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Aims: Many patients taking risperidone for the treatment of psychiatric disorders experience substantial body weight gain. Researchers have speculated that risperidone induces obesity by modulating central signals; however, the precise central mechanisms involved remain to be fully elucidated. Methods: Twenty‐four C57BL/6J mice were divided into four groups: a control group; a risperidone‐treated group; a lorcaserin‐treated group; and a combined risperidone + lorcaserin‐treated group. The mice were received the corresponding treatments for 4 weeks, and their brains were collected for in situ hybridization analysis. A subset of C57BL/6J mice was administrated with risperidone or placebo, and brains were collected 60 minutes post‐treatment for determination of c‐fos activity. In addition, brains of NPY‐GFP mice treated with or without risperidone were collected to perform colocalization of NPY and c‐fos, as well as NPY and 5‐HT2c receptor using immunohistochemistry. Results: There was significantly elevated c‐fos expression in the hypothalamic arcuate nucleus (Arc) of risperidone‐treated mice. More than 68% c‐fos‐positive neurons were NPY‐expressing neurons. Furthermore, in situ hybridization revealed that Arc NPY mRNA expression was significantly increased in the risperidone‐treated group compared with control group. Moreover, we identified that 95% 5‐HT2c receptors were colocalized with NPY positive neurons, and increased Arc NPY mRNA expression induced by risperidone was markedly reduced by cotreatment with lorcaserin, a specific 5‐HT2c receptor agonist. Conclusion: Our findings provide critical insight into the mechanisms underlying antipsychotic‐induced obesity, which may assist the development of therapeutic strategies to address metabolic side effects of risperidone. [ABSTRACT FROM AUTHOR]

Summary: Aim: Obesity impairs leptin‐induced regulation of brain‐derived neurotrophic factor (BDNF) expression and synaptogenesis, which has been considered to be associated with the incidence of neuronal degenerative diseases, cognitive decline, and depression. Ginsenoside Rb1 (Rb1), a major bioactive component of ginseng, is known to have an antiobesity effect and improve cognition. This study examined whether Rb1 can improve central leptin effects on BDNF expression and synaptogenesis in the prefrontal cortex during obesity using an in vivo and an in vitro model. Result: Ginsenoside Rb1 (Rb1) chronic treatment improved central leptin sensitivity, leptin‐JAK2‐STAT3 signaling, and leptin‐induced regulation of BDNF expression in the prefrontal cortex of high‐fat diet‐induced obese mice. In cultured prefrontal cortical neurons, palmitic acid, the saturated fat, impaired leptin‐induced BDNF expression, reduced the immunoreactivity and mRNA expression of synaptic proteins, and impaired leptin‐induced neurite outgrowth and synaptogenesis. Importantly, Rb1 significantly prevented these pernicious effects induced by palmitic acid. Conclusion: These results indicate that Rb1 reverses central leptin resistance and improves leptin‐BDNF‐neurite outgrowth and synaptogenesis in the prefrontal cortical neurons. Thus, Rb1 supplementation may be a beneficial avenue to treat obesity‐associated neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Background and Purpose ATP-sensitive potassium (K- ATP) channels couple energy metabolism with electric activity, which play important roles in brain diseases including stroke. However, the impacts of Kir6.1-containing K- ATP channels that mainly expressed on glia in stroke remain unclear. Methods and Results In this study, we found that expression of Kir6.1 was significantly decreased in the ischemic brain area of C57 BL/6J mice after 1-h middle cerebral artery occlusion ( MCAO) and 24-h reperfusion. Then, we subjected Kir6.1 heterozygote knockout (Kir6.1+/−) mice to cerebral ischemia/reperfusion (I/R) injury and found that Kir6.1+/− mice exhibited exacerbated neurological disorder and enlarged infarct size, companied by glial over-activation and blood-brain barrier ( BBB) damages. Furthermore, we showed that Kir6.1 knockdown aggravated endoplasmic reticulum ( ER) stress and thereby increased the levels of proinflammatory factors tumor necrosis factor-α and interleukin-1β ( TNF-α and IL-1β) in mouse brain. Conclusions Our findings reveal that Kir6.1 knockdown exacerbates cerebral I/R-induced brain damages via increasing ER stress and inflammatory response, indicating that Kir6.1-containing K- ATP channels may be a potential therapeutic target for stroke. [ABSTRACT FROM AUTHOR]

Background and Purpose Emerging evidence indicates that stimulating adult neurogenesis provides novel strategies for central nervous system diseases. Iptakalim ( Ipt), a novel ATP-sensitive potassium (K- ATP) channel opener, has been demonstrated to play multipotential neuroprotective effects in vivo and in vitro. However, it remains unknown whether Ipt could regulate the adult neurogenesis. Methods and Results Based on the finding that adult neural stem cells ( ANSCs) in hippocampus expressed Kir6.1/ SUR1-composed K- ATP channel, Kir6.1 heterozygotic ( Kir6.1+/−) mice were used to investigate whether and how Ipt regulates adult hippocampal neurogenesis. We showed that administration of Ipt (10 mg/kg) or fluoxetine ( Flx, 10 mg/kg) for 4 weeks significantly increased newborn ANSCs in subgranular zone ( SGZ) of Kir6.1+/+ mice but failed to affect those of Kir6.1+/− mice. Meanwhile, ANSCs in Kir6.1+/− mice exhibited decreased survival rate and impaired ability of differentiation into astrocytes. We further found that Kir6.1+/− mice showed lower level of brain-derived neurotrophic factor ( BDNF) in hippocampus compared with Kir6.1+/+ mice. Furthermore, Ipt increased the levels of BDNF and basic fibroblast growth factor ( FGF-2) throughout the hippocampus in Kir6.1+/+ mice but not in Kir6.1+/− mice. Moreover, Ipt and Flx enhanced the phosphorylation of Akt and CREB in the hippocampus of Kir6.1+/+ mice. Notably, these effects were completely abolished in Kir6.1+/− mice. Conclusions Our findings demonstrate that Ipt stimulates the adult hippocampal neurogenesis via activation of Akt and CREB signal following the opening of Kir6.1-composed K- ATP channels, which gives us an insight into the therapeutic implication of Ipt in the diseases with adult neurogenesis deficiency, such as major depression. [ABSTRACT FROM AUTHOR]

SUMMARY Background and purpose: d-Serine, the endogenous co-agonist of N-methyl- d-aspartate (NM dA) receptors, has been recognized as an important gliotransmitter in the mammalian brain. d-serine has been shown to prevent psychostimulant-induced decrease in hippocampal neurogenesis. However, the mechanism whereby d-serine regulates neurogenesis has not been fully characterized. Therefore, this study was designed to investigate the impacts of d-serine on the proliferation, migration, and differentiation of primary cultured neural stem cells (NSCs). Methods and results: Immunohistochemistry analysis revealed NSCs expressed d-serine as well as serine racemase (SR). Degradation of endogenous d-serine with d-amino acid oxidase ( dAAO) significantly inhibited the proliferation and neuronal differentiation of NSCs, but failed to affect their radial migration. Reversely, addition of exogenous d-serine did not affect the proliferation and migration of NSCs, but promoted NSC differentiation into neurons. Furthermore, dAAO could suppress the amplitude of glutamate-induced Ca2+ transient, and thereby, inhibited the phosphorylation of glycogen synthase kinase3β (GSK3β), extracellular signal-regulated kinases1/2 (ERK1/2), and cAMP-responsive element-binding protein (CREB). Conclusions: Our findings demonstrate for the first time that NSCs can synthesize d-serine and, thereby, promote themselves proliferation and neuronal differentiation, which may afford a novel therapeutic strategy for the neurological disorders that require nerve cell replenishment, such as neurodegenerative diseases and stroke. [ABSTRACT FROM AUTHOR]