MDA levels were rising in the Haloperidol and Risperidone groups. Also, the GSH level was significantly elevated in the Quetiapine and Aripiprazole groups. By causing oxidative stress and altering hormone levels, Haloperidol and Risperidone are damaging to male reproductivity. This study represents useful starting point for exploring further aspects of the underlying mechanisms reproductive toxicity of antipsychotics.

Filgrastim, a Recombinant Form of Granulocyte Colony-stimulating Factor, Ameliorates 3-nitropropionic Acid and Haloperidol-induced Striatal Neurotoxicity in Rats.

Striatal neurotoxicity is the pathological hallmark for a heterogeneous group of movement disorders like Tardive dyskinesia (TD) and Huntington's disease (HD). Both diseases are characterized by progressive impairment in motor function. TD and HD share common features at both cellular and subcellular levels. Filgrastim, a recombinant methionyl granulocyte colony-stimulating factor (GCSF), shows neuroprotective properties in in-vivo models of movement disorders. This study seeks to evaluate the neuroprotective effect of filgrastim in haloperidol and 3-NP-induced neurotoxicity in rats. The study was divided into two: in study one, rats were administered with haloperidol for 21 days, filgrastim at the dose of (20, 40, 60 µg/kg,s.c.) was administered once a day before haloperidol treatment and the following parameters (orofacial movements, rotarod, actophotometer) were performed to assess TD. Similarly, in the second study, rats were administered with 3-NP for 21 days, filgrastim at a dose of (20 and 40 µg/kg, s.c.) was administered, and the following parameters (rotarod, narrow beam walk, and open field test) were assessed for HD. On the 22nd day, animals were sacrificed and cortex and striatum isolated for oxidative stress (LPO, GSH, SOD, catalase, and nitrate) marker assessment. Results revealed that haloperidol and 3-NP treatment significantly impaired motor coordination, and oxidative defense inducing TD and HD-like symptoms. Treatment with filgrastim significantly averted haloperidol and 3-NP-induced behavioral and biochemical alterations. Conclusively, the neuroprotective effect of filgrastim is credited to its antioxidant properties. Hence, filgrastim might be a novel therapeutic candidate for the management of TD and HD.

Validation of Risk-Stratification Method for the Chronic Atrioventricular Block Cynomolgus Monkey Model and Its Mechanistic Interpretation Using 6 Drugs With Pharmacologically Distinct Profile.

Validation of risk-stratification method for the chronic atrioventricular block cynomolgus monkey model and its mechanistic interpretation was performed using 6 pharmacologically distinct drugs. The following drugs were orally administered in conscious state, astemizole: 1, 5, and 10 mg/kg (n = 6); haloperidol: 1, 10, and 30 mg/kg (n = 5); amiodarone: 30 mg/kg (n = 4); famotidine: 10 mg/kg (n = 4); levofloxacin: 100 mg/kg (n = 4); and tolterodine: 0.2, 1, and 4.5 mg/kg (n = 4). Astemizole of 5 and 10 mg/kg significantly prolonged ΔΔQTcF, whereas no significant change was observed by the others. Torsade de pointes (TdP) was induced by astemizole of 5 and 10 mg/kg in 3/6 and 6/6, and by haloperidol of 10 and 30 mg/kg in 1/5 and 1/5, respectively, which was not observed in the others. Torsadogenic risk of the drugs was quantified using the criteria for the monkey model specified in our previous study. Namely, high-risk drugs induced TdP at ≤ 3 times of their maximum clinical daily dose. Intermediate-risk drugs did not induce TdP at this dose range, but induced it at higher doses. Low/no-risk drugs never induced TdP at any dose tested. The magnitude of risk was intermediate for astemizole and haloperidol, and low/no risk for the others. The prespecified, risk-stratification method for the monkey model may solve the issue existing between nonclinical models and patients with labile repolarization, which can reinforce the regulatory decision-making and labeling at time of marketing application of nondouble-negative drug candidate (hERG assay positive and/or in vivo QT study positive).

Berberine Ameliorate Haloperidol and 3-Nitropropionic Acid-Induced Neurotoxicity in Rats.

Berberine due to its antioxidant properties, has been used around the globe significantly to treat several brain disorders. Also, oxidative stress is a pathological hallmark in neurodegenerative diseases like Huntington's disease (HD) and Tardive dyskinesia (TD). Berberine an alkaloid from plants has been reported to have neuroprotective potential in several animal models of neurodegenerative diseases. Hence, this study aims to evaluate the neuroprotective effect of berberine in the animal model of 3-nitropropionic acid (3-NP) induced HD and haloperidol induced tardive dyskinesia with special emphasis on its antioxidant property. The study protocol was divided into 2 phases, first phase involved the administration of 3-NP and berberine at the dose of (25, 50, and 100 mg/kg) intraperitoneally (i.p) and orally (p.o.) respectively for 21 days, and the following parameters (rotarod, narrow beam walk and photoactometer) as a measure of motor activity and striatal and cortical levels of (LPO, GSH, SOD, catalase, and nitrate) evaluated as a measure of oxidative stress were assessed for HD. Similarly in the second phase, TD was induced by using haloperidol, for 21 days and berberine at the dose of (25, 50, and 100 mg/kg) was administered, and both physical and biochemical parameters were assessed as mentioned for the HD study. The resultant data indicated that berberine attenuate 3-NP and haloperidol-induced behavioral changes and improved the antioxidant capcity in rodents. Hence berberine might be a novel therapeutic candidate to manage TD & HD.

Haloperidol alters the behavioral, hematological and biochemical parameters of freshwater African catfish, Clarias gariepinus (Burchell 1822).

The presence of drugs and their metabolites in surface waters and municipal effluents has been reported in several studies, but their impacts on aquatic organisms are not yet well studied. The present study investigated the effects of exposure to the antipsychotic drug, haloperidol on the behavioral, hematological and biochemical parameters in juvenile Clarias gariepinus. The fishes were exposed to 0.12, 0.24 and 0.48 mg/L haloperidol for 15 days and later withdrawn from the toxicant and allowed to recover for 5 days. Blood was sampled on days 1, 5, 10, 15, and after the 5-day recovery for hematological and biochemical analysis. The pack cell volume (PCV), red blood cells (RBC), hemoglobin (Hb), reticulocytes and lymphocyte counts were significantly reduced in the exposed fish. The neutrophil counts were increased while that of monocytes, basophils and eosinophils were not affected by the drug. The mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) were not different from the control on exposure to the drug. The activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and acid phosphatase (ACP); and serum creatinine, bile acid and bilirubin were increased on 15-day exposure to the drug. The activity of the clotting factor fibrinogen was reduced compared to the control after exposure to the drug. Haloperidol at concentrations used on 15-day exposure were toxic to fish, but the effect appeared short-lived, as it dissipated on 5-day withdrawal from the drug. While further studies are needed to ascertain the impact of prolonged exposure to environmentally relevant concentrations, caution is advised to avoid eco-toxicological damage to aquatic organisms.

Inhibition of drug induced Parkinsonism by chronic supplementation of quercetin in haloperidol-treated wistars.

Haloperidol is a neuroleptic medication that is used to treat a wide range of neuropsychiatric conditions. It has been shown to produce medicinal effects against hyperactivity, agitation and mania, as well as schizophrenia. Long-term usage of haloperidol raises the risk of acquiring a neurological condition like Parkinson's disease. Haloperidol causes drug-induced Parkinsonism (DIP) by blocking central dopamine receptors and causing extrapyramidal symptoms during long-term treatment. Quercetin has been shown to reduce the loss of striatal neurons, which may enhance motor capabilities and protect against agents that cause the production of reactive oxygen species (ROS). As a result, present study intended to evaluate the efficacy of quercetin on haloperidol-related motor abnormalities. To develop behavioral impairments, rats (n=24) randomly divided to control and haloperidol group for four weeks. The animals were split into four groups after four weeks: Control, quercetin, haloperidol and haloperidol + quercetin. Animals were administered haloperidol i.p injections of 5mg/kg and quercetin (100mg/kg) orally for 21 days. The treatment of haloperidol-treated rats with quercetin was successful in reversing the haloperidol alterations. It decreased animal food intake and alleviated anxiogenic behavior. The chronic treatment of quercetin further reduced the movement abnormalities in animal model of drug induced pseudo-Parkinson.

Resveratrol prevents haloperidol-induced mitochondria dysfunction through the induction of autophagy in SH-SY5Y cells.

BACKGROUND: Haloperidol is a commonly used antipsychotic drug and may increase neuronal oxidative stress associated with the side effects, including tardive dyskinesia and neurite withdraw. Autophagy plays a protective role in response to the accumulated reactive oxygen species (ROS) induced mitochondria damage. Resveratrol is an antioxidant compound having neuroprotective effects; however, it is unknown if resveratrol may stimulate autophagy and decrease mitochondria damage induced by haloperidol. HYPOTHESIS: We hypothesis that resveratrol stimulates the autophagic process and protects mitochondria lesion induced by haloperidol. METHODS: MitoSOX™ Red Mitochondrial Superoxide Indicator and MitoTracker™ Green FM staining were used to measure the amount of the mitochondria ROS production and mitochondria mass in human SH-SY5Y cells treated with haloperidol and/or resveratrol. Autophagic related dyes and Western blot were applied to study the autophagic process and related protein expression. Besides, tandem monomeric mRFP-GFP-LC3 was used to investigate the fusion of autophagosome and lysosome. Transmission electron microscopy was used to investigate the mitochondrial and autophagic ultrastructures with or without haloperidol and resveratrol treatment. RESULTS: Haloperidol administration significantly increased mitochondria ROS and mitochondrial mass, indicating the increase of mitochondria dysfunction. Although haloperidol increased the autophagosomes and lysosome formation, the autophagosome-lysosome fusion and degradation were impaired. This was because we found an increased p62 after haloperidol treatment, an indication of autophagy incompletion. Importantly, resveratrol promoted the degradation of p62, upregulated the formation of autophagolysosome, and reversed haloperidol-induced mitochondria damage. CONCLUSION: These results collectively suggest that resveratrol may be introduced as a protective compound against haloperidol-induced mitochondria impairment and aberrant autophagy.

Obesity Potentiates the Risk of Drug-Induced Long QT Syndrome - Preliminary Evidence from WNIN/Ob Spontaneously Obese Rat.

Drug-induced long QT syndrome (DI-LQTS) is fatal and known to have a higher incidence in women rather than in men. Multiple risk factors potentiate the incidence of DI-LQTS, but the actual contribution of obesity remains largely unexplored. Correspondingly, the present study is aimed to evaluate the susceptibility of DI-LQTS in WNIN/Ob rat in comparison with its lean counterpart using 3-lead electrocardiography. Four- and eight-month-old female WNIN/Ob and their lean controls were used for the experimentation. Non-invasive blood pressure measurement and total body electric conductivity (TOBEC) analysis were carried out. After the baseline evaluations, animals were anesthetized with Ketamine (50 mg/kg). Haloperidol (12.5 mg/kg single dose) was administered intraperitoneally and ECG was taken at 0, 10, 20, 30, 60 min, and 24 h time points. Myocardial lystes were used to assess the BNP, protein carbonylation, and hydroxyproline content. Adiposity, as assessed by TOBEC, is higher in obese rats with elevated mean arterial blood pressure. Baseline-corrected QT interval (QTc) is significantly higher in the obese rat with a wider QRS complex. The incidence of PVC and VT are more intense in the obese rat. Haloperidol-induced QT prolongation in obese rats was rapidly induced than in lean, which was observed to remain till 24 h in obese groups while normalized in lean controls. Higher levels of BNP, protein carbonylation, hydroxyproline content, and relative heart weights indicated the presence of cardiac hypertrophy. The study provides preliminary evidence that obesity can be a potential risk factor for DI-LQTS with faster onset and longer subsistence.

Haloperidol-induced catalepsy as an animal model for parkinsonism: A systematic review of experimental studies.

Several useful animal models for parkinsonism have been developed so far. Haloperidol-induced catalepsy is often used as a rodent model for the study of motor impairments observed in Parkinson's disease and related disorders and for the screening of potential antiparkinsonian compounds. The objective of this systematic review is to identify publications that used the haloperidol-induced catalepsy model for parkinsonism and to explore the methodological characteristics and the main questions addressed in these studies. A careful systematic search of the literature was carried out by accessing articles in three different databases: Web of Science, PubMed and SCOPUS. The selection and inclusion of studies were performed based on the abstract and, subsequently, on full-text analysis. Data extraction included the objective of the study, study design and outcome of interest. Two hundred and fifty-five articles were included in the review. Publication years ranged from 1981 to 2020. Most studies used the model to explore the effects of potential treatments for parkinsonism. Although the methodological characteristics used are quite varied, most studies used Wistar rats as experimental subjects. The most frequent dose of haloperidol used was 1.0 mg/kg, and the horizontal bar test was the most used to assess catalepsy. The data presented here provide a framework for an evidence-based approach to the design of preclinical research on parkinsonism using the haloperidol-induced catalepsy model. This model has been used routinely and successfully and is likely to continue to play a critical role in the ongoing search for the next generation of therapeutic interventions for parkinsonism.

Appraisal of anti-Parkinson activity of rhinacanthin-C in haloperidol-induced parkinsonism in mice: A mechanistic approach.

This study aimed to appraise the anti-Parkinson's potential of rhinacanthin-C (RC). RC (5, 10, and 20 mg/kg) was orally administered for 25 days in albino mice to treat haloperidol-induced parkinsonism (1 mg/kg). RC significantly (p < .05) improved the motor symptoms in block, bar, rotarod, and balance beam walking tests in treated mice. RC reduced the cataleptic effect dose-dependently. The RC therapy notably (p < .001) enhanced reduced glutathione, catalase, and superoxide dismutase levels while decreased malondialdehyde and nitrite levels in the tissue homogenates of the treated mice. The RC therapy significantly (p < .01-.001) restored the dopamine, norepinephrine, and serotonin levels in the brain tissue of treated mice as co-evidenced from brain histology. RC did not adversely affect complete blood count, and liver and kidney function tests. Taken together, these results have shown that RC is effective in treating motor and non-motor symptoms of Parkinson's disease. PRACTICAL APPLICATIONS: Rhinacanthus nasutus is a medicinally rich plant that has folklore use in several ailments. The plant possessed multiple pharmacological activities due to the presence of naphthoquinones. The major compound of this plant rhinacanthin-C was used in the present study to evaluate it's anti-Parkinson's activity. The results provide scientific evidence of the anti-Parkinson's potential of rhinacanthin-C that support the use of R. nasutus leaves in the prevention and treatment of Parkinson's disorder.

Naringin Ameliorates Haloperidol-Induced Neurotoxicity and Orofacial Dyskinesia in a Rat Model of Human Tardive Dyskinesia.

Animal models of haloperidol (HAL)-induced neurotoxicity and orofacial dyskinesia (OD) have long been used to study human tardive dyskinesia (TD). Similar to patients with TD, these models show strong pathophysiological characteristics such as striatal oxidative stress and neural cytoarchitecture alteration. Naringin (NAR), a bioflavonoid commonly found in citrus fruits, has potent antioxidative, anti-inflammatory, antiapoptotic, and neuroprotective properties. The present study evaluated the potential protective effects of NAR against HAL-induced OD in rats and the neuroprotective mechanisms underlying these effects. HAL treatment (1 mg/kg i.p. for 21 successive days) induced OD development, characterized by increased vacuous chewing movement (VCM) and tongue protrusion (TP), which were recorded on the 7th, 14th, and 21st day of drug treatment. NAR (30, 100, and 300 mg/kg) was administered orally 60 min before HAL injection for 21 successive days. On the 21st day, after behavioral testing, the rats were sacrificed, and the nitrosative and oxidative status, antioxidation power, neurotransmitter levels, neuroinflammation, and apoptotic markers in the striatum were measured. HAL induced OD development, with significant increases in the frequency of VCM and TP. NAR treatment (100 and 300 mg/kg) prevented HAL-induced OD significantly. Additionally, NAR treatment reduced the HAL-induced nitric oxide and lipid peroxide production, increased the antioxidation power and neurotransmitter levels in the striatum, and significantly reduced the levels of neuroinflammatory and apoptotic markers. Our results first demonstrate the neuroprotective effects of NAR against HAL-induced OD, suggesting that NAR may help in delaying or treating human TD in clinical settings.

Low frequency deep brain stimulation in the inferior colliculus ameliorates haloperidol-induced catalepsy and reduces anxiety in rats.

Deep brain stimulation (DBS) of the colliculus inferior (IC) improves haloperidol-induced catalepsy and induces paradoxal kinesia in rats. Since the IC is part of the brain aversive system, DBS of this structure has long been related to aversive behavior in rats limiting its clinical use. This study aimed to improve intracollicular DBS parameters in order to avoid anxiogenic side effects while preserving motor improvements in rats. Catalepsy was induced by systemic haloperidol (0.5mg/kg) and after 60 min the bar test was performed during which a given rat received continuous (5 min, with or without pre-stimulation) or intermittent (5 x 1 min) DBS (30Hz, 200-600µA, pulse width 100µs). Only continuous DBS with pre-stimulation reduced catalepsy time. The rats were also submitted to the elevated plus maze (EPM) test and received either continuous stimulation with or without pre-stimulation, or sham treatment. Only rats receiving continuous DBS with pre-stimulation increased the time spent and the number of entries into the open arms of the EPM suggesting an anxiolytic effect. The present intracollicular DBS parameters induced motor improvements without any evidence of aversive behavior, pointing to the IC as an alternative DBS target to induce paradoxical kinesia improving motor deficits in parkinsonian patients.

The mammalian target of rapamycin (mTOR) kinase mediates haloperidol-induced cataleptic behavior.

The mammalian target of rapamycin (mTOR) is a ubiquitously expressed serine/threonine kinase protein complex (mTORC1 or mTORC2) that orchestrates diverse functions ranging from embryonic development to aging. However, its brain tissue-specific roles remain less explored. Here, we have identified that the depletion of the mTOR gene in the mice striatum completely prevented the extrapyramidal motor side effects (catalepsy) induced by the dopamine 2 receptor (D2R) antagonist haloperidol, which is the most widely used typical antipsychotic drug. Conversely, a lack of striatal mTOR in mice did not affect catalepsy triggered by the dopamine 1 receptor (D1R) antagonist SCH23390. Along with the lack of cataleptic effects, the administration of haloperidol in mTOR mutants failed to increase striatal phosphorylation levels of ribosomal protein pS6 (S235/236) as seen in control animals. To confirm the observations of the genetic approach, we used a pharmacological method and determined that the mTORC1 inhibitor rapamycin has a profound influence upon post-synaptic D2R-dependent functions. We consistently found that pretreatment with rapamycin entirely prevented (in a time-dependent manner) the haloperidol-induced catalepsy, and pS6K (T389) and pS6 (S235/236) signaling upregulation, in wild-type mice. Collectively, our data indicate that striatal mTORC1 blockade may offer therapeutic benefits with regard to the prevention of D2R-dependent extrapyramidal motor side effects of haloperidol in psychiatric illness.

Ca2+ signaling as a mechanism of haloperidol-induced cytotoxicity in human astrocytes and assessing the protective role of a Ca2+ chelator.

Haloperidol, a typical antipsychotic medication, has been shown to possess various biological effects in different brain models. However, the impact of haloperidol on Ca2+ signaling in astrocytes is elusive. This study explored the effect of haloperidol on cytosolic free Ca2+ levels ([Ca2+]i) and viability, and established these two connections in Gibco® Human Astrocytes (GHAs) and DI TNC1 rat astrocytes. Haloperidol (5-20 µM) caused [Ca2+]i rises in a concentration-dependent manner in GHAs but not in DI TNC1 cells. Furthermore, removal of extracellular Ca2+ reduced haloperidol's effect by approximately 30% in GHAs. Haloperidol (20-40 µM) evoked concentration-dependent cytotoxicity in GHAs and DI TNC1 cells. However, chelating cytosolic Ca2+ with the Ca2+ chelator BAPTA/AM significantly reversed haloperidol's cytotoxicity only in GHAs. In GHAs, haloperidol-induced Ca2+ entry was inhibited by store-operated Ca2+ modulators (2-APB and SKF96365) and the protein kinase C (PKC) inhibitor GF109203X. This Ca2+ entry induced by haloperidol was confirmed by Mn2+ entry-induced quench of fura-2 fluorescence. In Ca2+-free medium, treatment with the endoplasmic reticulum Ca2+ pump inhibitor 2,5-di-tert-butylhydroquinone (BHQ) abolished haloperidol-induced [Ca2+]i rises. Conversely, treatment with haloperidol inhibited 45% of BHQ-evoked [Ca2+]i rises. Moreover, haloperidol-induced Ca2+ release from the endoplasmic reticulum was abolished by inhibition of phospholipase C (PLC) by U73122. Together, in GHAs but not in DI TNC1 cells, haloperidol caused Ca2+-associated cell death, induced Ca2+ entry via PKC-sensitive store-operated Ca2+ channels, and evoked PLC-dependent Ca2+ release from the endoplasmic reticulum. The protective effect of Ca2+ chelating on haloperidol-induced cytotoxicity in human astrocytes was also demonstrated.

Playback of 50-kHz ultrasonic vocalizations overcomes psychomotor deficits induced by sub-chronic haloperidol treatment in rats.

RATIONALE: In rodents, acute haloperidol treatment induces psychomotor impairments known as catalepsy, which models akinesia in humans and is characterized as an animal model of acute Parkinsonism, whereas sub-chronic haloperidol reduces exploratory behavior, which resembles bradykinesia. Haloperidol-induced catalepsy in rats can be ameliorated by playback of 50-kHz ultrasonic vocalizations (USV), an emotionally and motivationally relevant appetitive auditory stimulus, representing an animal model of paradoxical kinesia. In a condition like PD where patients suffer from chronic motor impairments, it is paramount to assess the long-term symptom relief in an animal model of Parkinsonism. OBJECTIVES: We investigated whether 50-kHz USV playback ameliorates psychomotor deficits induced by haloperidol in a sub-chronic dosing regimen. METHODS: In phase 1, distance traveled and number of rearing behavior were assessed in an activity chamber in order to investigate whether sub-chronic haloperidol treatment induced psychomotor impairments. In phase 2, we investigated whether 50-kHz USV playback could overcome these impairments by assessing exploratory behaviors and approach behavior towards the sound source in the 50-kHz USV radial maze playback paradigm. RESULTS: Sub-chronic haloperidol treatment led to psychomotor deficits since the distance traveled and number of rearing behavior were reduced as compared to saline control group or baseline. These psychomotor impairments were ameliorated during playback of 50-kHz USV, with haloperidol treated rats showing a clear social approach behavior towards the sound source exclusively during playback. CONCLUSIONS: This study provides evidence that 50-kHz USV playback induces paradoxical kinesia in rats exhibiting motor deficits after sub-chronic haloperidol, as we previously showed after acute haloperidol treatment.

Nose to brain delivery of rotigotine loaded chitosan nanoparticles in human SH-SY5Y neuroblastoma cells and animal model of Parkinson's disease.

Rotigotine, a non-ergoline dopamine agonist, has been shown to be highly effective for the treatment of Parkinson's disease (PD). However, despite its therapeutic potential, its' clinical applications were hindered due to low aqueous solubility, first-pass metabolism and low bioavailability. Therefore, we developed rotigotine-loaded chitosan nanoparticles (RNPs) for nose-to-brain delivery and evaluated its neuronal uptake, antioxidant and neuroprotective effects using cell-based studies. The pharmacological effects of nose-to-brain delivery of the RNPs were also evaluated in an animal model of PD. The average particle size, particle size distribution and entrapment efficiency of the RNPs were found to be satisfactory. Exposure of RNPs for 24 h did not show any cytotoxicity towards SH-SY5Y human neuroblastoma cells. Furthermore, the RNPs caused a decrease in alpha-synuclein (SNCA) and an increase in tyrosine hydroxylase (TH) expression in these cells, suggestion that the exposure alleviated some of the direct neurotoxic effects of 6-OHDA. Behavioral and biochemical testing of RNPs in haloperidol-induced PD rats showed a reversal of catalepsy, akinesia and restoration of swimming ability. A decrease in lactate dehydrogenase (LDH) and an increase in catalase activities were also observed in the brain tissues. The results from the animal model of PD show that intranasally-administered RNPs enhanced brain targeting efficiency and drug bioavailability. Thus, RNPs for nose-to-brain delivery has significant potential to be developed as a treatment approach for PD.

Vinpocetine prevents haloperidol-induced cognitive and working memory deficits through attenuation of oxidative and nitrosative stress in mice.

Vinpocetine has been shown to protect against degenerative senile cerebral dysfunction via enhancement of cerebral blood flow, cognition and neuroprotective action. This study sought to investigate the protective effect of vinpocetine against haloperidol-induced catalepsy in mice. Vinpocetine (5, 10 or 20 mg/kg, p.o.) was administered 1 h after haloperidol injection for 21 consecutive days. Effect on motor coordination, depressive-like behaviour and working memory were assessed with rotarod, forced swim (FST) and Y-maze tests, respectively. Brains were collected on day 21 for biochemical estimation of nitrosative and oxidative stress parameters. Vinpocetine (10 or 20 mg/kg, p.o.) significantly reversed haloperidol-induced motor deficit in rotarod test and open field test and reduced the duration of catalepsy during acute and chronic catalepsy tests as compared to trihexylphenidyl but failed to reverse haloperidol-induced memory deficit in the Y-maze test. Haloperidol-induced increase in malondialdehyde and nitrite generation as well as deficits in antioxidant enzymes activities were attenuated by chronic administration of vinpocetine. These findings suggest that vinpocetine protects against haloperidol-induced catalepsy and motor deficits through attenuation of oxidative/nitrosative stress.