Olanzapine attenuates 5-HT2cR and GHSR1a interaction to increase orexigenic hypothalamic NPY: Implications for neuronal molecular mechanism of metabolic side effects of antipsychotics.

The main cause of second-generation antipsychotic (SGA)-induced obesity is considered due to the antagonism of serotonin 2c receptors (5-HT2cR) and activation of ghrelin receptor type 1a (GHSR1a) signalling. It is reported that 5-HT2cR interacted with GHSR1a, however it is unknown whether one of the SGA olanzapine alters the 5-HT2cR/GHSR1a interaction, affecting orexigenic neuropeptide signalling in the hypothalamus. We found that olanzapine treatment increased average energy intake and body weight gain in mice; olanzapine treatment also increased orexigenic neuropeptide (NPY) and GHSR1a signaling molecules, pAMPK, UCP2, FOXO1 and pCREB levels in the hypothalamus. By using confocal fluorescence resonance energy transfer (FRET) technology, we found that 5-HT2cR interacted/dimerised with the GHSR1a in the hypothalamic neurons. As 5-HT2cR antagonist, both olanzapine and S242084 decreased the interaction between 5-HT2cR and GHSR1a and activated GHSR1a signaling. The 5-HT2cR agonist lorcaserin counteracted olanzapine-induced attenuation of interaction between 5-HT2cR and GHSR1a and inhibited activation of GHSR1a signalling and NPY production. These findings suggest that 5-HT2cR antagonistic effect of olanzapine in inhibition of the interaction of 5-HT2cR and GHSR1a, activation GHSR1a downstream signaling and increasing hypothalamic NPY, which may be the important neuronal molecular mechanism underlying olanzapine-induced obesity and target for prevention metabolic side effects of antipsychotic management in psychiatric disorders.

Investigating the Therapeutic Potential of Plants and Plant-Based Medicines: Relevance to Antioxidant and Neuroprotective Effects.

Oxidative stress is a common characteristic of psychiatric, neurological, and neurodegenerative disorders. Therefore, compounds that are neuroprotective and reduce oxidative stress may be of interest as novel therapeutics. Phenolic, flavonoid and anthocyanin content, ORAC and DPPH free radical scavenging, and Cu2+ and Fe2+ chelating capacities were examined in variations (fresh/capsule) of Queen Garnet plum (QGP, Prunus salicina), black pepper (Piper nigrum) clove (Syzygium aromaticum), elderberry (Sambucus nigra), lemon balm (Melissa officinalis) and sage (Salvia officinalis), plus two blends (Astralagus membranaceus-lemon balm-rich, WC and R8). The ability of samples to prevent and treat H2O2-induced oxidative stress in SH-SY5Y cells was investigated. Pre-treatment with WC, elderberry, QGP, and clove prevented the oxidative stress-induced reduction in cell viability, demonstrating a neuroprotective effect. Elderberry increased cell viability following oxidative stress induction, demonstrating treatment effects. Clove had the highest phenolic and flavonoid content, DPPH, and Cu2+ chelating capacities, whereas QGP and elderberry were highest in anthocyanins. Black pepper had the highest ORAC and Fe2+ chelating capacity. These findings demonstrate that plant extracts can prevent and treat oxidative stress-induced apoptosis of neuron-like cells in vitro. Further research into phytochemicals as novel therapeutics for oxidative stress in the brain is needed.

Butyrate Attenuates Hepatic Steatosis Induced by a High-Fat and Fiber-Deficient Diet via the Hepatic GPR41/43-CaMKII/HDAC1-CREB Pathway.

SCOPE: Hepatic steatosis is a major health issue that can be attenuated by a healthy diet. This study investigates the effects and molecular mechanisms of butyrate, a dietary fiber metabolite of gut microbiota, on lipid metabolism in hepatocytes. METHODS AND RESULTS: This study examines the effects of butyrate (0-8 mM) on lipid metabolism in primary hepatocytes. The results show that butyrate (2 mM) consistently inhibits lipogenic genes and activates lipid oxidation-related gene expression in hepatocytes. Furthermore, butyrate modulates lipid metabolism genes, reduces fat droplet accumulation, and activates the calcium/calmodulin-dependent protein kinase II (CaMKII)/histone deacetylase 1 (HDAC1)-cyclic adenosine monophosphate response element binding protein (CREB) signaling pathway in the primary hepatocytes and liver of wild-type (WT) mice, but not in G-protein-coupled receptor 41 (GPR41) knockout and 43 (GPR43) knockout mice. This suggests that butyrate regulated hepatic lipid metabolism requires GPR41 and GPR43. Finally, the study finds that dietary butyrate supplementation (5%) ameliorates hepatic steatosis and abnormal lipid metabolism in the liver of mice fed a high-fat and fiber-deficient diet for 15 weeks. CONCLUSION: This work reveals that butyrate improves hepatic lipid metabolism through the GPR41/43-CaMKII/HDAC1-CREB pathway, providing support for consideration of butyrate as a dietary supplement to prevent the progression of NAFLD induced by the Western-style diet.

Cannabidiol as a Treatment for Neurobiological, Behavioral, and Psychological Symptoms in Early-Stage Dementia: A Double-Blind, Placebo-Controlled Clinical Trial Protocol.

Rationale: The slowing of disease progression in dementia in the early stages of diagnosis is paramount to improving the quality of life for those diagnosed and their support networks. Accumulating evidence suggests that CBD, a constituent of Cannabis sativa, is associated with neuroprotective, neuroendocrine, and psychotherapeutic effects, suggesting that it may be beneficial to dementia treatment. However, no published human study to date has examined this possibility. This trial aims to determine whether daily treatment with CBD over a 12-week period is associated with improved neurobiological, behavioral, and psychological outcomes in individuals living with early-stage dementia. Methods: Sixty participants with early-stage dementia will be recruited for a randomized, double-blind, placebo-controlled clinical trial. Participants will be randomized into either 99.9% pure CBD or placebo treatment conditions and administered two capsules per day for 12 weeks. Participants will commence a 200 mg/day dose for 2 weeks before escalating to 300 mg/day for the remaining 10 weeks. Neuroimaging and blood-based neuroendocrine profiles will be assessed at baseline and post-treatment. Psychological and behavioral symptoms will be assessed at baseline, 6 weeks, and post-treatment. Monitoring of health and side-effects will be conducted through weekly home visits. Discussion: This study is among the first to investigate the effects of isolated CBD in improving neuroanatomical and neuroendocrine changes, alongside psychological symptoms, during the early stages of dementia diagnosis. The outcomes of this trial have the capacity to inform a potential novel and accessible treatment approach for individuals living with early-stage dementia, and in turn, improve quality of life, prognoses, and treatment outcomes. Trial Registration: This trial has been registered with the Therapeutic Goods Administration (CT-2020-CTN-03849-1v2) and the Australian and New Zealand Clinical Trials Registry (ACTRN12621001364864).

Data on enhanced wireless cell stimulation using soft and improved bipolar electroactive conducting polymer templates.

Data in this article is associated with our research article "Enhanced wireless cell stimulation using soft and improved bipolar electroactive conducting polymer templates" Qin et al. (2022). Primarily, the present article shows the data of PPy-PMAS/FTO, PPy-PMAS-collagen/FTO and PPy-PMAS-DS-collagen/FTO in conventional electrochemical process and bipolar electrochemical process along with in situ spectrometry for comprehensive supplement and comparison to help with better developing modified conducting polymers based bipolar electrochemistry. Secondly, the presented the complete dataset useful for modelling the soft and improved bipolar electroactive conducting polymers focusing on wireless cell (animal and human) stimulation, which are reported in the main article. All data reported were analysed using Origin 2019b 64Bit.

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

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.

Data on the bipolar electroactive conducting polymers for wireless cell stimulation.

Data in this article is associated with our research article "Bipolar Electroactive Conducting Polymers for Wireless Cell Stimulation" [1]. Primarily, the present article shows the data of PPy-pTS, PPy-DS and PPy-DS/collagen in conventional electrochemical process and bipolar electrochemical process for comprehensive supplement and comparison to help with better understanding and developing conducting polymers based bipolar electrochemistry. Secondly, the presented data of bipolar electrostimulation (BPES) protocol development constitute the complete dataset useful for modeling the bipolar electroactive conducting polymers focusing on wireless cell stimulation, which are reported in the main article. All data reported were analysed using Origin 2018b 64Bit.

DHA reduces hypothalamic inflammation and improves central leptin signaling in mice.

AIMS: Anti-obesity effects and improved leptin sensitivity from n-3 polyunsaturated fatty acids (n-3 PUFAs) have been reported in diet-induced obese animals. This study sought to determine the beneficial central effects and mechanism of docosahexaenoic acid (DHA, 22:6 n-3) in high-fat (HF) diet fed mice. MAIN METHODS: Male C57BL/6J mice were given HF diet with or without intracerebroventricular (icv) injection of docosahexaenoic acid (DHA, 22:6 n-3) for two days. Central leptin sensitivity, hypothalamic inflammation, leptin signaling molecules and tyrosine hydroxylase (TH) were examined by central leptin sensitivity test and Western blot. Furthermore, the expression of hepatic genes involved in lipid metabolism was examined by RT-PCR. KEY FINDINGS: We found that icv administration of DHA not only reduced energy intake and body weight gain but also corrected the HF diet-induced hypothalamic inflammation. DHA decreased leptin signaling inhibitor SOCS3 and improved the leptin JAK2-Akt signaling pathways in the hypothalamus. Furthermore, icv administration of DHA improved the effects of leptin in the regulation of mRNA expression of enzymes related to lipogenesis, fatty acid ß-oxidation, and cholesterol synthesis in the liver. DHA increased leptin-induced activation of TH in the hypothalamus. SIGNIFICANCE: Therefore, increasing central DHA concentration may prevent the deficit of hypothalamic regulation, which is associated with disorders of energy homeostasis in the liver as a result of a high-fat diet.

Supplement of microbiota-accessible carbohydrates prevents neuroinflammation and cognitive decline by improving the gut microbiota-brain axis in diet-induced obese mice.

BACKGROUND: Western pattern diets induce neuroinflammation and impair cognitive behavior in humans and animals. Neuroinflammation and cognitive impairment have been associated with microbiota dysbiosis, through the gut-brain axis. Furthermore, microbiota-accessible carbohydrates (MACs) found in dietary fiber are important in shaping the microbial ecosystem and have the potential to improve the gut-brain-axis. However, the effects of MACs on neuroinflammation and cognition in an obese condition have not yet been investigated. The present study aimed to evaluate the effect of MACs on the microbiota-gut-brain axis and cognitive function in obese mice induced by a high-fat and fiber deficient (HF-FD) diet. METHODS: C57Bl/6 J male mice were fed with either a control HF-FD or a HF-MAC diet for 15 weeks. Moreover, an additional group was fed with the HF-MAC diet in combination with an antibiotic cocktail (HF-MAC + AB). Following the 15-week treatment, cognitive behavior was investigated; blood, cecum content, colon, and brain samples were collected to determine metabolic parameters, endotoxin, gut microbiota, colon, and brain pathology. RESULTS: We report MACs supplementation prevented HF-FD-induced cognitive impairment in nesting building and temporal order memory tests. MACs prevented gut microbiota dysbiosis, including increasing richness, α-diversity and composition shift, especially in Bacteroidetes and its lower taxa. Furthermore, MACs increased colonic mucus thickness, tight junction protein expression, reduced endotoxemia, and decreased colonic and systemic inflammation. In the hippocampus, MACs suppressed HF-FD-induced neuroglia activation and inflammation, improved insulin IRS-pAKT-pGSK3ß-pTau synapse signaling, in addition to the synaptic ultrastructure and associated proteins. Furthermore, MACs' effects on improving colon-cognitive parameters were eliminated by wide spectrum antibiotic microbiota ablation. CONCLUSIONS: These results suggest that MACs improve cognitive impairments via the gut microbiota-brain axis induced by the consumption of an HF-FD. Supplemental MACs to combat obesity-related gut and brain dysfunction offer a promising approach to prevent neurodegenerative diseases associated with Westernized dietary patterns and obesity.

Olanzapine increases AMPK-NPY orexigenic signaling by disrupting H1R-GHSR1a interaction in the hypothalamic neurons of mice.

Second generation antipsychotics, particularly olanzapine, induce severe obesity, which is associated with their antagonistic effect on the histamine H1 receptor (H1R). We have previously demonstrated that oral administration of olanzapine increases the concentration of neuropeptide Y (NPY) in the hypothalamus of rats, accompanied by hyperphagia and weight gain. However, it is unclear if the increased NPY after olanzapine administration is due to its direct effect on hypothalamic neurons and its H1R antagonistic property. In the present study, we showed that with an inverted U-shape dose-response curve, olanzapine increased NPY expression in the NPY-GFP hypothalamic neurons; however, this was not the case in the hypothalamic neurons of H1R knockout mice. Olanzapine inhibited the interaction of H1R and GHSR1a (ghrelin receptor) in the primary mouse hypothalamic neurons and NPY-GFP neurons examined by confocal fluorescence resonance energy transfer (FRET) technology. Furthermore, an H1R agonist, FMPH inhibited olanzapine activation of GHSR1a downstream signaling pAMPK and transcription factors of NPY (pFOXO1 and pCREB) in the hypothalamic NPY-GFP cell. However, an olanzapine analogue (E-Olan) with lower affinity to H1R presented negligible enhancement of pCREB within the nucleus of NPY neurons. These findings suggest that the H1R antagonist property of olanzapine inhibits the interaction of H1R and GHSR1a, activates GHSR1a downstream signaling pAMPK-FOXO1/pCREB and increases hypothalamic NPY: this could be one of the important molecular mechanisms of H1R antagonism of olanzapine-induced obesity in antipsychotic management of psychiatric disorders.

[Reproductive characteristics and habitat factors of Acanthopanax giraldii].

The growth parameters,clonal propagation parameters and sexual reproduction parameters of Acanthopanax giraldii population were systematically investigated and analyzed by means of population ecology in this study. The correlation among the above mentioned parameters and the correlation among canopy density,topography and soil fertility factors were analyzed. It is clear that there was a significant correlation among the clonal ramets,the fruit production capacity of the cluster and the new shoot production capacity of the A. giraldii. Sexual reproduction and clonal reproduction played an important role in the continuation of the population. Illumination was the key ecological factor that determined growth type. The increase in canopy density changed the population from " group clonal growth" to " guerrilla clonal growth",and the higher stand closure degree and low-strength herb layer competition was a necessary condition for seed germination and colonization. Under the background of natural forest protection and sustainable development of resources,the reproductive characteristics of wild A. giraldii resulted in the decrease of its recoverable quantity.

Olanzapine-induced endoplasmic reticulum stress and inflammation in the hypothalamus were inhibited by an ER stress inhibitor 4-phenylbutyrate.

Antipsychotics are the most important treatment for schizophrenia. However, antipsychotics, particularly olanzapine and clozapine, are associated with severe weight gain/obesity side-effects. Although numerous studies have been carried out to identify the exact mechanisms of antipsychotic-induced weight gain, it is still important to consider other pathways. Endoplasmic reticulum (ER) stress signaling and its associated inflammation pathway is one of the most important pathways involved in regulation of energy balance. In the present study, we examined the role of hypothalamic protein kinase R like endoplasmic reticulum kinase- eukaryotic initiation factor 2α (PERK-eIF2α) signaling and the inflammatory IkappaB kinase ß- nuclear factor kappa B (IKKß-NFκB) signaling pathway in olanzapine-induced weight gain in female rats. In this study, we found that olanzapine significantly activated PERK-eIF2α and IKKß-NFκB signaling in SH-SY5Y cells in a dose-dependent manner. Olanzapine treatment for 8 days in rats was associated with activated PERK-eIF2α signaling and IKKß-NFκB signaling in the hypothalamus, accompanied by increased food intake and weight gain. Co-treatment with an ER stress inhibitor, 4-phenylbutyrate (4-PBA), decreased olanzapine-induced food intake and weight gain in a dose- and time-dependent manner. Moreover, 4-PBA dose-dependently inhibited olanzapine-induced activated PERK-eIF2α and IKKß-NFκB signaling in the hypothalamus. These results suggested that hypothalamic ER stress may play an important role in antipsychotic-induced weight gain.

Dietary Galacto-Oligosaccharides and Resistant Starch Protect Against Altered CB1 and 5-HT1A and 2A Receptor Densities in Rat Brain: Implications for Preventing Cognitive and Appetite Dysfunction During a High-Fat Diet.

SCOPE: A high-fat, but low-fiber, diet is associated with obesity and cognitive dysfunction, while dietary fiber supplementation can improve cognition. METHODS AND RESULTS: This study examines whether dietary fibers, galacto-oligosaccharides (GOS) and resistant starch (RS), could prevent high-fat (HF)-diet-induced alterations in neurotransmitter receptor densities in brain regions associated with cognition and appetite. Rats are fed a HF diet, HF diet with GOS, HF diet with RS, or a low-fat (LF, control) diet for 4 weeks. Cannabinoid CB1 (CB1R) and 5HT1A (5HT1A R) and 5-HT2A (5HT2A R) receptor binding densities are examined. In the hippocampus and hypothalamus, a HF diet significantly increases CB1R binding, while HF + GOS and HF + RS diets prevented this increase. HF diet also increases hippocampal and hypothalamic 5-HT1A R binding, while HF + GOS and HF + RS prevented the alterations. Increased 5-HT2A binding is prevented by HF + GOS and HF + RS in the medial mammillary nucleus. CONCLUSIONS: These results demonstrate that increased CB1R, 5-HT1A R and 5-HT2A R induced by a HF diet can be prevented by GOS and RS supplementation in brain regions involved in cognition and appetite. Therefore, increased fiber intake may have beneficial effects on improving learning and memory, as well as reducing excessive appetite, during the chronic consumption of a HF (standard Western) diet.

[Study on photosynthesis and physiological characteristics of Acanthopanax giraldii on different light intensity].

This article is aimed to study the response mechanism of Acanthopanax giraldii on different shading intensity to guide its artificial cultivation. The cultivated A. giraldii in Maoxian was used as the research object, set up different shading treatment groups, analyzed photosynthesis, physiology, submicroscopic structure to explore the response mechanism of A. giraldii to different light intensity. Light was the main influencing factor to photosynthetic rate.During morning and afternoon periods,the Pn of the CK group reduced by stomatal limitation and non stomatal limitation factors respectively. While during 14：30-18：30 period, the Pn of A1 and A2 groups reduced by non stomatal limitation factors.LSP, LCP and Rd of A1 and A2 groups were significantly lower than those of CK group;The content of SS and SP of A1 and A2 groups were lower than those of CK group. The content of Pro of CK group were significantly higher than those of group A2.The activities of SOD and POD of them was higher than that of CK group,CAT activity of A1 and POD activity of A2 were relatively higher In their respective free radical scavenging system. Starch grain increased and base grana declined in the chloropalst of those group CK. The study results indicated that response mechanism of different shading conditions of A. giraldii under field cultivation conditions. Its could effectively adapt to environmental changes of the home cultivation,which provided a reference for ensuring yield and quality.

Ginsenoside Rb1 improves leptin sensitivity in the prefrontal cortex in obese mice.

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.

Time-dependent effects of olanzapine treatment on the expression of histidine decarboxylase, H1 and H3 receptor in the rat brain: The roles in olanzapine-induced obesity.

Antipsychotic treatment, particularly olanzapine and clozapine, induces severe obesity. The Histamine H1 receptor is considered to be an important contributor to olanzapine-induced obesity, however how olanzapine modulates the histaminergic system is not sufficiently understood. This study examined the effect of olanzapine on key molecules of the histaminergic system, including histidine decarboxylase (HDC), H1 receptor (H1R) and H3 receptor (H3R), in the brain at different stages of olanzapine-induced obesity. During short-term treatment (8-day), olanzapine increased hypothalamic HDC mRNA expression and H1R binding in the arcuate nucleus (Arc) and ventromedial hypothalamus (VMH), without changing H3R binding density. HDC mRNA and Arc H1R binding were positively correlated with increased food intake, feeding efficiency and weight gain. When the treatment was extended to 16 and 36 days, H1R binding was increased not only in the hypothalamic Arc and VMH but also in the brainstem dorsal vagal complex (DVC). The H1R bindings in the Arc, VMH and DVC were positively correlated with weight gain induced by olanzapine treatment. However, the expression of HDC and H3R mRNA was not increased. These results suggest that olanzapine time-dependently modulates histamine neurotransmission, which suggested the different neuronal mechanisms underlying different stages of weight gain development. Treatment targeting the H1R may be effective for both short- and long-term olanzapine-induced weight gain.

Dietary teasaponin ameliorates alteration of gut microbiota and cognitive decline in diet-induced obese mice.

A high-fat (HF) diet alters gut microbiota and promotes obesity related inflammation and cognitive impairment. Teasaponin is the major active component of tea, and has been associated with anti-inflammatory effects and improved microbiota composition. However, the potential protective effects of teasaponin, against HF diet-induced obesity and its associated alteration of gut microbiota, inflammation and cognitive decline have not been studied. In this study, obesity was induced in C57BL/6 J male mice by feeding a HF diet for 8 weeks, followed by treatment with oral teasaponin (0.5%) mixed in HF diet for a further 6 weeks. Teasaponin treatment prevented the HF diet-induced recognition memory impairment and improved neuroinflammation, gliosis and brain-derived neurotrophic factor (BDNF) deficits in the hippocampus. Furthermore, teasaponin attenuated the HF diet-induced endotoxemia, pro-inflammatory macrophage accumulation in the colon and gut microbiota alterations. Teasaponin also improved glucose tolerance and reduced body weight gain in HF diet-induced obese mice. The behavioral and neurochemical improvements suggest that teasaponin could limit unfavorable gut microbiota alterations and cognitive decline in HF diet-induced obesity.

Improved Social Interaction, Recognition and Working Memory with Cannabidiol Treatment in a Prenatal Infection (poly I:C) Rat Model.

Neuropsychiatric disorders such as schizophrenia are associated with cognitive impairment, including learning, memory and attention deficits. Antipsychotic drugs are limited in their efficacy to improve cognition; therefore, new therapeutic agents are required. Cannabidiol (CBD), the non-intoxicating component of cannabis, has anti-inflammatory, neuroprotective and antipsychotic-like properties; however, its ability to improve the cognitive deficits of schizophrenia remains unclear. Using a prenatal infection model, we examined the effect of chronic CBD treatment on cognition and social interaction. Time-mated pregnant Sprague-Dawley rats (n=16) were administered polyinosinic-polycytidilic acid (poly I:C) (POLY; 4 mg/kg) or saline (CONT) at gestation day 15. Male offspring (PN56) were injected twice daily with 10 mg/kg CBD (CONT+CBD, POLY+CBD; n=12 per group) or vehicle (VEH; CONT+VEH, POLY+VEH; n=12 per group) for 3 weeks. Body weight, food and water intake was measured weekly. The Novel Object Recognition and rewarded T-maze alternation tests assessed recognition and working memory, respectively, and the social interaction test assessed sociability. POLY+VEH offspring exhibited impaired recognition and working memory, and reduced social interaction compared to CONT+VEH offspring (p<0.01). CBD treatment significantly improved recognition, working memory and social interaction deficits in the poly I:C model (p<0.01 vs POLY+VEH), did not affect total body weight gain, food or water intake, and had no effect in control animals (all p>0.05). In conclusion, chronic CBD administration can attenuate the social interaction and cognitive deficits induced by prenatal poly I:C infection. These novel findings present interesting implications for potential use of CBD in treating the cognitive deficits and social withdrawal of schizophrenia.

Chronic rhein treatment improves recognition memory in high-fat diet-induced obese male mice.

High-fat (HF) diet modulates gut microbiota and increases plasma concentration of lipopolysaccharide (LPS) which is associated with obesity and its related low-grade inflammation and cognitive decline. Rhein is the main ingredient of the rhubarb plant which has been used as an anti-inflammatory agent for several millennia. However, the potential effects of rhein against HF diet-induced obesity and its associated alteration of gut microbiota, inflammation and cognitive decline have not been studied. In this study, C57BL/6J male mice were fed an HF diet for 8 weeks to induce obesity, and then treated with oral rhein (120 mg/kg body weight/day in HF diet) for a further 6 weeks. Chronic rhein treatment prevented the HF diet-induced recognition memory impairment assessed by the novel object recognition test, neuroinflammation and brain-derived neurotrophic factor (BDNF) deficits in the perirhinal cortex. Furthermore, rhein inhibited the HF diet-induced increased plasma LPS level and the proinflammatory macrophage accumulation in the colon and alteration of microbiota, including decreasing Bacteroides-Prevotella spp. and Desulfovibrios spp. DNA and increasing Bifidobacterium spp. and Lactobacillus spp. DNA. Moreover, rhein also reduced body weight and improved glucose tolerance in HF diet-induced obese mice. In conclusion, rhein improved recognition memory and prevented obesity in mice on a chronic HF diet. These beneficial effects occur via the modulation of microbiota, hypoendotoxinemia, inhibition of macrophage accumulation, anti-neuroinflammation and the improvement of BDNF expression. Therefore, supplementation with rhein-enriched food or herbal medicine could be beneficial as a preventive strategy for chronic HF diet-induced cognitive decline, microbiota alteration and neuroinflammation.

Bardoxolone methyl prevents obesity and hypothalamic dysfunction.

High-fat (HF) diet-induced obesity is associated with hypothalamic leptin resistance and low grade chronic inflammation, which largely impairs the neuroregulation of negative energy balance. Neuroregulation of negative energy balance is largely controlled by the mediobasal and paraventricular nuclei regions of the hypothalamus via leptin signal transduction. Recently, a derivative of oleanolic acid, bardoxolone methyl (BM), has been shown to have anti-inflammatory effects. We tested the hypothesis that BM would prevent HF diet-induced obesity, hypothalamic leptin resistance, and inflammation in mice fed a HF diet. Oral administration of BM via drinking water (10 mg/kg daily) for 21 weeks significantly prevented an increase in body weight, energy intake, hyperleptinemia, and peripheral fat accumulation in mice fed a HF diet. Furthermore, BM treatment prevented HF diet-induced decreases in the anorexigenic effects of peripheral leptin administration. In the mediobasal and paraventricular nuclei regions of the hypothalamus, BM administration prevented HF diet-induced impairments of the downstream protein kinase b (Akt) pathway of hypothalamic leptin signalling. BM treatment also prevented an increase in inflammatory cytokines, tumour necrosis factor alpha (TNFα) and interleukin 6 (IL-6) in these two hypothalamic regions. These results identify a potential novel neuropharmacological application for BM in preventing HF diet-induced obesity, hypothalamic leptin resistance, and inflammation.