Gynura procumbens and selected metabolites: Amelioration of depressive-like behaviors in mice and risperidone-induced hyperprolactinemia in rats.

Gynura procumbens (Lour.) Merr., utilized in traditional Chinese medicine, is known for its liver-protective, liver-soothing, and depression-alleviating properties. This research examines the antidepressant and anti-hyperprolactinemia potentials of an ethanol extract from G. procumbens stems (EEGS) and specific metabolites. To model depression and hyperprolactinemia, chronic unpredictable mild stress (CUMS) was induced in mice and risperidone was administered to rats, respectively. Treatments involved administering low (5 mg/kg), medium (25 mg/kg), and high (125 mg/kg) doses of EEGS and certain metabolites to both models. Behavioral assessments were conducted in the CUMS-induced mice, while the CA3 neuronal damage in mice and histopathological alterations in rat mammary glands were evaluated using Nissl and Hematoxylin & Eosin staining techniques, respectively. EEGS decreased immobility times in the forced swimming and tail suspension tests in mice, enhancing their exploration of the central zone. It elevated the serum levels of 5-hydroxytryptamine, norepinephrine, estradiol, luteinizing hormone (LH), and testosterone in mice. Moreover, EEGS restored the neuronal cell arrangement in the CA3 area, reduced interleukin-1beta mRNA production, and increased the expression of interleukin-10 and beta-catenin mRNA. In the context of risperidone-induced hyperprolactinemia, EEGS lowered blood prolactin levels, reduced the dimensions of rat nipples, and enhanced LH, progesterone, and dopamine levels, alongside mitigating mammary hyperplasia. Among the EEGS selected metabolites, the combined effect of chlorogenic acid and trans-p-coumaric acid was found to be more effective than the action of each compound in isolation. Collectively, the findings indicate that EEGS and its selected metabolites offer promising antidepressant benefits while counteracting hyperprolactinemia.

Genotoxic and genoprotective effects of some antipsychotic drugs, methylphenidate and atomoxetine on human lymphocytes and HepG2 cells.

OBJECTIVE: Aripiprazole, risperidone, atomoxetine, and methylphenidate are drugs commonly prescribed for many psychiatric conditions and can be used alone or in combination in children and adolescents. This study aimed to investigate comparatively the possible genotoxic effects or genoprotective potentials of these drugs on human lymphocytes and HepG2 cells. MATERIALS AND METHODS: Cytotoxicity analysis was performed with the cell viability test on human lymphocytes and HepG2 cells, and half-maximal inhibitory concentration (IC50) values of the drugs were determined, and three different doses (» IC50, ½ IC50, and IC50) were applied for genetic analysis. For the determined doses, cells with and without DNA damage were examined by comet analysis. RESULTS: In lymphocytes, aripiprazole and risperidone increased DNA damage at moderate and maximum doses, whereas atomoxetine increased DNA damage only at the maximum dose. In HepG2 cells, risperidone reduced DNA damage at all doses, while atomoxetine increased DNA damage at all doses. On the other hand, in the DNA-damaged cells induced by hydrogen peroxide (H2O2), DNA damage decreased at all concentrations of all drugs in both lymphocytes and HepG2 cells. CONCLUSIONS: As a result, the genotoxicity of the drugs was found to be dose-dependent, and all drugs showed a genoprotective effect on DNA-damaged cells.

Olanzapine, risperidone and ziprasidone differently affect lysosomal function and autophagy, reflecting their different metabolic risk in patients.

The metabolic effects induced by antipsychotics in vitro depend on their action on the trafficking and biosynthesis of sterols and lipids. Previous research showed that antipsychotics with different adverse effects in patients cause similar alterations in vitro, suggesting the low clinical usefulness of cellular studies. Moreover, the inhibition of peripheral AMPK was suggested as potential aetiopathogenic mechanisms of olanzapine, and different effects on autophagy were reported for several antipsychotics. We thus assessed, in clinically-relevant culture conditions, the aetiopathogenic mechanisms of olanzapine, risperidone and ziprasidone, antipsychotics with respectively high, medium, low metabolic risk in patients, finding relevant differences among them. We highlighted that: olanzapine impairs lysosomal function affecting autophagy and autophagosome clearance, and increasing intracellular lipids and sterols; ziprasidone activates AMPK increasing the autophagic flux and reducing intracellular lipids; risperidone increases lipid accumulation, while it does not affect lysosomal function. These in vitro differences align with their different impact on patients. We also provided evidence that metformin add-on improved autophagy in olanzapine-treated cells and reduced lipid accumulation induced by both risperidone and olanzapine in an AMPK-dependent way; metformin also increased the production of bile acids to eliminate cholesterol accumulations caused by olanzapine. These results have different clinical implications. We demonstrated that antipsychotics with different metabolic impacts on patients actually have different mechanisms of action, thus supporting the possibility of a personalised antipsychotic treatment. Moreover, we found that metformin can fully revert the phenotype caused by risperidone but not the one caused by olanzapine, that still activates SREBP2.

Drugs prescribed for Phelan-McDermid syndrome differentially impact sensory behaviors in shank3 zebrafish models.

Background: Altered sensory processing is a pervasive symptom in individuals with Autism Spectrum Disorders (ASD); people with Phelan McDermid syndrome (PMS), in particular, show reduced responses to sensory stimuli. PMS is caused by deletions of the terminal end of chromosome 22 or point mutations in Shank3. People with PMS can present with an array of symptoms including ASD, epilepsy, gastrointestinal distress, and reduced responses to sensory stimuli. People with PMS are often medicated to manage behaviors like aggression and/or self-harm and/or epilepsy, and it remains unclear how these medications might impact perception/sensory processing. Here we test this using zebrafish mutant shank3ab PMS models that likewise show reduced sensory responses in a visual motor response (VMR) assay, in which increased locomotion is triggered by light to dark transitions. Methods: We screened three medications, risperidone, lithium chloride (LiCl), and carbamazepine (CBZ), prescribed to people with PMS and one drug, 2-methyl-6-(phenylethynyl) pyridine (MPEP) tested in rodent models of PMS, for their effects on a sensory-induced behavior in two zebrafish PMS models with frameshift mutations in either the N- or C- termini. To test how pharmacological treatments affect the VMR, we exposed larvae to selected drugs for 24 hours and then quantified their locomotion during four ten-minute cycles of lights on-to-off stimuli. Results: We found that risperidone normalized the VMR in shank3 models. LiCl and CBZ had no effect on the VMR in any of the three genotypes. MPEP reduced the VMR in wildtype (WT) to levels seen in shank3 models but caused no changes in either shank3 model. Finally, shank3 mutants showed resistance to the seizure-inducing drug pentylenetetrazol (PTZ), at a dosage that results in hyperactive swimming in WT zebrafish. Conclusions: Our work shows that the effects of drugs on sensory processing are varied in ways that can be highly genotype- and drug-dependent.

The effect of risperidone on behavioral reactions and gene expression of pro- and anti-inflammatory cytokines in neuropathic pain model induced by chronic constriction injury of the sciatic nerve in rat.

BACKGROUND: Neuropathic pain results from lesions or diseases affecting the somatosensory system. The management of a patient with chronic neuropathic pain remains a challenge several studies report the analgesic effect of serotonin receptor antagonists in different models of experimental pain. The present study was designed to study the effect of systemic administration of risperidone, on behavioral scores of neuropathic pains in chronic constriction (CCI) model in rats. METHODS: Inducing neuropathic pain with the CCI model which causes heat hyperalgesia, heat, and mechanical allodynia was performed on rats, and then, in two phases, risperidone effect was determined. In the acute phase, risperidone 1, 2, 4 mg was administered for three groups half an hour before behavioral tests on the 7th, 14th, and 21st day after surgery, and in the chronic phase, risperidone 1, 2, and 4 mg was administered for three different groups from the 1st to 14th days after surgery than on 14th-day behavioral scores were performed. For gene expression analysis, samples are taken from spinal cord tissues in lumbar segments. RESULTS: This study shows chronic administration of risperidone as an antipsychotic drug was effective on heat hyperalgesia and allodynia. However, only the max dosage (4 mg) of risperidone showed meaningful improvement in increasing mechanical allodynia. However, acute administering of risperidone did not show any meaningful changes in behavioral tests on neuropathic pain induced by chronic constriction injury of the sciatic nerve in rats. In addition, gene expression results showed an increase in IL-4 and IL-10 gene expression in the risperidone group compared to the sham group. CONCLUSION: This study suggests the helpful preventive effects of risperidone in developing and increasing neuropathic pain, but it does not have any instant effect.

Sex-specific differences and similarities of olanzapine and risperidone on avoidance suppression in rats in the conditioned avoidance response test.

It is well known that antipsychotic drugs (APDs) are more effective in reducing symptoms in women than in men, and that women are more sensitive to the side effects of APDs. Therefore, it is of great importance that sex differences in drug responses are considered already in the early stages of drug development. In this study, we investigated whether sex-specific differences could be observed in response to the commonly prescribed APDs olanzapine and risperidone using the conditioned avoidance response (CAR) test. To this end we tested the effect of 1.25 and 2.5 mg/kg olanzapine and 0.25 and 0.4 mg/kg risperidone using female and male Wistar rats in the CAR test. Whereas there were no significant differences between the female and male rats in response to either dose of olanzapine administration, an injection of 0.4 mg/kg risperidone significantly suppressed avoidance more in female rats than in male rats. In addition, we found that the estrous cycle of the female rats did not have a significant effect on the avoidance response. In conclusion, we show that there are sex-specific differences as well as similarities between female and male rats in the CAR test and novel APDs should be tested on female and male rats in the future.

Risperidone impedes glutamate excitotoxicity in a valproic acid rat model of autism: Role of ADAR2 in AMPA GluA2 RNA editing.

Several reports indicate a plausible role of calcium (Ca2+) permeable AMPA glutamate receptors (with RNA hypo-editing at the GluA2 Q/R site) and the subsequent excitotoxicity-mediated neuronal death in the pathogenesis of a wide array of neurological disorders including autism spectrum disorder (ASD). This study was designed to examine the effects of chronic risperidone treatment on the expression of adenosine deaminase acting on RNA 2 (Adar2), the status of AMPA glutamate receptor GluA2 editing, and its effects on oxidative/nitrosative stress and excitotoxicity-mediated neuronal death in the prenatal valproic acid (VPA) rat model of ASD. Prenatal VPA exposure was associated with autistic-like behaviors accompanied by an increase in the apoptotic marker "caspase-3" and a decrease in the antiapoptotic marker "BCL2" alongside a reduction in the Adar2 relative gene expression and an increase in GluA2 Q:R ratio in the hippocampus and the prefrontal cortex. Risperidone, at doses of 1 and 3 mg, improved the VPA-induced behavioral deficits and enhanced the Adar2 relative gene expression and the subsequent GluA2 subunit editing. This was reflected on the cellular level where risperidone impeded VPA-induced oxidative/nitrosative stress and neurodegenerative changes. In conclusion, the present study confirms a possible role for Adar2 downregulation and the subsequent hypo-editing of the GluA2 subunit in the pathophysiology of the prenatal VPA rat model of autism and highlights the favorable effect of risperidone on reversing the RNA editing machinery deficits, giving insights into a new possible mechanism of risperidone in autism.

Minocycline and antipsychotics inhibit inflammatory responses in BV-2 microglia activated by LPS via regulating the MAPKs/ JAK-STAT signaling pathway.

BACKGROUND: Abnormal activation of microglia is involved in the pathogenesis of schizophrenia. Minocycline and antipsychotics have been reported to be effective in inhibiting the activation of microglia and thus alleviating the negative symptoms of patients with schizophrenia. However, the specific molecular mechanism by which minocycline and antipsychotics inhibit microglial activation is not clear. In this study, we aimed to explore the molecular mechanism of treatment effect of minocycline and antipsychotics on schizophrenia. METHODS: Microglia cells were activated by lipopolysaccharide (LPS) and further treated with minocycline, haloperidol, and risperidone. Then cell morphology, specific marker, cytokines, and nitric oxide production process, and the proteins in related molecular signaling pathways in LPS-activated microglia were compared among groups. RESULTS: The study found that minocycline, risperidone, and haloperidol significantly inhibited morphological changes and reduced the expression of OX-42 protein induced by LPS. Minocycline significantly decreased the production of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-1beta (IL-1ß). Risperidone also showed significant decrease in the production of IL-6 and TNF-α, while haloperidol only showed significant decrease in the production of IL-6. Minocycline, risperidone, and haloperidol were found to significantly inhibit nitric oxide (NO) expression, but had no effect on inducible nitric oxide synthase (iNOS) expression. Both minocycline and risperidone were effective in decreasing the activity of c­Jun N­terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) in the mitogen-activated protein kinases (MAPKs) signal pathway. Additionally, minocycline and risperidone were found to increase the activity of phosphorylated-p38. In contrast, haloperidol only suppressed the activity of ERK. Minocycline also suppressed the activation of janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3), while risperidone and haloperidol only suppressed the activation of STAT3. CONCLUSIONS: The results demonstrated that minocycline and risperidone exert stronger anti-inflammatory and neuroprotective effects stronger than haloperidol, through MAPKs and Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathways in BV2 cells stimulated with LPS, revealing the underlying mechanisms of minocycline and atypical antipsychotics in the treatment of negative schizophrenia symptoms.

Effect of risperidone on morphine-induced conditioned place preference and dopamine receptor D2 gene expression in male rat hippocampus.

BACKGROUND: Previous studies suggest the possible effect of risperidone on brain reward system and D1 and D2 dopamine receptors' involvement in morphine-induced conditioned place preference (CPP). AIMS: The present study was designed to investigate the effect of risperidone as an atypical antipsychotic drug on morphine-induced CPP and D2-like dopamine receptor gene expression in rat. MATERIALS AND METHODS: An unbiased CPP paradigm was used to study the effect of risperidone. Intraperitoneal (i.p.) injection of risperidone (1, 2, and 4 mg/kg) was performed 30 min before the morphine (10 mg/kg, i.p.) injection and just after the rat was placed in the CPP box. The open field test was used to assay the locomotor activity of animal. The gene expression of D2 dopamine receptor in hippocampus was measured by real-time PCR technique. The hippocampi of rats were also used for histology evaluation. RESULTS: Morphine-produced (10 mg/kg) CPP and morphine-induced CPP were reversed only by the administration of a low dose of risperidone (1 mg/kg). Low dose of risperidone (1 mg/kg) showed no effect on locomotor activity but a higher dose of risperidone (2 and 4 mg/kg) decreased locomotor activity. Real-time PCR data analysis revealed that the gene expression of D2 dopamine receptor had significant difference between morphine and a 1 mg/kg dose of risperidone. Moreover, in histological evaluation, apoptosis was observed in the morphine group, whereas there was no evidence of apoptosis in the risperidone-treated groups. CONCLUSION: Our results suggest that risperidone (1 mg/kg) reverses the morphine-induced CPP and may reduce the rewarding properties of morphine. It is also demonstrated that risperidone decreases the expression of D2 receptor in rat hippocampus. Therefore, risperidone can be considered potential adjunct therapy in morphine dependence.

Risperidone response in patients with schizophrenia drives DNA methylation changes in immune and neuronal systems.

Background: The choice of efficient antipsychotic therapy for schizophrenia relies on a time-consuming trial-and-error approach, whereas the social and economic burdens of the disease call for faster alternatives. Material & methods: In a search for predictive biomarkers of antipsychotic response, blood methylomes of 28 patients were analyzed before and 4 weeks into risperidone therapy. Results: Several CpGs exhibiting response-specific temporal dynamics were identified in otherwise temporally stable methylomes and noticeable global response-related differences were observed between good and bad responders. These were associated with genes involved in immunity, neurotransmission and neuronal development. Polymorphisms in many of these genes were previously linked with schizophrenia etiology and antipsychotic response. Conclusion: Antipsychotic response seems to be shaped by both stable and medication-induced methylation differences.

The most common way to treat schizophrenia is antipsychotic medication. However, not all antipsychotics work for all patients. The only way to find a suitable antipsychotic is to prescribe one and wait, sometimes for months, to see if it works. Finding an alternative to this trial-and-error method would help reduce patient suffering and costs for healthcare systems. The idea is to look in the DNA of our blood cells for specific marks that can change in response to our lifestyle or health condition. These marks could help us predict how patients will react to the drug. In other words, they can serve as biomarkers of antipsychotic response. The current work examined the blood of schizophrenia patients before and 4 weeks after starting medication. The patients who did not respond well to the drug had different marks on the genes involved in immune defense and nervous system functioning. Some of these genes also play roles in the development of schizophrenia, whereas others can directly affect what happens to the drug in the patient's body. Although marks that predict how patients will react were not identified with certainty, valuable targets for future research were identified.

Effects of Early Risperidone Treatment on Metabolic Parameters in Socially Isolated Rats-Implication of Antipsychotic Intervention across Developmental Stages of Schizophrenia.

BACKGROUND: Second-generation antipsychotics (SGAs) is thought responsible for the metabolic abnormalities of schizophrenic patients, however, some untreated schizophrenic patients had already developed problems with glucose metabolism. The present study examined the hypothesis that schizophrenia itself but not risperidone, an extensively employed SGA, is accountable for metabolic abnormalities. METHODS: A 56-day risperidone regimen (1 mg/kg/day) was employed for rats of social isolation rearing (SIR) beginning at different developmental stage (28 or 56 days after weaning, i.e., adolescent and young adulthood, respectively). Metabolic parameters including body weight, systolic blood pressure (SBP), triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol, and plasma glucose were measured at baseline, 28, and 56 days of the regimen. Oral glucose tolerance test (OGTT) was performed at the end of the regimen. Insulin function was evaluated by area under the curve (AUC) of OGTT, homeostasis model assessment-insulin resistance (HOMA-ir), and Matsuda index. RESULTS: Our results demonstrated that: (i) SIR rats presented higher body weight, plasma triglyceride, and HOMA-ir than social controls. (ii) Higher insulin resistance was specifically presented in young adult rather than adolescent SIR rats. (iii) Adolescent drugged rats showed a lower level of LDL in day 28 of the regimen than young adult. Risperidone led to a lower LDL level in only young adult IR rats in day 56 than undrugged rats. (iv) SIR-induced dysregulation of insulin can be reversed by chronic risperidone treatment beginning at adolescence but not young adulthood. CONCLUSIONS: Our findings support the primary role of schizophrenia in metabolic abnormalities and risperidone appear beneficial when administered earlier.

Epigenetic clock analysis of blood samples in drug-naive first-episode schizophrenia patients.

BACKGROUND: Schizophrenia (SCZ) is a severe and chronic psychiatric disorder with premature age-related physiological changes. However, numerous previous studies examined the epigenetic age acceleration in SCZ patients and yielded inconclusive results. In this study, we propose to explore the epigenetic age acceleration in drug-naive first-episode SCZ (FSCZ) patients and investigate whether epigenetic age acceleration is associated with antipsychotic treatment, psychotic symptoms, cognition, and subcortical volumes. METHODS: We assessed the epigenetic age in 38 drug-naive FSCZ patients and 38 healthy controls by using three independent clocks, including Horvath, Hannum and Levine algorithms. The epigenetic age measurements in SCZ patients were repeated after receiving 8 weeks risperidone monotherapy. RESULTS: Our findings showed significantly positive correlations between epigenetic ages assessed by three clocks and chronological age in both FSCZ patients and healthy controls. Compared with healthy controls, drug-naive FSCZ patients have a significant epigenetic age deceleration in Horvath clock (p = 0.01), but not in Hannum clock (p = 0.07) and Levine clock (p = 0.43). The epigenetic ages of Hannum clock (p = 0.002) and Levine clock (p = 0.01) were significantly accelerated in SCZ patients after 8-week risperidone treatment. However, no significant associations between epigenetic age acceleration and psychotic symptoms, cognitive function, as well as subcortical volumes were observed in FSCZ patients. CONCLUSION: These results demonstrate that distinct epigenetic clocks are sensitive to different aspects of aging process. Further investigations with comprehensive epigenetic clock analyses and large samples are required to confirm our findings.

Virtual histology of morphometric similarity network after risperidone monotherapy and imaging-epigenetic biomarkers for treatment response in first-episode schizophrenia.

BACKGROUND: Antipsychotic treatment has been conceived to alter brain connectivity, but it is unclear how the changes of network phenotypes relate to the underlying transcriptomics. Given DNA methylation (DNAm) may alter transcriptional levels, we further integrated an imaging-transcriptomic-epigenetic analysis to explore multi-omics treatment response biomarkers. METHODS: Forty-two treatment-naive first-episode schizophrenia patients were scanned by TI weighted (T1W) imaging and DTI before and after 8-week risperidone monotherapy, and their peripheral blood genomic DNAm values were examined in parallel with MRI scanning. Morphometric similarity network (MSN) quantified with DTI and T1W data were used as a marker of treatment-related alterations in interareal cortical connectivity. We utilized partial least squares (PLS) to examine spatial associations between treatment-related MSN variations and cortical transcriptomic data obtained from the Allen Human Brain Atlas. RESULTS: Longitudinal MSN alterations were related to treatment response on cognitive function and general psychopathology symptoms, while DNAm values of 59 PLS1 genes were on negative and positive symptoms. Virtual-histology transcriptomic analysis linked the MSN alterations with the neurobiological, cellular and metabolic pathways or processes, and assigned MSN-related genes to multiple cell types, specifying neurons and glial cells as contributing most to the transcriptomic associations of longitudinal changes in MSN. CONCLUSIONS: We firstly reveal how brain-wide transcriptional levels and cell classes capture molecularly validated cortical connectivity alterations after antipsychotic treatment. Our findings represent a vital step towards the exploration of treatment response biomarkers on the basis of multiple omics rather than a single omics type as a strategy for advancing precise care.

Neuropharmacological effect of risperidone: From chemistry to medicine.

As the second-oldest atypical antipsychotic, risperidone has a long history of off-label usage for treating behavioural and psychological signs and symptoms of dementia (BPSD), such as agitation, aggressiveness, and psychosis. Risperidone has been shown in several trials to have a statistically significant benefit when used in a therapeutic context. Several lines of evidence suggest a possible role of risperidone via the antagonistic effect of Dopamine D2 and 5HT-receptor in different neurological diseases like cognitive dysfunction of schizophrenia, neuroinflammation, Huntington's disease, and sleep cycle management. Therefore, the pharmacological interactions of risperidone in all these diseases were investigated. Some reports on the use of risperidone in the treatment of dopaminergic psychosis have been slightly conflicting. However, more research is needed to evaluate the role of risperidone in the treatment of these neurological diseases.

Reversal and Preventive Pleiotropic Mechanisms Involved in the Antipsychotic-Like Effect of Taurine, an Essential ß-Amino Acid in Ketamine-Induced Experimental Schizophrenia in Mice.

Schizophrenia is a life disabling, multisystem neuropsychiatric disease mostly derived from complex epigenetic-mediated neurobiological changes causing behavioural deficits. Neurochemical disorganizations, neurotrophic and neuroimmune alterations are some of the challenging neuropathologies proving unabated during psychopharmacology of schizophrenia, further bedeviled by drug-induced metabolic derangements including alteration of amino acids. In first-episode schizophrenia patients, taurine, an essential ß-amino acid represses psychotic-symptoms. However, its anti-psychotic-like mechanisms remain incomplete. This study evaluated the ability of taurine to prevent or reverse ketamine-induced experimental psychosis and the underlying neurochemical, neurotrophic and neuroinmune mechanisms involved in taurine's clinical action. The study consisted of three different experiments with Swiss mice (n = 7). In the drug alone, mice received saline (10 mL/kg/p.o./day), taurine (50 and 100 mg/kg/p.o./day) and risperidone (0.5 mg/kg/p.o./day) for 14 days. In the preventive study of separate cohort, mice were concomitantly given ketamine (20 mg/kg/i.p./day) from days 8 to 14. In the reversal study, mice received ketamine for 14 days before taurine or risperidone treatments from days 8 to 14 respectively. Afterwards, stereotypy behaviour, social, non-spatial memory deficits, and body weights were assessed. Neurochemical (dopamine, 5-hydroxytryptamine, glutamic acid decarboxylase, (GAD)), brain derived-neurotrophic factor (BDNF) and pro-inflammatory cytokines [tumor necrosis factor-alpha, (TNF-α), interleukin-6, (IL-6)] were assayed in the striatum, prefrontal-cortex and hippocampal area. Taurine attenuates ketamine-induced schizophrenia-like behaviour without changes in body weight. Taurine reduced ketamine-induced dopamine and 5-hydroxytryptamine changes, and increased GAD and BDNF levels in the striatum, prefrontal-cortex and hippocampus, suggesting increased GABAergic and neurotrophic transmissions. Taurine decreases ketamine-induced increased in TNF-α and IL-6 concentrations in the striatum, prefrontal-cortex and hippocampus. These findings also suggest that taurine protects against schizophrenia through neurochemical modulations, neurotrophic enhancement, and inhibition of neuropathologic cytokine activities.

An unexpected effect of risperidone reveals a nonlinear relationship between cytosolic Ca2+ and mitochondrial Ca2+ uptake.

Mitochondria actively contribute to cellular Ca2+ homeostasis. The molecular mechanisms of mitochondrial Ca2+ uptake and release are well characterized and are attributed to the multi-protein assembly of the mitochondrial Ca2+ uniporter complex (MCUC) and the mitochondrial sodium-calcium exchanger (NCLX), respectively. Hence, Ca2+ transfer from the endoplasmic reticulum (ER) and store-operated Ca2+ entry (SOCE) into the mitochondrial matrix has been quantitatively visualized on the subcellular level using targeted fluorescent biosensors. However, a correlation between the amplitude of cytosolic Ca2+ elevation with that in the mitochondrial matrix has not been investigated in detail so far. In the present study, we combined the Ca2+-mobilizing agonist histamine with the H1-receptor antagonist risperidone to establish a well-tunable experimental approach allowing the correlation between low, slow, high, and fast cytosolic and mitochondrial Ca2+ signals in response to inositol 1,4,5-trisphosphate (IP3)-triggered ER Ca2+ release. Our present data confirm a defined threshold in cytosolic Ca2+, which is necessary for the activation of mitochondrial Ca2+ uptake. Moreover, our data support the hypothesis of different modes of mitochondrial Ca2+ uptake depending on the source of the ion (i.e., ER vs SOCE).

Granulocyte Colony-Stimulating Factor Improved Core Symptoms of Autism Spectrum Disorder via Modulating Glutamatergic Receptors in the Prefrontal Cortex and Hippocampus of Rat Brains.

Chronic neuroinflammation-induced anomalous glutamate receptor activation has been identified as one of the important factors in the pathogenesis of autism spectrum disorder (ASD). Thus, the current study was designed to elucidate the neuroprotective effect of the granulocyte colony-stimulating factor (G-CSF), a haemopoietic growth factor, an anti-inflammatory, and a neuroprotectant to decipher the underlying mechanism(s) in the valproic acid (VPA)-induced experimental model of ASD. Experimentally, the ASD rat model was induced by a single dose of VPA (600 mg/kg; i.p.) on gestation day 12.5 to the pregnant female rats. After birth, pups were treated with vehicle, normal saline 0.9% i.p., risperidone (2.5 mg/kg; i.p.), and G-CSF (10, 35, and 70 µg/kg; i.p.) from postnatal day (PND) 23 to 43. All the groups were subjected to various developmental and behavior tests from birth. The rats were sacrificed on PND 55, and their brain was excised and processed for biochemical parameters (oxidative stress, inflammatory markers, BDNF), histological examination (H&E, Nissl staining), NMDA, and AMPA receptor expression by immunohistochemistry, western blot, and real-time polymerase chain reaction evaluation. Also, the possible interaction of the G-CSF with NMDA and AMPA receptors was evaluated using the in-silico method. The results of the study showed that in VPA-exposed rats, postnatal treatment of G-CSF rescued all the behavioral abnormalities, oxidative stress, and inflammatory parameters in a dose-dependent manner while risperidone did not show any significant results. The in-silico analysis showed the direct interaction of G-CSF with NMDA and AMPA receptors. The upregulated expression of NMDA and AMPA both in the prefrontal cortex as well as hippocampus was alleviated by G-CSF thereby validating its anti-inflammatory and excitoprotective properties. Thus, G-CSF demonstrated neuroprotection against the core symptoms of autism in the VPA-induced rodent model, making it a potential candidate for the treatment of ASD.

Adjuvant palmitoylethanolamide therapy with risperidone improves negative symptoms in patients with schizophrenia: A randomized, double-blinded, placebo-controlled trial.

BACKGROUND: Primary negative symptoms of schizophrenia are usually resistant to monotherapy with antipsychotics. The present study sought to assess the efficacy and tolerability of Palmitoylethanolamide (PEA) adjunctive therapy in treatment of negative symptoms in patients with stable schizophrenia. METHODS: This 8-week (trial timepoints: baseline, week 4, week 8), double-blind, placebo-controlled clinical trial randomized patients with schizophrenia in a 1:1 ratio to compare the efficacy and safety of 600 mg twice a day of PEA and matched placebo alongside a stable dose of risperidone. Outcome measures were the positive and the negative syndrome scale (PANSS), the extrapyramidal symptom rating scale (ESRS), and the Hamilton depression rating scale (HDRS). The primary outcome was change in the negative subscale score during the trial period between the groups. Safety of interventions were controlled and addressed during the trial. RESULTS: A total of 50 participants completed the trial (25 in each group). Baseline characteristics of the groups were comparable (p>0.05). There was significant effect from time-treatment interaction on negative symptoms (p = 0.012) suggesting greater symptom improvement in the PEA group. In contrast, the longitudinal changes in positive symptoms and depressive symptoms were similar between groups (p values>0.05). Safety assessments showed no significant difference regarding extrapyramidal symptoms, measured by ESRS, and also frequency of other complications between PEA and placebo groups (p values>0.05). CONCLUSIONS: Adjunctive therapy with PEA and risperidone alleviates schizophrenia-related primary negative symptoms in a safe manner.

The long-lasting effects of early antipsychotic exposure during juvenile period on adult behaviours - A study in a poly I:C rat model.

Second generation antipsychotic drugs including aripiprazole, olanzapine and risperidone are prescribed increasingly (mostly off-label) to treat various mental disorders in children and adolescents. Early treatment with antipsychotics during this period may have long-lasting behavioural impacts, but to date there have been only limited investigations. Maternal infection could be implicated in the aetiology of various mental disorders including schizophrenia. Exposure of pregnant rodents to polyriboinosinic-polyribocytidylic acid (Poly I:C) causes schizophrenia-like behavioural abnormalities and neurodevelopmental conditions such as autism spectrum disorders in offspring. This study, using a Poly I:C rat model, investigated the long-lasting effects of early aripiprazole, olanzapine and risperidone treatment in the childhood/adolescent period (postnatal day 22-50) on adult behaviours of male rats. The study showed that early treatment with three antipsychotics had different effects on long-term behavioural changes in adults. Prenatal Poly I:C exposure (5 mg/kg) at gestation day 15 caused deficits in pre-pulse inhibition and social interaction, as well as cognitive impairments, that could be partially improved by early antipsychotic treatment in the juvenile period. Early antipsychotic treatment during the childhood-adolescent period resulted in similar long-lasting effects on pre-pulse inhibition, anxiety- and depressive-related behaviours in both Poly I:C and healthy (control) male rats. Overall, these results suggest that both prenatal Poly I:C exposure and early antipsychotic treatment in the childhood/adolescent period had long-lasting effects on adult behaviours of male rats, while early antipsychotic treatment could partly prevent the onset of behavioural abnormalities resulting from prenatal insult.

TRAF4 Maintains Deubiquitination of Caveolin-1 to Drive Glioblastoma Stemness and Temozolomide Resistance.

Glioblastoma (GBM) is the most common type of primary adult brain tumor. Glioma stem cell (GSC) residence and temozolomide (TMZ) resistance in GBM both contribute to poor patient outcome. TRAF4 is a scaffold protein with E3 ubiquitin ligase activity that has recently been discovered to promote invasion and metastasis in several malignancies, but the effects and functions of TRAF4 in GBM remain to be determined. Here, we report that TRAF4 is preferentially overexpressed in GSCs and is required for stem-like properties as well as TMZ sensitivity in GBM cells. TRAF4 specifically interacted with the N-terminal tail of Caveolin-1 (CAV1), an important contributor to the tumorigenicity of GBM cells. TRAF4 regulated CAV1 stability by preventing ZNRF1-mediated ubiquitination and facilitating USP7-mediated deubiquitination independently of its E3 ubiquitin ligase catalytic activity. TRAF4-mediated stabilization of CAV1 activated protumorigenic AKT/ERK1/2 signaling, and disruption of this axis resulted in defects in stemness maintenance. In addition, expression of TRAF4 and CAV1 was positively correlated and predicted poor prognosis in human GBM samples. Screening of common nervous system drugs identified risperidone interaction with TRAF4, and risperidone treatment resulted in the dissociation of TRAF4 and CAV1. Importantly, pharmacologic inhibition of TRAF4 with risperidone potently inhibited self-renewal, abrogated tumorigenicity, and reversed TMZ resistance in GBM. Overall, TRAF4-mediated stabilization of CAV1 promotes stemness and TMZ resistance in GBM, providing a therapeutic strategy that could improve patient outcomes. SIGNIFICANCE: The identification of a TRAF4/Caveolin-1 axis that plays a crucial role in malignant progression of glioblastoma provides new insights into the function of TRAF4 in ubiquitin signaling and suggests TRAF4 as a potential therapeutic target.