Subchronic Administration Research Articles

Ameliorative effect of diazepam against ethanol-induced mitochondrial disruption in brains of the mice

Brain oxidative damage and neurodegeneration by ethanol (ETH) are considered as important factors that triggered by oxidative stress. Recently, the abuse of diazepam (DZM) has increased by alcoholism-addicted patients. The present study evaluated the effects of combination treatment of ETH with DZM on oxidative damage induced in brain mitochondria of the mice. Only ETH (0.3, 0.6, and 2.5 g / kg) and ETH+ DZM (2.5 mg / kg) were administered intraperitoneally (ip) to the mice. Pathological changes and oxidative stress biomarkers including ROS, lipid peroxidation, carbonyl protein, mitochondrial function, and glutathione content were evaluated in brain mitochondria after 42 days. Results indicated that co-treatment of DZM and ETH significantly reduced mitochondrial toxicity, oxidative damage, pathological changes and increased level of glutathione. Subchronic ETH administration induced brain oxidative damage, mitochondrial disruption, and serious damage to the brain cells. Whereas, combination treatment improved oxidative damage, mitochondrial function, and pathological changes in brain cells after intoxication by ETH. These findings suggest antioxidant effect of DZM in combination with ETH and can be considered in reducing oxidative stress and mitochondrial damage attenuation in the brain. Combination therapy may be a better therapeutic candidate for prevention of brain oxidative damage induced by ETH.

Sub-Chronic Ketamine Administration Increases Dopamine Synthesis Capacity in the Mouse Midbrain: a Preclinical In Vivo PET Study

PurposeThere is robust evidence that people with schizophrenia show elevated dopamine (DA) synthesis capacity in the striatum. This finding comes from positron emission tomography (PET) studies using radiolabelled l-3,4-dihydroxyphenylalanine (18F-DOPA). DA synthesis capacity also appears to be elevated in the midbrain of people with schizophrenia compared to healthy controls. We therefore aimed to optimise a method to quantify 18F-DOPA uptake in the midbrain of mice, and to utilise this method to quantify DA synthesis capacity in the midbrain of the sub-chronic ketamine model of schizophrenia-relevant hyperdopaminergia.ProceduresAdult male C57Bl6 mice were treated daily with either ketamine (30 mg/kg, i.p.) or vehicle (saline) for 5 days. On day 7, animals were administered 18F-DOPA (i.p.) and scanned in an Inveon PET/CT scanner. Data from the saline-treated group were used to optimise an atlas-based template to position the midbrain region of interest and to determine the analysis parameters which resulted in the greatest intra-group consistency. These parameters were then used to compare midbrain DA synthesis capacity (KiMod) between ketamine- and saline-treated animals.ResultsUsing an atlas-based template to position the 3.7 mm3 midbrain ROI with a T*–Tend window of 15–140 min to estimate KiMod resulted in the lowest intra-group variability and moderate test–retest agreement. Using these parameters, we found that KiMod was elevated in the midbrain of ketamine-treated animals in comparison to saline-treated animals (t(22) = 2.19, p = 0.048). A positive correlation between DA synthesis capacity in the striatum and the midbrain was also evident in the saline-treated animals (r2 = 0.59, p = 0.005) but was absent in ketamine-treated animals (r2 = 0.004, p = 0.83).ConclusionsUsing this optimised method for quantifying 18F-DOPA uptake in the midbrain, we found that elevated striatal DA synthesis capacity in the sub-chronic ketamine model extends to the midbrain. Interestingly, the dysconnectivity between the midbrain and striatum seen in this model is also evident in the clinical population. This model may therefore be ideal for assessing novel compounds which are designed to modulate pre-synaptic DA synthesis capacity.

The Subchronic Effect Of Water Extract Leaves Ofsoursop (Annona Muricata L.) Bax Expression Of Neuron Rat Hippocampus Gyrus Dentatus (Rattus Norvegicus)

Soursop (Annona muricata) is a plant that is rich in benefits and widely used in the community as one of the traditional medicines. Annona muricata itself contains a compound known as acetogenin toxic if consumed continuously, In addition to the benefits so many of Annona muricata can give side effects to the body one of which is the part of the brain is called the gyrus dentatus. Anonaine, compound acetogenin could induce Bax expression in cancer cells resulting in apoptosis. This study wanted to find out if Annona muricata can induce Bax expression of neuron hippocampus gyrus dentatus female rats (rattus nervous). The purpose of this study was to subchronic effect of aqueous extract of soursop leaves (Annona muricata L.) Bax expression of neuron rat hippocampus gyrus dentatus(Rattus norvegicus). This study was a simple experimental study design using a post-test control group design to see Bax expression of neuron rat hippocampus gyrus dentatus (Rattus norvegicus) in subchronic administration of aqueous extract of soursop leaves (Annona muricata L.). The subjects were adult female rats (Rattus norvegicus) that met the inclusion criteria. The samples were 10 rats. Subjects were divided into 2 groups and each group consisted of 5 rats.

Cholinergic deficit induced memory retrieval impairment and hippocampal CaMKII-alpha deregulation is counteracted by sub-chronic agmatine treatment in mice

ABSTRACT Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative disease characterized by brain cholinergic dysfunction. Evidence suggests the impairment of memory retrieval phase in AD. It has been shown that CaMKII-α expressing neurons are selectively reduced in the hippocampus in AD brains. The present study aimed to investigate the effect of scopolamine on the memory retrieval phase and the hippocampal CaMKII-α signaling. In addition, the effect of sub-chronic administration of agmatine against scopolamine induced memory and possible hippocampal CaMKII-α deregulation was investigated in mice. Adult male NMRI mice were administered with agmatine at the doses of 5, 10, 20, 30 and 40 mg/kg/i.p. or saline for 11 days. Acquisition and retrieval tests of passive avoidance task were performed on days 10 and 11, respectively (30 Min following agmatine treatment). Scopolamine (1 mg/kg/i.p.) was administered once, 30 Min before retrieval test. Upon completion of the behavioral tasks, the hippocampi were isolated for western blot analysis to detect the phosphorylated and total levels of CaMKII-α and beta actin proteins. The results showed that scopolamine induced memory retrieval deficit and decreased the phosphorylated level of hippocampal CaMKII-α. Sub-chronic agmatine treatment at the dose of 40 mg/kg prevented scopolamine induced memory retrieval deficit and restored the level of hippocampal phosphorylated CaMKII-α. This study suggests that hippocampal CaMKII-α might play a role in scopolamine induced amnesia and sub-chronic agmatine prevents the impairing effect of scopolamine on the retrieval phase of memory and the phosphorylation of hippocampal CaMKII-α protein.

Evaluation of sub-acute and sub-chronic toxicity of aqueous extract of Coptosapelta flavescens Korth. in a Swiss albino mice model

Coptosapelta flavescens Korth. is one of the medicinal plants used as a traditional medicine in Vietnam for a long time. However, few documents proved its safety for a long time. Therefore, the study aimed to determine the toxicity effects of the aqueous extract of C. flavescens by determining its effects after subchronic oral administration in Swiss albino mice. The toxicity of C. flavescens extract was tested at doses of 400 and 1200 mg/kg, respectively, over 30 and 60 days on an in vivo model. Animal weight, behavior, and condition changes were monitored throughout the process. At the end of the observation periods, hematological indices and histopathological features of the animal specimens were analyzed. The administration of C. flavescens extract at doses of 400 and 1200 mg/kg caused a weight difference in male mice after 30 days and in both sexes after 60 days of administration compared to the control group. There were no significant changes in hematological parameters and biochemical indexes of the liver and kidney compared with the control group. The histological structure of the liver showed changes when treated with C. flavescens at both doses after 60 days, whereas the histological structure of the kidneys exhibited differences only at the dose of 400 mg/kg. Overall, the findings of this study indicate that Coptosapelta flavescens Korth. is unlikely to have subacute and subchronic oral toxicity. However, there are some minor effects on the liver and kidneys.

Effects of sub-chronic exposure to microcystin-LR on the endocrine system of male rats

Microcystins (MCs) can cause reproductive and developmental toxicity and disrupt endocrine homeostasis in mammals. In the present study, male, Sprague-Dawley (SD) rats were administrated 3 or 30 μg MC-LR/kg, body mass (bm) per day via intraperitoneal (i.p.) injections for 6 weeks. Effects of MC-LR on histology, hormone concentrations, gene transcriptional profiles and protein expressions along the hypothalamic-pituitary-adrenal (HPA), ‐gonad (HPG) and -thyroid (HPT) axes were assessed. Sub-chronic administration with MC-LR caused histological damage to hypothalamus, pituitary, adrenal, testes and thyroid and affected relative masses of pituitary, adrenal and testes. The HPA axis was activated and serum concentrations of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were significantly augmented. Along the HPG axis, serum concentrations of gonadotropin-releasing hormone (GnRH) and dihydrotestosterone (DHT) were diminished, while concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T) and estradiol (E2) were augmented. For the HPT axis, only concentrations of free tetra-iodothyronine (fT4) were significantly diminished, while concentrations of thyrotropin-releasing hormone (TRH), thyroid-stimulating hormone (TSH) or free tri-iodothyronine (fT3) were not significantly changed. Also, several genes and proteins related to synthesis of steroid hormones were significantly altered. Findings of the present study illustrate that MC-LR can cause endocrine-disrupting effects through the disruption of synthesis and secretion of hormones along the HPA, HPG and HPT axes and negative feedback regulation. Also, there could be crosstalk among HPA, HPG and HPT axes. These findings elucidate mechanisms of endocrine-disrupting effects of MCs.

Effect of the dipeptide retro-analog of cholecystokinin tetrapeptide (GB-115) on the behavior of rhesus monkeys in isolation

Introduction. The developed domestic dipeptide retro-analog of cholecystokinin (CCK) tetrapeptide (N-(6-phenylhexanoyl)-glycyltryptophan amide, compound GB-115) with antagonistic properties towards CCK1 receptors has anxiolytic activity, previously shown in preclinical and clinical studies. Purpose of the study. Evaluation of the anxiolytic effect of GB-115 in tablet dosage form with subchronic oral administration in comparison with phenazepam in laboratory primates. Methods. The experiment was performed on four male rhesus monkeys (Macaca mulatta) aged 5.7–6.7 years. After a 30-day period of adaptation to the conditions of individual housing, an experiment was performed with GB-115 (0.001 g tablets) and then with phenazepam (0.0005 g tablets). Both drugs were given one at a time (7 days), and then 2 tablets (7 days). Behavior was assessed by observing the object with registration according to the “Yes-No” principle of ethogram elements in the background periods, during the administration of drugs and during their withdrawal. Using enzyme immunoassay, the content of stress response biomarkers: cortisol and dehydroepiandrosterone sulfate (DHEA-S) was determined in blood serum. Results. GB-115 (0.001 g each) and phenazepam (0.001 g each) reduced the stay of animals in the upper part of the cage compared to the background period, which indicates a decrease in the stress response. GB-115 (0.002 g each) decreased the cortisol/DHEA-S ratio. Phenazepam dose-dependently reduced serum cortisol levels without affecting DHEA-S levels; with the administration of phenazepam (0.001 g), a decrease in the cortisol/DHEA-S ratio was also recorded. Conclusion. A positive effect of GB-115, when administered subchronically, on the weakening of the emotional stress reaction and restoration of adaptive behavior in rhesus monkeys was revealed, comparable to the effect of phenazepam, which confirms the possibility of using blockade of CCK1 receptors as one of the approaches for the treatment of anxiety disorders.

Effects of sub-chronic oral administration of hydromethanolic stem extract of Costus afer Ker Gawl. (Costaceae) on body weight, relative organ weight (ROW) and histopathology of selected organs in rats

Adverse effects of plant extracts on body weight, relative organ weight and histopathology are important indicators of toxicity. The aim of this study was to evaluate the acute and sub-chronic toxicity of the hydromethanolic stem extract of Costus afer Ker Gawl. (Costaceae). OECD (2008) Guideline 425 was used to evaluate oral acute toxicity of the extract. Sub-chronic oral administration of the extract on body weight, relative organ weight (ROW) and histopathology of selected organs in Wistar rats were evaluated using OECD 1995 guideline 407. Forty Wistar rats of both sexes were divided into 4 groups. Rats in control group (Group I) received 1 ml/kg/day distilled water while Groups II, III and IV rats received 250, 500, and 1000 mg/kg/day of the extract respectively for 28 days. All treatments were administered orally. The rats were sacrificed under light halothane anaesthesia on the 29th day and the target organs were harvested, weighed and examined macroscopically for any morphological changes and microscopically for any lesions. There were no significant changes in mean body weights of rats and relative organ weights of selected organs in the extract treated groups when compared with the control group (distilled water). Although histological features of the brain, heart, stomach mucosa, lungs, spleen, ovaries and uterus in the extract treated groups were similar to those of control, slight to moderate renal and hepatic necrosis and necrosis of secondary spermatogenic cells at doses of 500 mg/kg and above of the extract were observed in the kidneys, liver and testes respectively. Caution should be exercised on sub-chronic administration of this extract as it may be toxic to the kidneys, liver and testes.

The Protective Effects of the Echium amoenum Seed Oil Against Seizures Induced by Pentylenetetrazole

Background: Many recent studies have documented that polyunsaturated fatty acids (PUFAs) as a safe supplement raise seizure thresholds. However, the evidence of seed oil supplements on seizure susceptibility remains controversial, and among them, Echium seed oil (EO) is a mixture of ω-3 and ω-6 PUFAs. Objectives: This study aimed to test the effects of the sub-chronic administration of EO on intravenous pentylenetetrazole (PTZ) seizure threshold, considering its antioxidant activity and biochemical parameters. Methods: Fifty male mice were divided into five groups (10 in each), including control (no treatment), vehicle (sesame oil), and EO (1, 3, and 5 g/kg) groups. Vehicle and EO were administered p.o. once a day for four weeks. Then, the intravenous PTZ induced-seizure threshold was determined. Finally, the serum concentration of lipid, creatinine, alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and the activity of superoxide dismutase (SOD) was assessed. Results: Pretreatment with EO raised the seizure threshold dose-dependently compared to the vehicle. Pretreatment with EO had no adverse effect on the serum concentration of ALP, AST, ALT, creatinine, high-density lipoprotein (HDL), and low-density lipoprotein (LDL), but at the dosages of 3 and 5 g/kg decreased the concentration of cholesterol, very low-density lipoprotein (VLDL) (P < 0.05), and triglyceride (TG) (P < 0.01). Also, 1 and 3 g/kg of EO improved the activity of SOD (P < 0.01). Conclusions: Pretreatment with EO increases the seizure threshold without negative impacts on the liver and kidney biomarkers, correlated with its positive effects on antioxidant activity and serum lipid profiles.

Panaxcerol D from Panax ginseng ameliorates the memory impairment induced by cholinergic blockade or Aβ25–35 peptide in mice

BackgroundAlzheimer's disease (AD) has memory impairment associated with aggregation of amyloid plaques and neurofibrillary tangles in the brain. Although anti-amyloid β (Aβ) protein antibody and chemical drugs can be prescribed in the clinic, they show adverse effects or low effectiveness. Therefore, the development of a new drug is necessarily needed. We focused on the cognitive function of Panax ginseng and tried to find active ingredient(s). We isolated panaxcerol D, a kind of glycosyl glyceride, from the non-saponin fraction of P. ginseng extract. MethodsWe explored effects of acute or sub-chronic administration of panaxcerol D on cognitive function in scopolamine- or Aβ25-35 peptide-treated mice measured by several behavioral tests. After behavioral tests, we tried to unveil the underlying mechanism of panaxcerol D on its cognitive function by Western blotting. ResultsWe found that pananxcerol D reversed short-term, long-term and object recognition memory impairments. The decreased extracellular signal-regulated kinases (ERK) or Ca2+/calmodulin-dependent protein kinase II (CaMKII) in scopolamine-treated mice was normalized by acute administration of panaxcerol D. Glial fibrillary acidic protein (GFAP), caspase 3, NF-kB p65, synaptophysin and brain-derived neurotrophic factor (BDNF) expression levels in Aβ25-35 peptide-treated mice were modulated by sub-chronic administration of panaxcerol D. ConclusionPananxcerol D could improve memory impairments caused by cholinergic blockade or Aβ accumulation through increased phosphorylation level of ERK or its anti-inflammatory effect. Thus, panaxcerol D as one of non-saponin compounds could be used as an active ingredient of P. ginseng for improving cognitive function.

Relationship between two forms of impulsivity in mice at baseline and under acute and sub-chronic atomoxetine treatment

RationaleImpulsivity is a symptom of various mental disorders, including attention deficit hyperactivity disorder (ADHD), bipolar disorder, and addiction. Impulsivity is not a unitary construct, but is present in different forms, yet only a few rodent studies have explored the relationship between these forms within individual subjects. ObjectivesIn this study, we compared behaviors representing two impulsivity forms, delay discounting (choice impulsivity) and premature responding (waiting impulsivity), within the same mice. MethodsC57BL/6J male mice were concurrently trained and tested in the delay discounting task and the rodent continuous performance test in a counterbalanced design. The effects of the ADHD medication atomoxetine were tested in both tasks, after both acute (0.3–5.0 mg/kg) and sub-chronic (0.3 mg/kg twice daily for seven days) administration. ResultsThere was no correlation between the two impulsivity forms at baseline. Acute atomoxetine treatment (1, 3, and 5 mg/kg) significantly reduced premature responding. Furthermore, sub-chronic treatment with 0.3 mg/kg of atomoxetine caused a stable decrease in premature responding. Atomoxetine had no significant effect on delay discounting after acute or sub-chronic administration, although the acute administration of 1 mg/kg showed a trend towards increasing delay discounting. ConclusionsThe present results support that delay discounting and premature responding represent two different forms of impulsivity that show dissimilar responses to atomoxetine treatment. The consistency with findings in humans lends support to the translatability of the results in mice.

Acute and sub-chronic toxicity studies of 5-methylcoumarin-4-β-glucoside isolated from <i>Vernonia glaberrima</i> in Wistar rats

5-methylcoumarin-4-β-glucoside is a natural product isolated from Vernonia glaberrima – a plant used in African traditional medicine for the treatment of cancer and skin diseases. This compound possesses significant in-vitro antiproliferative potentials against colon cancer cell lines. However, safety assessment in several laboratory animals is required before commencing the in-vivo anticancer evaluation of the compound. This study is designed to evaluate the safety of 5-methylcoumarin-4-β-glucoside using 28 days sub-chronic toxicity model in Wistar rats. Acute toxicity study was carried out at a single oral dose of 10 mg/kg, 100 mg/kg and 1000 mg/kg body weight (phase 1) for 24 hours, and 1600 mg/kg, 2900 mg/kg, and 5000 mg/kg body weight (phase 2). Sub-chronic toxicity was conducted by oral administration of distilled water, 1%hydroxypropyl cellulose in distilled water as controls, and graded doses of 10 mg/kg, 50 mg/kg, and 100 mg/kg body weight of 5-methylcoumarin-4β-glucoside freshly prepared in 1% hydroxypropyl cellulose as vehicle to five groups of six rats each for 28 days. The result indicates that 5-methylcoumarin-4β-glucoside at a dose of 100 mg/kg body weight is non-toxic as serological indices like liver and kidney functioning test, serum lipid profile, oxidative stress markers and hematological indices remained in the normal range after the 28 days sub-chronic administration of the compound. Moreover, the histopathology findings revealed no alteration in the normal tissue architecture. Overall, the findings in Wistar rats corroborate the initial findings in mice. Conclusively, the compound 5-methylcoumarin-4β-glucoside is safe at the prescribed doses for further preclinical in vivo investigations.

Subchronic Administration of High-dose Monosodium Glutamate Causes Spatial Memory Dysfunction and Structural Deficits of Rat Hippocampus

Introduction: The toxicity of high concentration monosodium glutamate (MSG) has become a controversial issue because of its inconsistent results in human and animal studies. This present study aims to evaluate the effect of subchronic high-doses oral administration of MSG on spatial memory performance and hippocampal pyramidal cells number. Methods: This study involved twenty-eight male Wistar rats, which were divided into a control group of NaCl 0.9% and three intervention groups of MSG 1.0 mg/g bodyweight (M1), 2.0 mg/g bodyweight (M2), and 4.0 mg/g bodyweight (M3) for 30 days. Statistical analysis used a One-way ANOVA test. Results: The result showed significant differences in spatial memory on the Morris Water Maze (MWM) test, including path length (p = 0.020) and escape latency (p = 0.011) according to general linear model repeated measurement analysis. The mean difference of estimated hippocampal pyramidal cells total number among the groups showed volume (p = 0.001), numerical density (p = 0.590), and cells number (p = 0.004). Furthermore, Post-Hoc analysis in both spatial memory and hippocampal pyramidal cells showed that the increasing MSG dose from 1.0 to 4.0 mg/g bodyweight led to a decrease in the results of spatial memory performance on the MWM test and a decrease in hippocampal cells. Conclusion: The present study has provided novel quantitative data that subchronic administration of high-dose MSG caused deleterious effects on the spatial memory function and the volume and number of hippocampal pyramidal cells.

Antihyperglycemic and Antidyslipidemic Effects of Artemisia arborescens Aqueous Extract on Streptozotocin-induced Diabetic Rats.

This study aimed to investigate the antidiabetic activity of Artemisia arborescens. Artemisia arborescens is an aromatic, medicinal, and endemic plant mostly found in the Mediterranean region. This plant is widely used as alternative medicine. The study was designed to examine the antihyperglycemic and antihyperlipidemic activities of Artemisia arborescens aqueous extract (AEAA) in normal and streptozotocin (STZ)- induced diabetic rats. The effect of AEAA (40 mg/kg and 80 mg/kg) on plasma glucose levels and plasma lipid profile was investigated in normal and STZ-induced diabetic rats. The plasma glucose levels were determined after a single (6 hours) and subchronic oral administration (7 days), and plasma lipid profiles were evaluated after both acute and subchronic oral administration. Additionally, the glycogen content in the liver, extensor digitorum longus (EDL), and soleus muscles was measured using a standard method. Moreover, the aqueous extract was tested for its 1.1-diphenyl-2- picrylhydrazyl (DPPH) radical-scavenging activity. In diabetic rats, AEAA oral administration (40 mg/kg and 80 mg/kg) produced a significant decrease in blood glucose levels after 7 days of oral administration (P<0.0001). Moreover, a significant decrease in plasma triglyceride levels was reported on the last day of treatment by AEAA (80 mg/kg) (P<0.05). Furthermore, a significant decrease in total cholesterol levels was observed after 7 days of AEAA oral administration in diabetic rats (P<0.01). Moreover, a significant increase in HDL-c concentration was noted after one week of AEAA (80 mg/kg) oral administration (P<0.001). In addition, AEAA oral administration (80 mg/kg) significantly increased the glycogen content in the liver and extensor digitorum longus (P<0.05). On the other hand, qualitative and quantitative phytochemical screenings revealed the presence of various compounds, such as polyphenols, flavonoids, and tannins. In summary, the study demonstrates that Artemisia arborescens oral administration exhibited a significant antihyperglycemic effect on diabetic rats and revealed a significant amelioration in lipid profile and glycogen content.

Antidepressant-like effects of L-menthol mediated by alleviating neuroinflammation and upregulating the BDNF/TrkB signaling pathway in subchronically lipopolysaccharide-exposed mice

L-menthol (LM) is a safe and bioactive monoterpenoid from Mentha haplocalyxBriq., with which an acute treatment has shown significant antidepressant-like effects potentially mediated by the modification of monoamine system in mice. Nonetheless, the above conclusions were all based on the forced swimming test. The antidepressant-like effects of acute and subchronic administrations with LM on other depression models have never been illuminated, and its potential mechanisms require further explorations. In this study, the antidepressant-like effects and potential mechanisms of an acute treatment with LM were validated through behavioral despair tests, reserpine-induced ptosis, akinesia and hypothermia test, and 5-hydroxytryptophan-induced head-twitch test in mice. The antidepressant-like effects of subchronic treatments with LM were evaluated in a modified lipopolysaccharide (LPS)-induced depression model. Furthermore, the effects of subchronic treatments with LM on the microglial activation, hippocampal neurogenesis and brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) signaling pathway in LPS-induced mice were detected through immunofluorescence assay, enzyme-linked immunosorbent assay and western blotting analysis. Our results showed that acute and subchronic administrations with LM exerted significant antidepressant-like effects in different depression models, which might be mediated by modulating the monoamine system, alleviating neuroinflammation and upregulating the BDNF/TrkB signaling pathway in mice. Taken together, the current study systematically explored the potential of LM as a new candidate for depression therapy, and provided a modified LPS-induced depression model with better apparent and predictive validity.

Subchronic exposure to Tamoxifen modulates the hippocampal BDNF/ERK/Akt/CREB pathway and impairs memory in intact female rats

Tamoxifen (TAM), a Selective Estrogen Receptor Modulator (SERM), is commonly used to treat and prevent breast cancer. Memory impairment has been noticed in patients who experience hormone therapy in the case of TAM and other SERMs. Animal studies that mimic the TAM longer exposure effects are needed to better elucidate the adverse effects of continuous treatment in humans. This study evaluated the effects of TAM subchronic administration on the memory performance and hippocampal neural plasticity of intact female Wistar rats. Animals were treated intragastrically with TAM (0.25 and 2.5 mg/kg) for 59 days. The rats were subjected to the Object Location Test (OLT) and Object Recognition Test (ORT) to evaluate memory performance. After euthanasia, the hippocampus samples were excised and the protein levels of the BDNF/ERK/Akt/CREB pathway were evaluated. The rat's locomotor activity and hippocampal TrkB levels were similar among the experimental groups. TAM at both doses reduced the memory performance of female rats in the OLT and short-term memory of ORT, and impaired hippocampal levels of mBDNF, proBDNF, and pCREB/CREB. TAM only at the dose of 2.5 mg/kg reduced the memory performance of rats in the long-term memory of ORT and hippocampal pERK/ERK and pAkt/Akt ratios. TAM subchronic administration induced amnesic effects and modulated the hippocampal BDNF/ERK/Akt/CREB pathway in intact young adult female Wistar rats.

Dietary medium-chain fatty acids reduce food intake via the GDF15-GFRAL axis in mice

ObjectiveMedium chain fatty acids (MCFAs), which are fatty acids with chain lengths of 8–12 carbon atoms, have been shown to reduce food intake in rodents and humans, but the underlying mechanisms are unknown. Unlike most other fatty acids, MCFAs are absorbed from the intestine into the portal vein and enter first the liver. We thus hypothesized that MCFAs trigger the release of hepatic factors that reduce appetite. MethodsThe liver transcriptome in mice that were orally administered MCFAs as C8:0 triacylglycerol (TG) was analyzed. Circulating growth/differentiation factor 15 (GDF15), tissue Gdf15 mRNA and food intake were investigated after acute oral gavage of MCFAs as C8:0 or C10:0 TG in mice. Effects of acute and subchronic administration of MCFAs as C8:0 TG on food intake and body weight were determined in mice lacking either the receptor for GDF15, GDNF Family Receptor Alpha Like (GFRAL), or GDF15. ResultsHepatic and small intestinal expression of Gdf15 and circulating GDF15 increased after ingestion of MCFAs, while intake of typical dietary long-chain fatty acids (LCFAs) had no effect. Plasma GDF15 levels also increased in the portal vein with MCFA intake, indicating that in addition to the liver, the small intestine contributes to the rise in circulating GDF15. Acute oral provision of MCFAs decreased food intake over 24 h compared with a LCFA-containing bolus, and this anorectic effect required the GDF15 receptor, GFRAL. Moreover, subchronic oral administration of MCFAs reduced body weight over 7 days, an effect that was blunted in mice lacking either GDF15 or GFRAL. ConclusionsWe have identified ingestion of MCFAs as a novel nutritional approach that increases circulating GDF15 in mice and have revealed that the GDF15-GFRAL axis is required for the full anorectic effect of MCFAs.

Possible involvement of Interleukin-17A in the deterioration of prepulse inhibition on acoustic startle response in mice.

Proinflammatory cytokines such as interleukin-6 (IL-6) and IL-17A have been implicated in the pathophysiology of schizophrenia which often shows sensorimotor gating abnormalities. This study aimed to examine whether a proinflammatory cytokine, IL-17A, induces impairment in sensorimotor gating in mice. We also examined whether IL-17A administration affects GSK3α/β protein level or phosphorylation in the striatum. Recombinant mouse IL-17A (low-dose: 0.5 ng/mL and high-dose: 50 ng/mL with 10 μL/g mouse body weight, respectively) or vehicle was intraperitoneally administered into C57BL/6 male mice 10 times in 3 weeks (sub-chronic administration). Prepulse inhibition test using acoustic startle stimulus was conducted 4 weeks after the final IL-17A administration. We evaluated the effect of IL-17A administration on protein level or phosphorylation of GSK3α/β in the striatum by using Western blot analysis. Administration of IL-17A induced significant PPI deterioration. Low-dose of IL-17A administration significantly decreased both GSK3α (Ser21) and GSK3β (Ser9) phosphorylation in mouse striatum. There was no significant alteration of GSK3α/β protein levels except for GSK3α in low-dose IL-17A administration group. We demonstrated for the first time that sub-chronic IL-17A administration induced PPI disruption and that IL-17A administration resulted in decreased phosphorylation of GSKα/β at the striatum. These results suggest that IL-17A could be a target molecule in the prevention and treatment of sensorimotor gating abnormalities observed in schizophrenia.

The causal involvement of the BDNF-TrkB pathway in dentate gyrus in early-life stress-induced cognitive deficits in male mice

Cognitive dysfunction is a significant, untreated clinical need in patients with psychiatric disorders, for which preclinical studies are needed to understand the underlying mechanisms and to identify potential therapeutic targets. Early-life stress (ELS) leads to long-lasting deficits of hippocampus-dependent learning and memory in adult mice, which may be associated with the hypofunction of the brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, tropomyosin receptor kinase B (TrkB). In this study, we carried out eight experiments using male mice to examine the causal involvement of the BDNF-TrkB pathway in dentate gyrus (DG) and the therapeutic effects of the TrkB agonist (7,8-DHF) in ELS-induced cognitive deficits. Adopting the limited nesting and bedding material paradigm, we first demonstrated that ELS impaired spatial memory, suppressed BDNF expression and neurogenesis in the DG in adult mice. Downregulating BDNF expression (conditional BDNF knockdown) or inhibition of the TrkB receptor (using its antagonist ANA-12) in the DG mimicked the cognitive deficits of ELS. Acute upregulation of BDNF (exogenous human recombinant BDNF microinjection) levels or activation of TrkB receptor (using its agonist, 7,8-DHF) in the DG restored ELS-induced spatial memory loss. Finally, acute and subchronic systemic administration of 7,8-DHF successfully restored spatial memory loss in stressed mice. Subchronic 7,8-DHF treatment also reversed ELS-induced neurogenesis reduction. Our findings highlight BDNF-TrkB system as the molecular target of ELS-induced spatial memory deficits and provide translational evidence for the intervention at this system in the treatment of cognitive deficits in stress-related psychiatric disorders, such as major depressive disorder.

Altered GABAergic, glutamatergic and endocannabinoid signaling is accompanied by neuroinflammatory response in a zebrafish model of social withdrawal behavior.

Deficits in social communication are in the core of clinical symptoms characterizing many neuropsychiatric disorders such as schizophrenia and autism spectrum disorder. The occurrence of anxiety-related behavior, a common co-morbid condition in individuals with impairments in social domain, suggests the presence of overlapping neurobiological mechanisms between these two pathologies. Dysregulated excitation/inhibition balance and excessive neuroinflammation, in specific neural circuits, are proposed as common etiological mechanisms implicated in both pathologies. In the present study we evaluated changes in glutamatergic/GABAergic neurotransmission as well as the presence of neuroinflammation within the regions of the Social Decision-Making Network (SDMN) using a zebrafish model of NMDA receptor hypofunction, following sub-chronic MK-801 administration. MK-801-treated zebrafish are characterized by impaired social communication together with increased anxiety levels. At the molecular level, the behavioral phenotype was accompanied by increased mGluR5 and GAD67 but decreased PSD-95 protein expression levels in telencephalon and midbrain. In parallel, MK-801-treated zebrafish exhibited altered endocannabinoid signaling as indicated by the upregulation of cannabinoid receptor 1 (CB1R) in the telencephalon. Interestingly, glutamatergic dysfunction was positively correlated with social withdrawal behavior whereas defective GABAergic and endocannabinoid activity were positively associated with anxiety-like behavior. Moreover, neuronal and astrocytic IL-1β expression was increased in regions of the SDMN, supporting the role of neuroinflammatory responses in the manifestation of MK-801 behavioral phenotype. Colocalization of interleukin-1β (IL-1β) with β2-adrenergic receptors (β2-ARs) underlies the possible influence of noradrenergic neurotransmission to increased IL-1β expression in comorbidity between social deficits and elevated anxiety comorbidity. Overall, our results indicate the contribution of altered excitatory and inhibitory synaptic transmission as well as excessive neuroinflammatory responses in the manifestation of social deficits and anxiety-like behavior of MK-801-treated fish, identifying possible novel targets for amelioration of these symptoms.