Prenatal infection promotes olanzapine-induced obesity in rats: implications for antipsychotic-induced obesity in schizophrenia

Abstract of a poster presentation

Propionate Protects Haloperidol-Induced Neurite Lesions Mediated by Neuropeptide Y

Haloperidol is a commonly used antipsychotic drug for treating schizophrenia. Clinical imaging studies have found that haloperidol can cause volume loss of human brain tissue, which is supported by animal studies showing that haloperidol reduces the number of synaptic spines. The mechanism remains unknown. Gut microbiota metabolites, short chain fatty acids including propionate, are reported to have neuroprotective effect and influence gene expression. This study aims to investigate the effect and mechanism of propionate in the protection of neurite lesion induced by haloperidol. This study showed that 10 μM haloperidol (clinical relevant dose) impaired neurite length in human blastoma SH-SY5Y cells, which were confirmed by using primary mouse striatal spiny neurons. We found that haloperidol impaired neurite length were accompanied by a decreased neuropeptide Y (NPY) expression, but no effect on GSK3β signaling. Importantly, this project research found that propionate was capable of protecting against haloperidol-induced neurite lesions and preventing NPY reduction. To confirm this finding, we used specific siRNAs targeting NPY which blocked the protective effect of propionate on haloperidol-induced neurite lesions. Furthermore, since NPY is regulated by the nuclear transcription factor CREB, we measured pCREB that was decreased by haloperidol and was normalized by propionate. Therefore, propionate has a protective effect against pCREB-NPY mediated haloperidol-induced neurite lesions

N-acetylcysteine prevents olanzapine-induced oxidative stress in mHypoA-59 hypothalamic neurons

2020, The Author(s). Olanzapine is a second-generation antipsychotic (AP) drug commonly prescribed for the treatment of schizophrenia. Recently, olanzapine has been found to cause brain tissue volume loss in rodent and primate studies; however, the underlying mechanism remains unknown. Abnormal autophagy and oxidative stress have been implicated to have a role in AP-induced neurodegeneration, while N-acetylcysteine (NAC) is a potent antioxidant, shown to be beneficial in the treatment of schizophrenia. Here, we investigate the role of olanzapine and NAC on cell viability, oxidative stress, mitochondrial mass and mitophagy in hypothalamic cells. Firstly, cell viability was assessed in mHypoA-59 and mHypoA NPY/GFP cells using an MTS assay and flow cytometric analyses. Olanzapine treated mHypoA-59 cells were then assessed for mitophagy markers and oxidative stress; including quantification of lysosomes, autophagosomes, LC3B-II, p62, superoxide anion (O2-) and mitochondrial mass. NAC (10 mM) was used to reverse the effects of olanzapine (100 µM) on O2−, mitochondrial mass and LC3B-II. We found that olanzapine significantly impacted cell viability in mHypoA-59 hypothalamic cells in a dose and time-dependent manner. Olanzapine inhibited mitophagy, instigated oxidative stress and prompted mitochondrial abnormalities. NAC was able to mitigate olanzapine-induced effects. These findings suggest that high doses of olanzapine may cause neurotoxicity of hypothalamic neurons via increased production of reactive oxygen species (ROS), mitochondrial damage and mitophagy inhibition. This could in part explain data suggesting that APs may reduce brain volume

Neuropathology of muscarinic receptor in the prenatal infection - rat model

Abstract of a poster presentation

Olanzapine differentially corrects altered NMDA receptor binding induced by prenatal polyIC and LPS

Abstract of a poster presentation

Prenatal PolyIC and LPS exposure alters serotonin transporter and 5-HT2A receptor binding densities in rodents: implications for schizophrenia

Abstract of a poster presentation

Quinolinic acid impairs mitophagy promoting microglia senescence and poor healthspan in C. elegans: a mechanism of impaired aging process

Abstract Senescent microglia are a distinct microglial phenotype present in aging brain that have been implicated in the progression of aging and age-related neurodegenerative diseases. However, the specific mechanisms that trigger microglial senescence are largely unknown. Quinolinic acid (QA) is a cytotoxic metabolite produced upon abnormal activation of microglia. Brain aging and age-related neurodegenerative diseases have an elevated concentration of QA. In the present study, we investigated whether QA promotes aging and aging-related phenotypes in microglia and C. elegans. Here, we demonstrate for the first time that QA, secreted by abnormal microglial stimulation, induces impaired mitophagy by inhibiting mitolysosome formation and consequently promotes the accumulation of damaged mitochondria due to reduced mitochondrial turnover in microglial cells. Defective mitophagy caused by QA drives microglial senescence and poor healthspan in C. elegans. Moreover, oxidative stress can mediate QA-induced mitophagy impairment and senescence in microglial cells. Importantly, we found that restoration of mitophagy by mitophagy inducer, urolithin A, prevents microglial senescence and improves healthspan in C. elegans by promoting mitolysosome formation and rescuing mitochondrial turnover inhibited by QA. Thus, our study indicates that mitolysosome formation impaired by QA is a significant aetiology underlying aging-associated changes. QA-induced mitophagy impairment plays a critical role in neuroinflammation and age-related diseases. Further, our study suggests that mitophagy inducers such as urolithin A may offer a promising anti-aging strategy for the prevention and treatment of neuroinflammation-associated brain aging diseases

Propionate protects haloperidol-induced neurite lesions mediated by neuropeptide Y

Haloperidol is a commonly used antipsychotic drug for treating schizophrenia. Clinical imaging studies have found that haloperidol can cause volume loss of human brain tissue, which is supported by animal studies showing that haloperidol reduces the number of synaptic spines. The mechanism remains unknown. Gut microbiota metabolites, short chain fatty acids including propionate, are reported to have neuroprotective effect and influence gene expression. This study aims to investigate the effect and mechanism of propionate in the protection of neurite lesion induced by haloperidol. This study showed that 10 μM haloperidol (clinical relevant dose) impaired neurite length in human blastoma SH-SY5Y cells, which were confirmed by using primary mouse striatal spiny neurons. We found that haloperidol impaired neurite length were accompanied by a decreased neuropeptide Y (NPY) expression, but no effect on GSK3β signaling. Importantly, this project research found that propionate was capable of protecting against haloperidol-induced neurite lesions and preventing NPY reduction. To confirm this finding, we used specific siRNAs targeting NPY which blocked the protective effect of propionate on haloperidol-induced neurite lesions. Furthermore, since NPY is regulated by the nuclear transcription factor CREB, we measured pCREB that was decreased by haloperidol and was normalized by propionate. Therefore, propionate has a protective effect against pCREB-NPY mediated haloperidol-induced neurite lesions

Serum NCAM levels and cognitive deficits in first episode schizophrenia patients versus health controls

Background: Neural cell adhesion molecule (NCAM) is a glycoprotein and plays an important role in cell-cell adhesion, neural migration, neurite outgrowth, synaptic plasticity and brain development. We investigated the relationship between the serum NCAM concentration and cognitive deficit in first episode drug naïve schizophrenia (FES) patients. Methods: Thirty FES patients and thirty healthy controls were recruited for this study. Psychiatric symptoms were assessed by the positive and negative syndrome scale (PANSS). Cognitive functions were assessed by measurement and treatment research to improve cognition in schizophrenia (MATRICS) and consensus cognitive battery (MCCB). Serum levels of NCAM were determined by ELISA. Results: Schizophrenia patients had decreased serum NCAM concentrations than controls (−30%, p Conclusions: There were a close relationship between the serum NCAM concentrations and cognitive deficits in FES patients. Since NCAM has an important role in neurodevelopmental processes, these results support the neurodevelopmental dysfunction hypothesis of schizophrenia and suggest that an altered NCAM may be one of the risk factors for schizophrenia including cognitive deficits