Monoamine Levels Research Articles

Homocysteine can aggravate depressive like behaviors in a middle cerebral artery occlusion/reperfusion rat model: a possible role for NMDARs-mediated synaptic alterations

ABSTRACT Background Post-stroke depression (PSD), the most frequent psychiatric complication following stroke, could have a negative impact on the recuperation of stroke patients. Hyperhomocysteinemia (HHCY) has been reported to be a modifiable risk factor of stroke. Objective The study tries to explore the effect of HHCY on PSD and the role of N-methyl-d-aspartate receptors (NMDARs)-mediated synaptic alterations. Methods Forty-five adult male Sprague–Dawley rats were randomly allocated into five groups: sham operation group, middle cerebral artery occlusion group (MCAO), HCY-treated MCAO group HCY and MK-801 co-treated MCAO group and MK-801-treated MCAO group. 1.6 mg/kg/d D, L-HCY was administered by tail vein injection for 28 d prior to SHAM or MCAO operationand up to 14 d after surgery. The MK-801 (3 mg/kg) was administered by intraperitoneal injection 15 min prior to MCAO operation. Results HCY treatment aggravated depressive-like disorders of post-stroke rats by the open field test and sucrose preference test. Further, HCY significantly decreased central monoamines levels in the MCAO rats by HPLC. The transmission electron microscopy results showed that the number of synapses and the area of postsynaptic density decreased in the hippocampus of the HCY-treated MCAO rats. Additionally, HCY augmented ischemia-induced up-regulation of NMDARs, decreased the levels of synaptic structure-related marker PSD-95and the synaptic transmission-associated synaptic proteins (VGLUT1, SNAP-25 and Complexin Ι/ΙΙ). These effects of HCY were partly reversed by the NMDA antagonist MK-801. Conclusions The current study suggested that NMDARs-mediated synaptic plasticity may be involved in the adverse effect of HCY on PSD.

The Effect of Glutathione Deficit During Early Postnatal Brain Development on the Prepulse Inhibition and Monoamine Levels in Brain Structures of Adult Sprague-Dawley Rats.

Recent studies suggest that impaired glutathione synthesis and distorted dopaminergic transmission are important factors in the pathophysiology of schizophrenia. In the present study, on the postnatal days p5-p16, male pups were treated with the inhibitor of glutathione synthesis, L-buthionine-(S,R)- sulfoximine (BSO, 3.8 or 7.6mmol/kg), and the dopamine uptake inhibitor, GBR 12,909 (5mg/kg) alone or in combination, and prepulse inhibition of the acoustic startle response (PPI) was evaluated in adult 90-day-old rats. Moreover, the monoamine levels in the cortex and hippocampus of 16-day-old rats or 91-day-old rats were measured. The present results showed that administration of BSO at 3.8mmol/kg led to a decreasing tendency in PPI for all tested prepulse intensities. In contrast, a combined treatment with BSO in both studied doses and GBR 12,909 did not induce significant deficits in PPI. Moreover, the results of biochemical studies indicated that treatment with BSO or GBR 12,909 alone induced a weak increase in the activity of dopaminergic, serotonergic, and noradrenergic systems in the frontal cortex and hippocampus of 16-day-old rats and 91-day-old rats. However, the combined administration of both substances allowed for maintaining the normal activity of monoaminergic systems in the rat brain. The most significant changes in the functioning of monoaminergic systems were observed in the frontal cortex of 16-day-old rats. Therefore, it seems that the frontal cortex of rat puppies is most sensitive to glutathione deficiencies resulting in increased oxidative stress in neurons. As a result, it can lead to cognitive and memory impairment.

Trace Amine-Associated Receptor 2 Is Expressed in the Limbic Brain Areas and Is Involved in Dopamine Regulation and Adult Neurogenesis.

Trace amines are a group of biogenic amines that are structurally and functionally close to classical monoamine neurotransmitters. Trace amine-associated receptors (TAARs) are emerging as promising targets for treating neuropsychiatric disorders. It has been documented that all TAARs, apart from TAAR1, function as olfactory receptors involved in sensing innate odors encoded by volatile amines. However, recently, brain expression and function of TAAR5 were also demonstrated. In this study, we assessed the behavior, brain neurochemistry, and electrophysiology changes in knock-out mice lacking Trace amine-associated receptor 2 (TAAR2) but expressing beta-Galactosidase mapping expression of TAAR2 receptors. As expected, we detected beta-Galactosidase staining in the glomerular layer of the olfactory bulb. However, we also found staining in the deeper layers of the olfactory bulb and several brain regions, including the hippocampus, cerebellum, cortex, raphe nuclei, hypothalamus, and habenula, indicating that TAAR2 receptors are not only expressed in the olfactory system but are also present in the limbic brain areas that receive olfactory input. In behavioral experiments, TAAR2 knock-out (TAAR2-KO) mice showed increased locomotor activity and less immobility in the forced swim test, with no changes in anxiety level. Furthermore, TAAR2-KO mice showed alterations in brain electrophysiological activity—particularly, decreased spectral power of the cortex and striatum in the 0, 9–20 Hz range. TAAR2-KO mice also had elevated tissue dopamine levels in the striatum and an increased dopaminergic neuron number in the Substantia Nigra. In addition, an increased brain-derived neurotrophic factor (BDNF) mRNA level in the striatum and Monoamine Oxidase B (MAO-B) mRNA level in the striatum and midbrain was found in TAAR2-KO mice. Importantly, TAAR2-KO mice demonstrated an increased neuroblast-like and proliferating cell number in the subventricular and subgranular zone, indicating increased adult neurogenesis. These data indicate that in addition to its role in the innate olfaction of volatile amines, TAAR2 is expressed in limbic brain areas and regulates the brain dopamine system, neuronal electrophysiological activity, and adult neurogenesis. These findings further corroborated observations in TAAR1-KO and TAAR5-KO mice, indicating common for TAAR family pattern of expression in limbic brain areas and role in regulating monoamine levels and adult neurogenesis, but with variable involvement of each subtype of TAAR receptors in these functions.

Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications.

Major depressive disorder (MDD) was previously hypothesized to be a disease of monoamine deficiency in which low levels of monoamines in the synaptic cleft were believed to underlie depressive symptoms. More recently, however, there has been a paradigm shift towards a neuroplasticity hypothesis of depression in which downstream effects of antidepressants, such as increased neurogenesis, contribute to improvements in cognition and mood. This review takes a top-down approach to assess how changes in behavior and hippocampal-dependent circuits may be attributed to abnormalities at the molecular, structural and synaptic level. We conclude with a discussion of how antidepressant treatments share a common effect in modulating neuroplasticity and consider outstanding questions and future perspectives.

Mirtazapine treatment in a young female mouse model of Rett syndrome identifies time windows for the rescue of early phenotypes

Rett Syndrome (RTT) is a rare X-linked neurodevelopmental disorder, mainly caused by mutations in the MECP2 gene. Reduction in monoamine levels in RTT patients and mouse models suggested the possibility to rescue clinical phenotypes through antidepressants. Accordingly, we tested mirtazapine (MTZ), a noradrenergic and specific-serotonergic tetracyclic antidepressant (NaSSA). In previous studies, we showed high tolerability and significant positive effects of MTZ in male Mecp21m1.1Bird-knock-out mice, adult female Mecp2tm1.1Bird-heterozygous (Mecp2+/−) mice, and adult female RTT patients. However, it remained to explore MTZ efficacy in female Mecp2+/− mice at young ages. As RTT-like phenotypes in young Mecp2+/− mice have been less investigated, we carried out a behavioural characterization to analyze Mecp2+/− mice in “early adolescence” (6 weeks) and “young adulthood” (11 weeks) and identified several progressive phenotypes. Then, we evaluated the effects of either a 15- or a 30-day MTZ treatment on body weight and impaired motor behaviours in 11-week-old Mecp2+/− mice. Finally, since defective cortical development is a hallmark of RTT, we performed a histological study on the maturation of perineuronal nets (PNNs) and parvalbuminergic (PV) neurons in the primary motor cortex. The 30-day MTZ treatment was more effective than the shorter 15-day treatment, leading to the significant rescue of body weight, hindlimb clasping and motor learning in the accelerating rotarod test. Behavioural improvement was associated with normalized PV immunoreactivity levels and PNN thickness. These results support the use of MTZ as a new potential treatment for adolescent girls affected by RTT and suggest a possible mechanism of action.

Comprehensive Preclinical Assessment of Sensory, Functional, Motivational-Affective, and Neurochemical Outcomes in Neuropathic Pain: The Case of the Sigma-1 Receptor.

Chronic pain remains a major health problem and is currently facing slow drug innovation. New drug treatments should address not only the sensory-discriminative but also functional and motivational-affective components of chronic pain. In a mouse model of neuropathic pain induced by partial sciatic nerve ligation (PSNL), we analyzed sensory and functional-like outcomes by hindpaw mechanical stimulation and automated gait analysis (CatWalk). We characterized over time a reward-seeking task based on diminished motivation for natural reinforcers (anhedonic-like behavior). To differentiate the appetitive ("wanting") and consummatory ("liking") aspects of motivational behavior, we quantified the latency and number of approaches to eat white chocolate, as well as the eating duration and amount consumed. We explored a putative chronic pain-induced dysregulation of monoamine function by measuring monoamine levels in the nucleus accumbens (NAc), a well-known brain reward area. Finally, we investigated the role of sigma-1 receptor (σ1R) modulation, a nonopioid target, in these multiple dimensions by genetic deletion and pharmacological dose-response studies. After 6 weeks, PSNL increased the approach latency and reduced the consumption of white chocolate in 20-25% of the mice, while around 50-60% had one or the other parameter affected independently. After 10 weeks, sham-operated mice also displayed anhedonic-like behavior. PSNL was associated with reduced extracellular baseline dopamine and increased norepinephrine in the NAc and with a suppression of increased dopamine and serotonin efflux in response to the rewarding stimulus. Genetic and pharmacological blockade of σ1R relieved these multiple alterations in nerve-injured mice. We comprehensively describe sensory, functional, and depression-like impairment of key components of motivated behavior associated with nerve injury. We provide a neurochemical substrate for the depressed mesocorticolimbic reward processing in chronic pain, with a potentially increased translational value. Our results also highlight σ1R for the therapeutic intervention of neuropathic pain.

Perturbation of monoamine metabolism and enhanced fear responses in mice defective in the regeneration of tetrahydrobiopterin.

Increasing evidence suggests the involvement of peripheral amino acid metabolism in the pathophysiology of neuropsychiatric disorders, whereas the molecular mechanisms are largely unknown. Tetrahydrobiopterin (BH4) is a cofactor for enzymes that catalyze phenylalanine metabolism, monoamine synthesis, nitric oxide production, and lipid metabolism. BH4 is synthesized from guanosine triphosphate and regenerated by quinonoid dihydropteridine reductase (QDPR), which catalyzes the reduction of quinonoid dihydrobiopterin. We analyzed Qdpr-/- mice to elucidate the physiological significance of the regeneration of BH4. We found that the Qdpr-/- mice exhibited mild hyperphenylalaninemia and monoamine deficiency in the brain, despite the presence of substantial amounts of BH4 in the liver and brain. Hyperphenylalaninemia was ameliorated by exogenously administered BH4, and dietary phenylalanine restriction was effective for restoring the decreased monoamine contents in the brain of the Qdpr-/- mice, suggesting that monoamine deficiency was caused by the secondary effect of hyperphenylalaninemia. Immunohistochemical analysis showed that QDPR was primarily distributed in oligodendrocytes but hardly detectable in monoaminergic neurons in the brain. Finally, we performed a behavioral assessment using a test battery. The Qdpr-/- mice exhibited enhanced fear responses after electrical foot shock. Taken together, our data suggest that the perturbation of BH4 metabolism should affect brain monoamine levels through alterations in peripheral amino acid metabolism, and might contribute to the development of anxiety-related psychiatric disorders. Cover Image for this issue:https://doi.org/10.1111/jnc.15398.

Low concentrations of the antidepressant venlafaxine affect courtship behaviour and alter serotonin and dopamine systems in zebrafish (Danio rerio).

Venlafaxine, a serotonin-noradrenaline reuptake inhibitor, is a widely used antidepressant drug routinely detected in aquatic environments. However, its potential impact on courtship behaviour in zebrafish is unknown. We tested the hypothesis that venlafaxine disrupts brain monoamine levels and molecular responses essential for courtship behaviour in zebrafish. Zebrafish (Danio rerio) were exposed to venlafaxine (1, 10, and 100μg/L) for 20 days. We evaluated the molecular levels and neuronal basis of the effect of venlafaxine on courtship behaviour. Here, we show that venlafaxine inhibited courtship behaviour in zebrafish and increased the transcript levels of 5-ht1a and 5-ht2c while decreasing the transcript levels of genes involved in the dopaminergic system, including th1, th2, drd1b, and drd2b. Venlafaxine upregulated 5-HT levels and downregulated dopamine levels. Moreover, the subordinate fish from the venlafaxine-exposed group had significantly lower motor activity than the subordinate fish of the control group. Collectively, our results reveal that venlafaxine can disturb brain monoamine levels, affecting courtship behaviour in adult zebrafish.

Abnormal brain development of monoamine oxidase mutant zebrafish and impaired social interaction of heterozygous fish

ABSTRACTMonoamine oxidase (MAO) deficiency and imbalanced levels of brain monoamines have been associated with developmental delay, neuropsychiatric disorders and aggressive behavior. Animal models are valuable tools to gain mechanistic insight into outcomes associated with MAO deficiency. Here, we report a novel genetic model to study the effects of mao loss of function in zebrafish. Quantitative PCR, in situ hybridization and immunocytochemistry were used to study neurotransmitter systems and expression of relevant genes for brain development in zebrafish mao mutants. Larval and adult fish behavior was evaluated through different tests. Stronger serotonin immunoreactivity was detected in mao+/− and mao−/− larvae compared with their mao+/+ siblings. mao−/− larvae were hypoactive, and presented decreased reactions to visual and acoustic stimuli. They also had impaired histaminergic and dopaminergic systems, abnormal expression of developmental markers and died within 20 days post-fertilization. mao+/− fish were viable, grew until adulthood, and demonstrated anxiety-like behavior and impaired social interactions compared with adult mao+/+ siblings. Our results indicate that mao−/− and mao+/− mutants could be promising tools to study the roles of MAO in brain development and behavior. This article has an associated First Person interview with the first author of the paper.

Insulin normalized brain metabolic status on a Model of Anorexia Nervosa in Mice

Anorexia nervosa is a psycho-socio-biological disease, characterized by self-starvation and distorted perception of body weight. Patients often over-exercise. Insulin is an anabolic hormone that increases food intake and restores body fat and is present in low levels in anorexia nervosa patients: thus may have therapeutic potential in treating anorexia nervosa. to explore whether low levels insulin administration may result in recovery of cerebral function and restoration of metabolic disorder providing a treatment option for anorexia nervosa. Female Sabra mice maintained on DR of 2.0 hours per day for 32 days, in cages with or without wheel attached to an electronic counter (activity wheel). They were then permitted to eat ad libitum for additional 15 days. On the second week, mice were injected ip with 0.5U/kg long acting Insulin(Lantus) or saline and cognitive function was evaluated. Insulin administered three times a week during days 8-32. Mice euthanized on day 48 and cerebral levels of monoamines, 2-AG and expression of genes associated with metabolic status were evaluated. Activity wheel mice decreased body weight, 2-AG, dopamine levels and 5-HT1A and increased Camkk2 and SIRT1 gene expression compared to mice without it. Insulin increased body weight, decreased revolutions, enhanced NPY and normalized Camkk2, SIRT-1, BDNF, elevated 2-AG and improved cognition in the wheel group. low dose insulin administration to animal model of anorexia associated with exercise, led to alterations and normalization in brain metabolic status and improved cognition. Insulin should be further explored as potential novel treatment for anorexia nervosa.

Neuromodulatory Mechanisms of a Memory Loss-Preventive Effect of Alpha-Lipoic Acid in an Experimental Rat Model of Dementia.

This study evaluates some of the neuromodulatory mechanisms of the memory loss preventive effect of alpha-lipoic acid (ALA) in a scopolamine (Sco)-induced rat model of Alzheimer's disease (AD) type dementia. Our results confirmed that Sco administration induces significant memory impairment, worsens exploratory behaviour and habituation, increases acetylcholinesterase (AChE) activity, and induces pathological monoamine content changes in the prefrontal cortex and hippocampus. ALA administration largely prevented Sco-induced memory impairment. It also improved exploratory behaviour and preserved habituation, and it decreased AChE activity, reversing it to control group levels, and corrected aberrant monoamine levels in the prefrontal cortex and hippocampus. According to the data available, this is the first time that ALA-induced changes in AChE and monoamine levels in the prefrontal cortex and hippocampus (brain structures related to learning and memory) have been demonstrated in a Sco-induced rat model of AD type dementia.

A novel preclinical model of environment-like combined benzene, toluene, ethylbenzene, and xylenes (BTEX) exposure: Behavioral and neurochemical findings

Environmental exposure to toxicants is a major health issue and a leading risk factor for premature mortality worldwide, including environmental exposures to volatile organic compounds (VOCs), specifically Benzene, Toluene, Ethylbenzene, and Xylene (BTEX). While exposure to these compounds individually has shown behavioral and neurochemical effects, this investigation examined the impact of exposure to combined BTEX using a preclinical model. Male Swiss Webster mice were exposed to BTEX vapors designed to approximate environmental levels in urban communities. Animals were exposed to one of four treatment conditions: a 0-ppm (air control), two BTEX groups representing levels of environmental-like exposure, and a fourth group modeling occupational-like exposure. These exposures were conducted in 1.5-h sessions, 2 sessions/day, 5 days/week, for 3 weeks. Effects on coordination (i.e., rotarod and inverted screen test), learning and memory (i.e., Y-maze), and locomotor behavior (i.e., movement during exposure) were assessed during and after exposure. Monoamine levels in the medial prefrontal cortex and nucleus accumbens were assessed immediately following exposure. Effects of BTEX exposure were found on the variance of locomotor activity but not in other behavioral or neurochemical assessments. These results indicate that the combination of inhaled BTEX at environmentally representative concentrations has demonstrable, albeit subtle, effects on behavior.

Substrate-triggered occlusion in the human serotonin transporter unveiled a new and fully occluded structure

The serotonin transporter (SERT; SLC6A4) is an important pre-synaptic protein involved in sodium-dependent re-uptake of serotonin (5HT), shaping the concentration of 5HT available for the post-synaptic receptor binding. Inadequate handling of synaptic monoamine levels have been associated with neuropsychiatric diseases like major depression disorder, affecting over 260 million people world-wide. SERT has therefore been implicated as an upmost important pharmacological target. High-resolution structures of SLC6 members including SERT confirmed its conserved 12 transmembrane helical architecture and the presence of the orthosteric binding site (S1) halfway through the membrane.

Ormosanine confers protection on neuronal function via regulation of inflammatory cytokine levels and oxidative stress


 
 
 
 Purpose: To investigate the neuroprotective effect of ormosanine on rat model of Alzheimer’s disease (AD), and the mechanism(s) of action involved.
 Methods: Rats were randomly assigned to 4 groups (10 rats/group): control group, AD group, 25 mg ormosanine/kg group, and 50 mg ormosanine/kg group. Alzheimer’s disease (AD) was induced in the rats via intracerebroventricular (ICV) injection of amyloid-β (Aβ)25-35 at a concentration of 1 mg/mL. Cognitive function was determined by Morris water maze test (MWMT), while lipid profile, oxidative stress parameters and cytokine level were assayed using their respective assay kits. The levels of monoamines were determined in brain tissues using high-performance liquid chromatography (HPLC), while terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was used to determine apoptosis in neuronal cells.
 Results: Cognitive function was significantly improved (p < 0.05) in ormosanine treated group than AD group of rats. Ormosanine significantly and dose-dependently reduced lipid and cytokines levels as well as activities of AST and ALT, but it significantly increased the level of HDL-C in a dose-dependent fashion (p < 0.05). Moreover, ormosanine significantly and dose-dependently increased SOD activity, but reduced MDA level and neuronal cell apoptosis in brain tissues of AD rats (p < 0.05). Treatment of AD rats with ormosanine led to significant and dose-dependent increase in the levels of monoamines and BDNF in rat brain tissues (p < 0.05).
 Conclusion: These results show that ormosanine confers protection on neuronal function via regulation of inflammatory cytokine levels and oxidative stress, and therefore, could potentially be developed for the management of Alzheimer’s disease.
 
 
 

Preventive treatment with fish oil facilitates the antidepressant-like effect of antidepressant drugs in type-1 diabetes mellitus rats: Implication of serotonergic system

Treating depression associated with type-1 diabetesmellitus(T1DM) is a major clinical challenge. Fish oil (FO), composed mostly of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), has been pointed out as quite promising for the treatment of depression given its neuroprotective property. Although DHA and EPA exert several physiological actions, DHA is known to play a critical role in postnatal brain development. This study aimed to investigate the effect of preventive treatment with FO (with more DHA in the composition) alone or associated with antidepressant drugs on depression-like behaviors and brain monoamines levels of juvenile induced-T1DM rats. Thus, prepubescent rats were submitted to a prolonged treatment with vehicle (VEH) or FO (50% of DHA and 20% EPA) starting 4 weeks before the induction of experimental T1DM (on day 28) by streptozotocin. When combined, the treatment with vehicle, fluoxetine (FLX, a selective serotonin reuptake inhibitor) or imipramine (IMI, a tricyclic antidepressant) started at week 6 (day 42) and lasted for 2 weeks (until day 56). The behavioral tests were conducted on days 55 and 56, followed by hippocampal and prefrontal cortex dissection for neurochemical analyses. Our results showed that induced-T1DM rats pretreated with FO showed a significant increase of EPA and DHA in plasma, indicative of an increase in the systemic availability of these acids. As previously observed, induced-T1DM rats presented increased immobility and decreased swimming and climbing frequencies in the modified forced swimming test, indicative of depressive-like behavior. Only the combined treatment – FO plus antidepressants (FLX or IMI – both in the highest dose) - was able to induce a significant improvement of depressive-like behaviors. Here, it is noteworthy that swimming behavior has been associated with an increase in serotonergic neurotransmission. Interestingly, our data showed that the combined treatment (FO + antidepressants - including the ineffective dose of FLX) was able to increase the swimming of animals more significantly compared to animals not pretreated with FO. In addition, confirming these assumptions, the decreased 5-HT levels in the hippocampus from induced-T1DM rats were increased after treatment with FLX (highest dose) or IMI (both doses), being this increase more pronounced in animal pretreated with FO. Intriguingly, in these animals pretreated with FO, the ineffective dose of FLX in association with FO was able to increase the levels of 5-HT. The decreased hippocampal levels of noradrenaline were increased only after IMI treatment, not being influenced by FO pretreatment. In conclusion, ours results pointed out that the choice of the DHA/EPA ratio may be an important factor to be considered for the FO antidepressant-like effectper se,but the FO treatment in this composition associated with the antidepressant drugs - especially that ones that increase preferentially the availability of 5-HT -, may represent a better alternative of treatment to individuals with T1DM-associated depression.

The Neonicotinoid Thiacloprid Interferes with the Development, Brain Antioxidants, and Neurochemistry of Chicken Embryos and Alters the Hatchling Behavior: Modulatory Potential of Phytochemicals.

Simple SummaryThe present experiment was performed to investigate the toxic impact of thiacloprid (TH) on the brain of developing chicken embryos and also to measure its influence on the behavioral responses of hatchlings. The role of chicoric acid (CA) and rosmarinic acid (RA) in modulating the resulted effects was also investigated. TH resulted neurotoxic to chicken embryos and possibly neurotoxic to embryos of other vertebrates. Moreover, CA and RA exerted both an antioxidant and a neuroprotective effect on embryos.The present experiment was performed to investigate the toxic impact of thiacloprid (TH) on the brain of developing chicken embryos and also to measure its influence on the behavioral responses of hatchlings. The role of chicoric acid (CA) and rosmarinic acid (RA) in modulating the resulted effects was also investigated. The chicken eggs were in ovo inoculated with TH at different doses (0.1, 1, 10, and 100 ug/egg). TH increased the mortality and abnormality rates and altered the neurochemical parameters of exposed embryos dose-dependently. TH also decreased the brain level of monoamines and amino acid neurotransmitters and decreased the activities of acetylcholine esterase (AchE) and Na+/K+-ATPase. The brain activity of catalase (CAT) and superoxide dismutase (SOD) was diminished with downregulation of their mRNA expressions in the brain tissue. When TH was co-administered with CA and RA, the toxic impacts of the insecticide were markedly attenuated, and they showed a complementary effect when used in combination. Taken together, these findings suggested that TH is neurotoxic to chicken embryos and is possibly neurotoxic to embryos of other vertebrates. The findings also demonstrated the antioxidant and neuroprotective effects of CA and RA. Based on the present findings, the CA and RA can be used as invaluable ameliorative of TH-induced toxicity.

MED1/BDNF/TrkB pathway is involved in thalamic hemorrhage-induced pain and depression by regulating microglia

Central post-stroke pain (CPSP) and associated depression remain poorly understood and pharmacological treatments are unsatisfactory. Recently, microglia activation was suggested to be involved in CPSP pathophysiology. The goal of this study was to investigate the effectiveness of a co-ultramicronized combination of N-palmitoylethanolamide and luteolin (PEALut) in a mouse model of thalamic hemorrhage (TH)-induced CPSP. TH was established through the collagenase-IV injection in thalamic ventral-posterolateral-nucleus. PEALut effects in CPSP-associated behaviors were evaluated during a 28-days observation period.We found that repeated administrations of co-ultra PEALut significantly reduced mechanical hypersensitivity after TH, as compared to vehicle, by reducing the early microglial activation in the perilesional site. Moreover, PEALut prevented the development of depressive-like behavior (21 days post-TH). These effects were associated with the restoration of synaptic plasticity in LEC-DG pathway and monoamines levels found impaired in TH mice. Hippocampal MED1 and TrkB expressions were significantly increased in TH compared to sham mice 21 days post-TH, whereas BDNF levels were decreased. PEALut restored MED1/TrkB/BDNF expression in mice. Remarkably, we found significant overexpression of MED1 in the human autoptic brain specimens after stroke, indicating a translational potential of our findings.These results pave the way for better-investigating depression in TH- induced CPSP, together with the involvement of MED1/TrkB/BDNF pathway, proposing PEALut as an adjuvant treatment.

Effects of Supplemental Japanese Pepper Seed on Thermoregulation, and Blood Monoamines in Heat Exposed Broiler Chicks

Background: This study was carried out to assess the effects of enriched feed with Japanese Pepper Seeds (1 and 2%) on plasma monoamine and thermoregulation in broilers. Materials and Methods: A day old male broiler chicks were obtained from hatchery (Fukuda, Japan), and were kept in cages with floor of wire-mesh; 3 broilers in each cage. The surrounding heat was controlled at 30 ± 1 0C for three days in the beginning of experiment, and gently lowered to 26 ± 1 0C until broilers reached 11 days of age. Findings: The study result indicated that after 6 days of feeding, their feed intake and body weight gain were not significantly different among groups of control and supplemented with Japanese pepper seeds. However, feed conversion ratio decreased significantly with feed of 1% Japanese pepper seeds against 2% in Japanese pepper seeds broilers (P<0.05). Subsequently, all groups were subjected to high heat at 38o C, for 3 hours with water but not feed. The tendency was in wing drop and panting during temperature exposure groups (P>0.05). With acute heat stress, the temperature of all groups was elevated. The effects of time and Japanese pepper seeds were significant (P<0.05) in temperature exposed broilers. The interaction between time and Japanese pepper seeds were measured to reflect a tendency of significance (P<0.01). The affinities were measured in rectal temperature of control group and 2.0% group of Japanese pepper seeds broilers to reduce after 2h, although they kept advancing in 1% group of Japanese pepper seeds. There were no significant differences in the level of plasma monoamines in 5- HT, Ad and NA among groups (P>0.05), although the level of DA in plasma in 2% Japanese pepper seeds in broilers was lower than control one (P<0.05). Conclusion: Present investigation recommend that Japanese pepper seeds affect thermoregulation through the catecholaminergic system in broilers. Nevertheless, it may have adverse effects under long period high temperature in chicks.

Changes in motivational-emotional behavior and passive avoidance learning in “depressive” rats with high immobility and decreased level of brain monoamines

Changes in motivational-emotional behavior and passive avoidance learning in “depressive” rats with high immobility and decreased level of brain monoamines

Dietary Supplementation throughout Life with Non-Digestible Oligosaccharides and/or n-3 Poly-Unsaturated Fatty Acids in Healthy Mice Modulates the Gut-Immune System-Brain Axis.

The composition and activity of the intestinal microbial community structures can be beneficially modulated by nutritional components such as non-digestible oligosaccharides and omega-3 poly-unsaturated fatty acids (n-3 PUFAs). These components affect immune function, brain development and behaviour. We investigated the additive effect of a dietary combination of scGOS:lcFOS and n-3 PUFAs on caecal content microbial community structures and development of the immune system, brain and behaviour from day of birth to early adulthood in healthy mice. Male BALB/cByJ mice received a control or enriched diet with a combination of scGOS:lcFOS (9:1) and 6% tuna oil (n-3 PUFAs) or individually scGOS:lcFOS (9:1) or 6% tuna oil (n-3 PUFAs). Behaviour, caecal content microbiota composition, short-chain fatty acid levels, brain monoamine levels, enterochromaffin cells and immune parameters in the mesenteric lymph nodes (MLN) and spleen were assessed. Caecal content microbial community structures displayed differences between the control and dietary groups, and between the dietary groups. Compared to control diet, the scGOS:lcFOS and combination diets increased caecal saccharolytic fermentation activity. The diets enhanced the number of enterochromaffin cells. The combination diet had no effects on the immune cells. Although the dietary effect on behaviour was limited, serotonin and serotonin metabolite levels in the amygdala were increased in the combination diet group. The combination and individual interventions affected caecal content microbial profiles, but had limited effects on behaviour and the immune system. No apparent additive effect was observed when scGOS:lcFOS and n-3 PUFAs were combined. The results suggest that scGOS:lcFOS and n-3 PUFAs together create a balance—the best of both in a healthy host.