Effects of Stevia rebaudiana Bertoni extracts in the rat model of epilepsy induced by pentylenetetrazol: Sirt-1, at the crossroads between inflammation and apoptosis.

The current study investigated the effects of stevia extracts on a PTZ-induced epileptic rat model and its potential mechanism. Thirty male Sprague-Dawley rats were equally subdivided into 3 groups; (1) normal control (NC) group, (2) PTZ-group: received PTZ (50 mg/kg, i.p. every other day) for 2 weeks, and (3) PTZ+ Stevia group: received PTZ and stevia (200 mg/kg orally daily) for 4 weeks (2 weeks before the start of PTZ treatment and 2 weeks with PTZ administration). The first jerk latency and the seizure score were assessed in rats. Also, brain tissue samples were collected by the end of the experiment, and oxidative stress markers (catalase, MDA, and total antioxidant capacity (TAC)) were measured by biochemical analysis in hippocampal brain homogenates. Also, in the hippocampus, the expression of IL6 and Bcl-2 at the mRNA level and expression of Sirt-1, P53, caspase-3, GFAP, and NF-kB in CA3 hippocampal region by immunohistochemistry was investigated. PTZ substantially increased the seizure score and decreased the seizure latency. Also, PTZ significantly increased MDA, GFAP, IL-6, NF-kB, caspase-3, and p53 and significantly reduced Sirt-1, TAC, and Bcl-2 in hippocampal tissues compared to the control group (p < 0.01). However, Stevia Rebaudiana Bertoni (Stevia R.) significantly attenuated the PTZ-induced seizures, improved oxidative stress markers, downregulated GFAP, IL-6, NF-kB, caspase-3, and p53, and upregulated Sirt-1 and Bcl-2 in the CA3 hippocampal region (p < 0.01). In conclusion, Stevia R. exhibits neuroprotective and antiepileptic actions in PTZ-induced epilepsy due to its antioxidant, anti-apoptotic, and anti-inflammatory effects. Additionally, the Sirt-1 pathway might be involved in the antiepileptic and neuroprotective effects of stevia in PTZ-kindled epileptic rat model.

Phytoestrogen genistein modulates neuron-microglia signaling in a mouse model of chronic social defeat stress.

Microglia, resident immune cells in the brain, are shown to mediate the crosstalk between psychological stress and depression. Interestingly, increasing evidence indicates that sex hormones, particularly estrogen, are involved in the regulation of immune system. In this study, we aimed to understand the potential effects of chronic social defeat stress (CSDS) and genistein (GEN), an estrogenic compound of the plant origin, on neuron-microglia interactions in the mouse hippocampus. The time spent in the avoidance zone in the social interaction test was increased by CSDS 1 day after the exposure, while the avoidance behavior returned to control levels 14 days after the CSDS exposure. Similar results were obtained from the elevated plus-maze test. However, the immobility time in the forced swim test was increased by CSDS 14 days after the exposure, and the depression-related behavior was in part alleviated by GEN. The numerical densities of microglia in the hippocampus were increased by CSDS, and they were decreased by GEN. The voxel densities of synaptic structures and synaptic puncta colocalized with microglia were decreased by CSDS, and they were increased by GEN. Neither CSDS nor GEN affected the gene expressions of major pro-inflammatory cytokines. Conversely, the expression levels of genes related to neurotrophic factors were decreased by CSDS, and they were partially reversed by GEN. These findings show that GEN may in part alleviate stress-related symptoms, and the effects of GEN may be associated with the modulation of neuron-microglia signaling via chemokines and neurotrophic factors in the hippocampus.

Fermented rice bran supplementation attenuates chronic colitis-associated extraintestinal manifestations in female C57BL/6N mice.

Patients with inflammatory bowel disease (IBD) have higher incidence of extraintestinal manifestations (EIM), including liver disorders, sarcopenia, and neuroinflammation. Fermented rice bran (FRB), generated from rice bran (RB), is rich in bioactive compounds, and exhibits anti-colitis activity. However, its role in EIM prevention is still unclear. Here, for the first time, we investigated whether EIM in female C57Bl/6N mice is attenuated by FRB supplementation. EIM was induced by repeated administration of 1.5% dextran sulfate sodium (DSS) in drinking water (4 d) followed by drinking water (12 d). Mice were divided into 3 groups-control (AIN93M), 10% RB, and 10% FRB. FRB ameliorated relapsing colitis and inflammation in muscle by significantly lowering proinflammatory cytokines Tnf-α and Il-6 in serum and advanced glycation end product-specific receptor (Ager) in serum and muscle when compared with the RB and control groups. As FRB reduced aspartate aminotransferase levels and oxidative stress, it might prevent liver disorders. FRB downregulated proinflammatory cytokine and chemokine transcripts responsible for neuroinflammation in the hippocampus and upregulated mRNA expression of G protein coupled receptors (GPRs), Gpr41 and Gpr43, in small and large intestines, which may explain the FRB-mediated protective mechanism. Hence, FRB can be used as a supplement to prevent IBD-associated EIM.

Metformin reduces oxandrolone- induced depression-like behavior in rats via modulating the expression of IL-1ß, IL-6, IL-10 and TNF-α.

Oxandrolone (OXA) is an androgen and anabolic steroid (AAS) that is used to reverse weight loss associated with some medical conditions. One of the side effects of OXA is its potential to induce depressive symptoms. Growing evidence suggested that neuroinflammation and cytokines play crucial roles in sickness behavioral and associated mood disturbances. Previous studies showed that metformin attenuated neuroinflammation. This study investigated the potential protective role of metformin against OXA-induced depression-like behavior and neuroinflammation. Twenty- four Wistar male rats were randomly grouped into four groups: the control group (Control) received only vehicle; the oxandrolone group (OXA) received oxandrolone (0.28 mg/kg, i.p); the metformin group (MET) received metformin (100 mg/kg, i.p); and the oxandrolone / metformin group (OXA + MET) received both oxandrolone (0.28 mg/kg, i.p) and metformin (100 mg/kg, i.p). These treatments were administered for fourteen consecutive days. Behavioral tests to measure depression-like behavior were conducted before and after treatments. qRT-PCR was used to measure the relative expression of proinflammatory and anti-inflammatory cytokines in the hippocampus and hypothalamus. The results showed that oxandrolone induced depression-like behavior and dysregulated pro-/anti-inflammatory cytokines, while metformin attenuated these effects. These findings suggest that metformin is a potential treatment to reverse the depressive effects induced by oxandrolone that involve neuroinflammatory effects.

Obesity Prevents S-Adenosylmethionine-Mediated Improvements in Age-Related Peripheral and Hippocampal Outcomes.

BACKGROUND: Age predisposes individuals to a myriad of disorders involving inflammation; this includes stress-related neuropsychiatric disorders such as depression and anxiety, and neurodegenerative diseases. Obesity can further exacerbate these effects in the brain. We investigated whether an inexpensive dietary supplement, s-adenosylmethionine (SAMe), could improve age- and/or obesity-related inflammatory and affective measures in the hippocampus. METHODS: Mice were placed on their diets at six weeks of age and then aged to 14 months, receiving SAMe (0.1 g/kg of food) for the final six weeks of the experiment. Prior to tissue collection, mice were tested for anxiety-like behaviors in the open field test and for metabolic outcomes related to type 2 diabetes. RESULTS: SAMe treatment significantly improved outcomes in aged control mice, where fasting glucose decreased, liver glutathione levels increased, and hippocampal microglia morphology improved. SAMe increased transforming growth factor ß-1 mRNA in both control mice, potentially accounting for improved microglial outcomes. Obese mice demonstrated increased anxiety-like behavior, where SAMe improved some, but not all, open field measures. CONCLUSIONS: In summary, SAMe boosted antioxidant levels, improved diabetic measures, and hippocampal inflammatory and behavioral outcomes in aged mice. The effects of SAMe in obese mice were more subdued, but it could still provide some positive outcomes for obese individuals dealing with anxiety and having difficulty changing their behaviors to improve health outcomes.

Meningeal lymphatics affect microglia responses and anti-Aß immunotherapy.

Alzheimer's disease (AD) is the most prevalent cause of dementia1. Although there is no effective treatment for AD, passive immunotherapy with monoclonal antibodies against amyloid beta (Aß) is a promising therapeutic strategy2,3. Meningeal lymphatic drainage has an important role in the accumulation of Aß in the brain4, but it is not known whether modulation of meningeal lymphatic function can influence the outcome of immunotherapy in AD. Here we show that ablation of meningeal lymphatic vessels in 5xFAD mice (a mouse model of amyloid deposition that expresses five mutations found in familial AD) worsened the outcome of mice treated with anti-Aß passive immunotherapy by exacerbating the deposition of Aß, microgliosis, neurovascular dysfunction, and behavioural deficits. By contrast, therapeutic delivery of vascular endothelial growth factor C improved clearance of Aß by monoclonal antibodies. Notably, there was a substantial overlap between the gene signature of microglia from 5xFAD mice with impaired meningeal lymphatic function and the transcriptional profile of activated microglia from the brains of individuals with AD. Overall, our data demonstrate that impaired meningeal lymphatic drainage exacerbates the microglial inflammatory response in AD and that enhancement of meningeal lymphatic function combined with immunotherapies could lead to better clinical outcomes.

Electroacupuncture with Bushen Jiannao improves cognitive deficits in senescence-accelerated mouse prone 8 mice by inhibiting neuroinflammation.

OBJECTIVE: To investigate effect of electroacupuncture (EA) with Bushen Jiannao on learning and memory ability in senescence-accelerated mouse prone 8 (SAMP8) mice and the related mechanisms. METHODS: 8-month-old senescence-accelerated-resistant (SAMR1) and SAMP8 mice were treated with EA at Baihui (GV 20), Shenshu (BL 23), and Taixi (KI 3) acupoint once a week for 8 weeks. The Morris water maze, enzyme linked immunosorbent assay, immunohistochemistry, and Western blot were used to assess Alzheimer's disease (AD)-associated cognitive and neuroinflammatory phenotypes. RESULTS: Our data showed that EA treatment decreased activation of microglia and astrocytes, decreased levels of inflammatory factors including tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-17, and improved spatial memory deficits in SAMP8 mice. EA therapy with Bushen Jiannao exhibited anti-inflammatory properties and improved cognitive function. CONCLUSION: The present study indicates that EA treatment based on the interaction between kidney and brain can improve learning and memory ability by inhibiting activation of astrocytes and microglia and decreasing expression of pro-inflammatory cytokines, TNF-α and IL-17. EA treatment based on the interaction between kidney and brain may be an effective treatment for AD.

Salvianolic Acid B improves cognitive impairment by inhibiting neuroinflammation and decreasing Aß level in Porphyromonas gingivalis-infected mice.

Amyloid-ß (Aß) accumulation is one of the main pathological hallmarks of Alzheimer's disease (AD). Porphyromonas gingivalis (P. gingivalis), the pathogen of chronic periodontitis, could cause Aß accumulation and was identified in the brain of AD patients. Salvianolic Acid B (SalB) has been proven to have the neuroprotective effect. Whether SalB could protect against P. gingivalis-induced cognitive impairment is still unknown. In this study, a P. gingivalis-infected mouse model was employed to study the neuroprotective role of SalB. The results showed that SalB (20 and 40 mg/kg) treatment for 4 weeks could shorten the escape latency and improve the percentage of spontaneous alternation in the P. gingivalis-infected mice. SalB inhibited the levels of reactive oxygen species and malondialdehyde, while increased the levels of antioxidative enzymes (superoxide dismutase and glutathione peroxidase). SalB decreased the levels of IL-1ß and IL-6, increased the mRNA levels of bdnf and ngf in the brain of P. gingivalis-infected mice. In addition, SalB obviously decreased the level of Aß. SalB elevated the protein expression of ADAM10, while downregulated BACE1 and PS1. SalB increased the protein expression of LRP1, while decreased RAGE. In conclusion, SalB could improve cognitive impairment by inhibiting neuroinflammation and decreasing Aß level in P. gingivalis-infected mice.

Ellagic acid protects mice against sleep deprivation-induced memory impairment and anxiety by inhibiting TLR4 and activating Nrf2.

Sleep disorder has become a prevalent issue in current society and is connected with the deterioration of neurobehaviors such as mood, cognition and memory. Ellagic acid (EA) is a phenolic phytoconstituent extracted from grains and fruits that has potent neuroprotective properties. This research aimed to study the alleviative effect and mechanism of EA on memory impairment and anxiety caused by sleep deprivation (SD). EA ameliorated behavioral abnormalities in SD mice, associated with increased dendritic spine density, and reduced shrinkage and loss of hippocampal neurons. EA reduced the inflammatory response and oxidative stress injury caused by SD, which may be related to activation of the Nrf2/HO-1 pathway and mitigation of the TLR4-induced inflammatory response. In addition, EA significantly reduced the mortality and ROS levels in glutamate (Glu)-induced hippocampal neuron injury, and these effects of EA were enhanced in TLR4 siRNA-transfected neurons. However, knockdown of Nrf2 dramatically restrained the protective impact of EA on Glu-induced toxicity. Taken together, EA alleviated memory impairment and anxiety in sleep-deprived mice potentially by inhibiting TLR4 and activating Nrf2. Our findings suggested that EA may be a promising nutraceutical ingredient to prevent cognitive impairment and anxiety caused by sleep loss.

Notopterygium incisum extract (NRE) rescues cognitive deficits in APP/PS1 Alzhneimer's disease mice by attenuating amyloid-beta, tau, and neuroinflammation pathology.

ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD) is a frequently occurring disease of the elderly, and "deficiency" is the root of AD. Most famous experts of traditional Chinese medicine believe that the disease is based on deficiency, and the deficiency of kidney essence is the basis. Notopterygium incisum (Qiang huo) is beneficial to bladder, liver, and kidneys. It is used to treat liver and kidney deficiency, language difficulties, and mental coma. Qiang huo yu feng tang has been used to treat liver and kidney deficiency, unclear language and mental paralysis in many traditional Chinese medicine books and records. In modern times, it has been used to treat AD and exhibited favourable efficacy. AIM OF THE STUDY: This study attempts to investigate the effects of furocoumarins from Notopterygium incisum (NRE) on the Aß cascade, tau pathology and inflammatory pathology of AD. MATERIALS AND METHODS: In this study, we reported a detailed protocol for stabilizing HEK APPswe293T cells with lentivirus for the first time. This cell line can secrete high concentration of Aß. In addition, we treated N2a cells with AKT/PKC specific inhibitors (wortmannin/GF-109203X) and established a tau pathological cell model (AKT/PKC N2a) by activating GSK3ß and triggering hyperphosphorylation of tau. The Aß levels and the expression of phosphorylated tau were detected by ELISA and Western blot. The cognitive ability of NRE on APP/PS1 mice was detected using a Morris water maze (MWM) assay and Aß contents were also evaluated. RESULTS: In HEK APPswe293T cells, NRE (10, 20, 40 µg/mL) significantly inhibited the secretion and production of Aß in dose dependent manner. In addition, NRE also suppressed the expression of phosphorylated tau in wortmannin/GF-109203X treated N2a cells. Furthermore, NRE ameliorated the cognitive impairment of APP/PS1 mice, and the contents of Aß, IL-1ß and TNF-α were significantly depressed in hippocampus and cortex. CONCLUSION: In conclusion, our results demonstrated that NRE has a potential anti-AD effect via the inhibition of the Aß cascade, tau pathology and neuroinflammation in vitro and in vivo.

Gestational B-vitamin supplementation alleviates PM2.5-induced autism-like behavior and hippocampal neurodevelopmental impairment in mice offspring.

Gestational exposure to PM2.5 is a worldwide environmental issue associated with long-lasting behavior abnormalities and neurodevelopmental impairments in the hippocampus of offspring. PM2.5 may induce hippocampus injury and lead to autism-like behavior such as social communication deficits and stereotyped repetitive behavior in children through neuroinflammation and neurodegeneration. Here, we investigated the preventive effect of B-vitamin on PM2.5-induced deleterious effects by focusing on anti-inflammation, antioxidant, synaptic remodeling and neurodevelopment. Pregnant mice were randomly divided into three groups including control group (mice subject to PBS only), model group (mice subject to both 30 µL PM2.5 of 3.456 µg/µL and 10 mL/(kg·d) PBS), and intervention group (mice subject to both 30 µL PM2.5 of 3.456 µg/µL and 10 mL/(kg·d) B-vitamin supplementation (folic acid, vitamin B6 and vitamin B12 with concentrations at 0.06, 1.14 and 0.02 mg/mL, respectively)). In the current study B-vitamin significantly alleviated neurobehavioral impairment reflected in reduced social communication disorders, stereotyped repetitive behavior, along with learning and spatial memory impairment in PM2.5-stimulated mice offspring. Next, B-vitamin corrected synaptic loss and reduced mitochondrial damage in hippocampus of mice offspring, demonstrated by normalized synapse quantity, synaptic cleft, postsynaptic density (PSD) thickness and length of synaptic active area. Furthermore, significantly down-regulated expression of pro-inflammatory cytokines including NF-κB, TNF-α and IL-1ß, and lipid peroxidation were found. We observed elevated levels of oxidant-related genes (SOD, GSH and GSH-Px). Moreover, decreased cleaved caspase-3 and TUNEL-positive cells suggested inhibited PM2.5-induced apoptosis by B-vitamin. Furthermore, B-vitamin increased neurogenesis by increasing EdU-positive cells in the subgranular zone (SGZ) of offspring. Collectively, our results suggest that B-vitamin supplementation exerts preventive effect on autism-like behavior and neurodevelopmental impairment in hippocampus of mice offspring gestationally exposed to PM2.5, to which alleviated mitochondrial damage, increased anti-inflammatory and antioxidant capacity and synaptic efficiency, reduced neuronal apoptosis and improved hippocampal neurogenesis may contribute.

Sex differences in the effects of early life stress exposure on mast cells in the developing rat brain.

Early life stress leads to long lasting effects on behavior. Neuroimmune cells have been implicated as key mediators of experience-induced changes in brain and behavioral development, in that they are highly responsive to stress. Mast cells are one such type of neuroimmune cell, but little is known about their role in brain development or following early life stress. Here, we assessed the impact of three different early life stress exposure paradigms on mast cell dynamics in the developing brain of male and female rats, focusing on the hippocampus and hypothalamus, where most mast cells reside. We found that exposure to two weeks of chronic variable stress during gestation led to increased mast cell number and activation in the female offspring hypothalamus on the day of birth. Acute exposure to maternal separation stress on postnatal day (PN) 2 led to significant decreases in mast cells within the hypothalamus and hippocampus of females, but not males. In contrast, one week of exposure to brief daily maternal separation stress (e.g., handling), increased mast cell numbers in the female, but not male, hippocampus. We found significant sex differences in mast cell number and activation, including males having more mast cells than females in the hippocampus on the day of birth and males having significantly more degranulated mast cells on PN11. Thus, mast cells may be an unappreciated mediator of sex-specific brain development in response to early life perturbations.

Inhibition of LPS-induced brain injury by NR2B antagonists through reducing assembly of NR2B-CaMKII-PSD95 signal module.

Background: Accumulating evidence suggests that inflammation is a contributor to the cause and progression of neurodegenerative disease, such as Alzheimer's disease (AD) and Parkinson disease (PD). However, the exact mechanisms of neuroinflammation are still unclear. Here, we discussed the potential mechanisms of lipopolysaccharide (LPS)-induced brain injury via NR2B antagonists (Ro25-6981) treatment in mice. Methods: Neuroinflammation was induced in mice by virtue of LPS (1 mg/kg) by intraperitoneal injection. Immunoprecipitation was performed to measure the assembly of NR2B-calmodulin dependent protein kinase II (CaMKII)-Postsynaptic density protein 95 (PSD95) signal module in the hippocampus and frontal cortex. Nissl's staining was employed to access neuron injury in the brain. Results: Data demonstrated that LPS could induce neuron damage, and promote the assembly of NR2B-CaMKII-PSD95 signal module and increase the expression of phosphorylated CaMKII and c-Jun N-terminal kinase (JNK) in the frontal cortex and hippocampus. However, NR2B antagonists could protect neuron injury against LPS-induced inflammation, inhibit the assembly of NR2B-CaMKII-PSD95 signal module and decrease the level of phosphorylated CaMKII and JNKs in mice. Conclusions: These findings indicated that the assembly of NR2B-CaMKII-PSD95 signal module is related to LPS-induced neuroinflammation, NR2B plays a key role in the assembly of NR2B-CaMKII-PSD95 signal module and NR2B antagonists could alleviate LPS-related inflammation through the reduced assembly of NR2B-CaMKII-PSD95 signal module in frontal cortex and hippocampus.

Neuro-inflammatory effects of photodegradative products of bilirubin.

Phototherapy was introduced in the early 1950's, and is the primary treatment of severe neonatal jaundice or Crigler-Najjar syndrome. Nevertheless, the potential biological effects of the products generated from the photodegradation of bilirubin during phototherapy remain unknown. This is very relevant in light of recent clinical observations demonstrating that the use of aggressive phototherapy can increase morbidity or even mortality, in extremely low birthweight (ELBW) infants. The aim of our study was to investigate the effects of bilirubin, lumirubin (LR, its major photo-oxidative product), and BOX A and B (its monopyrrolic oxidative products) on the central nervous system (CNS) using in vitro and ex vivo experimental models. The effects of bilirubin photoproducts on cell viability and expression of selected genes were tested in human fibroblasts, three human CNS cell lines (neuroblastoma SH-SY5Y, microglial HMC3, and glioblastoma U-87 cell lines), and organotypic rat hippocampal slices. Neither bilirubin nor its photo-oxidative products affected cell viability in any of our models. In contrast, LR in biologically-relevant concentrations (25 µM) significantly increased gene expression of several pro-inflammatory genes as well as production of TNF-α in organotypic rat hippocampal slices. These findings might underlie the adverse outcomes observed in ELBW infants undergoing aggressive phototherapy.

Changes in Activity of Cysteine Cathepsins B and L in Brain Structures of Mice with Aggressive and Depressive-Like Behavior Formed under Conditions of Social Stress.

We studied activity of lysosomal cysteine proteases, cathepsins B and L, in brain structures (frontal cortex, caudate nucleus, hippocampus, and hypothalamus) of C57Bl/6J mice with aggressive and depressive-like behavior formed under conditions of chronic social stress (repeated experience of victories and defeats within 20 days). Mice with depressive-like behavior showed increased activity of cathepsin В in the hypothalamus and nucleus caudatus and increased activity of cathepsin L in the hippocampus compared to control animals not subjected to agonistic confrontations. In mice with aggressive behavior, protease activity in the studied brain structures was not changed. In 4 h after immune system activation with LPS (250 µg/kg), cathepsin L activity in the hippocampus of control mice increased in comparison with mice receiving saline. In contrast to control animals, LPS caused a decrease in activity of the enzyme in the caudate nucleus and frontal cortex of aggressive mice and in the hippocampus of mice with depressive-like behavior.

Electroacupuncture at Guanyuan (CV 4), Zusanli (ST 36) and Baihui (DU 20) regulate the aging-related changes in gene expression profile of the hippocampus in sub-acutely aging rats.

To investigate the molecular mechanisms of sub-acutely aging and demonstrate the effect of electroacupuncture (EA) at the Guanyuan (CV 4), Zusanli (ST 36) and Baihui (DU 20) acupoint on the sub-acutely aging brain, cDNA microarrays and bioinformatics analyses were carried out. Thirty Sprague-Dawley (SD) male rats were selected and randomly divided into three groups: the control group (C), the sub-acutely aging model group (M) and the electroacupuncture group (M+EA). Sub-acutely aging model rats were obtained by D-galactose s.c. injection continuously for 40 days. Total RNA was extracted from the hippocampus area of brains in three groups for cDNA microarrays. The data of different groups were compared and analyzed by differential expression analysis, Gene ontology (GO) term enrichment, Kyoto Encyclopedia of Genes Genomes (KEGG) pathway enrichment and quantitative real-time PCR. According to the results, 4052 DE genes were identified in our study. Among them, there were 3079 differentially expressed (DE) genes between group M and group C, and these genes are associated with the aging of rats. Moreover, 983 genes were expressed differently in group M+EA compared with group M, revealing that points stimuli could regulate gene expression in brain with aging. Gene ontology (GO) term enrichment and KEGG enrichment were performed to further classify the differential expression genes. Important GO terms and KEGG pathways connected with sub-acutely aging EA effects were identified. At last, 3 significant differentially expressed genes were selected for real-time quantitative PCR to clarify the cDNA microarray results. In conclusion, the cDNA microarray data first compared and analyzed the differences of gene expression profile in the hippocampus of rats in different groups, which contribute to our knowledge on the molecular mechanisms of EA towards sub-acutely aging.

Fish oil supplementation attenuates neuroinflammation and alleviates depressive-like behavior in rats submitted to repeated lipopolysaccharide.

PURPOSE: Depression is frequently associated with inflammation, whereas omega-3 polyunsaturated fatty acids (PUFAs) primarily found in fish oil possess anti-inflammatory properties. Although converging studies suggest an antidepressant effect of PUFAs, there is limited evidence directly linking the neuro-immune modulating features of PUFAs to the antidepressant actions. METHODS: Therefore, we assessed the effects of fish oil (FO) supplementation on behavioral changes, inflammatory cytokine expression and oxidative reactions in frontal cortex and hippocampus of rats following repeated peripheral immune challenge by lipopolysaccharide (LPS) for 2 weeks (500 µg/kg every other day). RESULTS: Repeated LPS administration induced the rats to a depressive-like state and increased mRNA expression of pro-inflammatory cytokines, including 1L-1ß, 1L-6 and TNF-α, in frontal cortex and hippocampus. FO supplementation attenuated the LPS-induced abnormal behavior and brain inflammatory response. Concurrent with the antidepressant action, FO also reduced LPS-induced oxidative reactions and neural apoptosis in the rat brain, as evidenced by decreased malondialdehyde (MDA) production, increased catalase activities and inhibited pro-apoptotic protein Bax mRNA expression. In addition, FO inhibited activation of NF-κB and iNOS induced by LPS. Interestingly, we found FO suppressed the activation of the inflammasome NLRP3 and ionotropic purinergic receptor P2X7R evoked by LPS, suggesting a potential anti-inflammatory mechanism for PUFAs. Besides, FO also restored the LPS-induced neurochemical disturbance, especially the balance between serotonin and kynurenine branches of tryptophan metabolism, which is tightly associated with depression. CONCLUSIONS: These findings provide novel insights into the antidepressant action of PUFAs and further strengthen the link between inflammation and depression.

The effects of vitamin D administration on brain inflammatory markers in high fat diet induced obese rats.

BACKGROUND: Obesity induced brain inflammation is associated with cognitive disorders. We aimed to investigate the influence of vitamin D on hypothalamus and hippocampus inflammatory response in high-fat diet induced obese rats. METHODS: In the beginning of the study, 40 rats were divided into two groups: control diet and high fat diet (HFD) for 16 weeks; then each group subdivided into two groups including: N, ND + vitamin D, HFD and HFD + vitamin D. Vitamin D supplementation was done for 5 weeks at 500 IU/kg dosage. IL-6, IL-1ß, NF-Kß and acetylcholine (ACH) and brain derived neurotropic factor (BDNF) concentrations in hippocampus and hypothalamus homogenate samples were measured by commercial ELISA kits. RESULTS: Vitamin D administration, reduced food intake and weight gain in studied groups (P < 0.001). Vitamin D reduced hippocampus acetylcholine concentrations in ND + vitamin D group (P < 0.001). High fat diet increased hippocampus IL-6 concentrations significantly (P < 0.05) compared with normal diet receiving groups. Vitamin D could not have significant effects on IL-6 concentrations. Vitamin D administrations reduced IL-1ß, NF-Kß and acetylcholine concentration and BDNF concentrations in ND + vitamin D compared with ND group. These reductions were not significant in HFD + vitamin D versus HFD group. CONCLUSION: According to our results, vitamin D reduced food intake and weight gain and modulated the HFD induced inflammatory response in hippocampus and hypothalamus of high fat diet induced obesity. Therefore, this neurosteroid, can be suggested as a supplemental therapeutic tool in prevention of obesity related cognitive and neurodegenerative problems.

Choline and Choline alphoscerate Do Not Modulate Inflammatory Processes in the Rat Brain.

Choline is involved in relevant neurochemical processes. In particular, it is the precursor and metabolite of acetylcholine (ACh). Choline is an essential component of different membrane phospholipids that are involved in intraneuronal signal transduction. On the other hand, cholinergic precursors are involved in ACh release and carry out a neuroprotective effect based on an anti-inflammatory action. Based on these findings, the present study was designed to evaluate the effects of choline and choline precursor (Choline alphoscerate, GPC) in the modulation of inflammatory processes in the rat brain. Male Wistar rats were intraperitoneally treated with 87 mg of choline chloride/kg/day (65 mg/kg/day of choline), and at choline-equivalent doses of GPC (150 mg/kg/day) and vehicle for two weeks. The brains were dissected and used for immunochemical and immunohistochemical analysis. Inflammatory cytokines (Interleukin-1ß, IL-1ß; Interleukin-6 , IL-6 and Tumor Necrosis Factor-α, TNF-α) and endothelial adhesion molecules (Intercellular Adhesion Molecule, ICAM-1 and Vascular cell Adhesion Molecule, VCAM-1) were studied in the frontal cortex, hippocampus, and cerebellum. The results clearly demonstrated that treatment with choline or GPC did not affect the expression of the inflammatory markers in the different cerebral areas evaluated. Therefore, choline and GPC did not stimulate the inflammatory processes that we assessed in this study.

EPA and DHA, but not ALA, have antidepressant effects with 17ß-estradiol injection via regulation of a neurobiological system in ovariectomized rats.

Our previous studies found that n-3 polyunsaturated fatty acids (PUFAs) and estrogen had synergistic antidepressant-like effects. The purpose of the present study was to investigate the hypothesis that three major n-3 PUFAs, α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), individually had antidepressant effects combined with 17ß-estradiol-3-benzoate (E) through a neurobiological pathway in ovariectomized rats. Rats were fed a modified American Institute of Nutrition-93G diet with 0% n-3 PUFAs and 1% ALA, EPA and DHA relative to total energy intake for 12 weeks and were injected with corn oil or E every 4 days during the last 3 weeks. Supplementation of EPA, DHA and E increased serum concentrations of serotonin and climbing behavior, and decreased immobility during a forced swimming test. Supplementation with EPA, DHA and E also decreased hippocampal expressions of interleukin-6 and tumor necrosis factor-α, and increased cAMP response element binding protein, brain-derived neurotrophic factor (BDNF) and estrogen receptor-α. Immunofluorescence staining consistently showed elevated expressions of BDNF. Magnetic resonance spectroscopy showed that E increased glucose and decreased glutamate, glutamine and myo-inositol concentrations regardless of n-3 PUFA supplementation. In addition, supplementation with EPA, DHA and E decreased levels of nitrite and nitrate. However, ALA had no antidepressant effect. The present study suggested that the antidepressant-like effects of EPA and DHA supplementation and E injection could be due to the regulation of serotonergic neurotransmission and inflammatory cytokines rather than due to the antioxidative system. Supplementation with n-3 PUFA and E had the additional function of modulating neurometabolites in the hippocampus.