Cytoprotective effects of Hangekobokuto against corticosterone-induced cell death in HT22 cells.

The hypothalamic-pituitary-adrenal (HPA) system plays an important role in stress response. Chronic stress is thought to induce neuronal damage and contribute to the pathogenesis of psychiatric disorders by causing dysfunction of the HPA system and promoting the production and release of glucocorticoids, including corticosterone and cortisol. Several clinical studies have demonstrated the efficacy of herbal medicines in treating psychiatric disorders; however, their effects on corticosterone-induced neuronal cell death remain unclear. Here, we used HT22 cells to evaluate the neuroprotective potential of herbal medicines used in neuropsychiatry against corticosterone-induced hippocampal neuronal cell death. Cell death was assessed using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) reduction and Live/Dead assays. Hangekobokuto, Kamikihito, Saikokaryukotsuboreito, Kamishoyosan, and Yokukansan were supplied in the form of water-extracted dried powders. Exposure of HT22 cells to ≥ 100 µM corticosterone decreased MTT values. Exposure to 500 µM corticosterone alone reduced MTT values to 18%, while exposure to 10 µM Mifepristone (RU486)-a glucocorticoid receptor antagonist-restored values to 36%. Corticosterone-induced cell death was partially suppressed by treatment with RU486. At 100 µg/mL, Hangekobokuto significantly suppressed the decrease in MTT values (15-32%) and increase in the percentage of ethidium homodimer-1-positive dead cells caused by corticosterone exposure (78-36%), indicating an inhibitory effect on cell death. By contrast, Kamikihito, Saikokaryukotsuboreito, Kamishoyosan, and Yokukansan did not affect corticosterone-induced cell death. Therefore, our results suggest that Hangekobokuto may ameliorate the onset and progression of psychiatric disorders by suppressing neurological disorders associated with increased levels of glucocorticoids.

Structural elucidation of a non-starch polysaccharides from Lilii Bulbus and its protective effects against corticosterone-induced neurotoxicity in PC12 cells.

Lilii Bulbus is a folk medicine for both culinary and medicinal purpose. In traditional medicine theory, Lilii Bulbus is usually used as an complementary therapy for nourishing the heart and lung, clearing heat in the treatment of mental instability and depression. In this study, NLPS-1a (Mw = 2610 Da, DP = 16), a water-soluble non-starch Lilii Bulbus polysaccharides, was isolated and purified. Structural analysis showed that NLPS-1a mainly contained Man and Glc with a molar ratio of 11.137 and 9.427. The glycosidic linkages of NLPS-1a were 1,3-Manp (59.93%), 1,2-Glcp (37.93%), T-Glcp (1.21%) and T-Manp (0.93%), indicating the highly-linear structures. In addition, NLPS-1a could significantly repair the injury of PC12 cells induced by corticosterone (CORT), reduce Lactate dehydrogenase (LDH) leakage and decrease the cell apoptosis in a dose-dependent manner. Above all, the results indicated that NLPS-1a had protective effects against CORT-induced neurotoxicity in PC12 cells, and might be a natural antidepressant, which enriched the study of the metabolic mechanism between herbal polysaccharides and antidepressant.

Anti-depressive effects of Jiao-Tai-Wan on CORT-induced depression in mice by inhibiting inflammation and microglia activation.

ETHNOPHARMACOLOGICAL RELEVANCE: Jiao-Tai-Wan (JTW) is a very famous traditional Chinese medicine formula for the treatment of psychiatric disorders, especially in anxiety, insomnia and depression. However, its molecular mechanism of treatment remains indistinct. AIM OF THE STUDY: We aimed to reveal the action mechanism of JTW on anti-depression via inhibiting microglia activation and pro-inflammatory response both in vivo and in vitro. MATERIAL AND METHODS: The corticosterone (CORT)-induced depression mouse model was used to evaluate the therapeutic efficacy of JTW. Behavioral tests (open field, elevated plus maze, tail suspension and forced swim test) were conducted to evaluate the effect of JTW on depressive-like behaviors. The levels of inflammatory factors and the concentration of neurotransmitters were detected by RT-qPCR or ELISA assays. Then three hippocampal tissue samples per group (Control, CORT, and JTW group) were sent for RNA sequencing (RNA-seq). Transcriptomics data analysis was used to screen the key potential therapeutic targets and signaling pathways of JTW. Based on 8 bioactive species of JTW by our previous study using High-performance liquid chromatography (HPLC) analysis, molecular docking analyses were used to predict the interaction of JTW-derived compounds and depression targets. Finally, the results of transcriptome and molecular docking analyses were combined to verify the targets, key pathways, and efficacy of JTW treatment in vivo and vitro. RESULTS: JTW ameliorated CORT-induced depressive-like behaviors, neuronal damage and enhanced the levels of monoamine neurotransmitters in the serum of mice. JTW also inhibited CORT-induced inflammatory activation of microglia and decreased the serum levels of interleukin- 6(IL-6) and interleukin- 1ß (IL-1ß) in vivo. Transcriptomic data analysis showed there were 10 key driver analysis (KDA) genes with the strongest correlation which JTW regulated in depression mice. Molecular docking analysis displayed bioactive compound Magnoflorine had the strongest binding force to the key gene colony-stimulating factor 1 receptor (CSF1R), which is the signaling microglia dependent upon for their survival. Meanwhile, CSF1R staining showed it was consistent with inflammatory activation of microglia. Our vitro experiment also showed JTW and CSF1R inhibitor significantly reduced lipopolysaccharide (LPS)/interferon-gamma (IFNÉ£)-induced inflammatory activation response in macrophage cells. CONCLUSIONS: Our study suggests that JTW might ameliorate CORT-induced neuronal damage in depression mice by inhibiting CSF1R mediated microglia activation and pro-inflammatory response.

Dysfunction in Sertoli cells participates in glucocorticoid-induced impairment of spermatogenesis.

The effect of stress on male fertility is a widespread public health issue, but less is known about the related signaling pathway. To investigate this, we established a hypercortisolism mouse model by supplementing the drinking water with corticosterone for four weeks. In the hypercortisolism mice, the serum corticosterone was much higher than in the control, and serum testosterone was significantly decreased. Moreover, corticosterone treatment induced decrease of sperm counts and increase of teratozoospermia. Increased numbers of multinucleated giant cells and apoptotic germ cells as well as downregulated meiotic markers suggested that corticosterone induced impaired spermatogenesis. Further, upregulation of macrophage-specific marker antigen F4/80 as well as inflammation-related genes suggested that corticosterone induced inflammation in the testis. Lactate content was found to be decreased in the testis and Sertoli cells after corticosterone treatment, and lactate metabolism-related genes were downregulated. In vitro phagocytosis assays showed that the phagocytic activity in corticosterone-treated Sertoli cells was downregulated and accompanied by decreased mitochondrial membrane potential, while pyruvate dehydrogenase kinase-4 inhibitor supplementation restored this process. Taken together, our results demonstrated that dysfunctional phagocytosis capacity and lactate metabolism in Sertoli cells participates in corticosterone-induced impairment of spermatogenesis.

Phosphodiesterase 2 inhibitor Hcyb1 reverses corticosterone-induced neurotoxicity and depression-like behavior.

RATIONALE: Currently available PDE2 inhibitors have poor brain penetration that limits their therapeutic utility in the treatment of depression. Hcyb1 is a novel selective PDE2 inhibitor that was introduced more lipophilic groups with polar functionality to the scaffold pyrazolopyrimidinone to improve the blood-brain barrier (BBB) penetration. Our previous study suggested that Hcyb1 increased the neuronal cell viability and exhibited antidepressant-like effects, which were parallel to the currently available PDE2 inhibitor Bay 60-7550. OBJECTIVES: The present study investigated whether Hcyb1 protected HT-22 cells against corticosterone-induced neurotoxicity and produced antidepressant-like effects in behavioral tests in stressed mice. METHODS: The neuroprotective effects of Hcyb1 against corticosterone-induced cell lesion were examined by cell viability (MTS) assay. The enzyme-linked immunosorbent assay (ELISA) and immunoblot analysis were used to determine the levels of cAMP or cGMP and expression of pCREB or BDNF, respectively, in the corticosterone-treated HT-22 cells. The antidepressant-like effects of Hcyb1 were determined in the tail suspension and novelty suppressed feeding tests in stressed mice. RESULTS: In the cell-based assay, Hcyb1 significantly increased cell viability of HT-22 cells against corticosterone-induced neurotoxicity in a time- and dose-dependent manner. Hcyb1 also rescued corticosterone-induced decreases in both cGMP and cAMP levels, pCREB/CREB and BDNF expression. These protective effects of Hcyb1 were prevented by pretreatment with either the PKA inhibitor H89 or the PKG inhibitor KT5823. Moreover, Hcyb1 reversed acute stress-induced increases in immobility time and the latency to feed in the tail suspension and novelty suppressed feeding tests, respectively, which were prevented by pretreatment with H89 or KT5823. CONCLUSION: These findings provide evidence that the neuroprotective effects of Hcyb1 are mediated by PDE2-dependent cAMP/cGMP signaling.

N-(3-Methozybenzyl)-(9Z,12Z,15Z)-octadecatrienamide from maca (Lepidium meyenii Walp.) ameliorates corticosterone-induced testicular toxicity in rats.

This study investigated the protective effects of maca ethanol extract (EEM) and N-(3-methozybenzyl)-(9Z,12Z,15Z)-octadecatrienamide (M 18:3) on corticosterone (CORT)-induced testicular toxicity. Male Wistar rats were divided into 5 groups. Except for the control group, CORT (40 mg per kg·bw) was injected subcutaneously for 21 consecutive days to induce testicular toxicity. 1 h before CORT injection, the rats were treated with EEM (400 mg per kg·bw) and M 18:3 (5 mg per kg·bw, 25 mg per kg·bw) by gavage, except for the control group and model group. Epididymal sperm and biochemical, and histological parameters were evaluated for the protective effects of the drugs. EEM (400 mg per kg·bw) and M 18:3 (5 mg per kg·bw, 25 mg per kg·bw) increased the sperm concentration and sperm motility, decreased the production of abnormal sperms, and increased the number of spermatogonia and primary spermatocytes in the seminiferous tubules of CORT-induced rats. Moreover, EEM and M 18:3 decreased the MDA levels and the positive expression rates of TUNEL, whereas they increased the activities of SOD, CAT, GSH-Px, and GST, and the contents of GSH in the testicles of CORT-induced rats. Furthermore, EEM and M 18:3 alleviated CORT-induced reduction in the positive expression rates of PCNA and Ki67 in the testicles of rats. Besides, EEM and M 18:3 reduced the expression levels of Keap-1 and increased the expression levels of Nrf2, HO-1, γ-GCS, and NQO1 in the testicles of CORT-induced rats. In summary, the protective effects of EEM and M 18:3 may be attributed to their anti-oxidative and anti-apoptotic properties.

Erxian decoction, a famous Chinese medicine formula, antagonizes corticosterone-induced injury in PC12 cells, and improves depression-like behaviours in mice.

Context: In folk medicine, erxian decoction (EXD) is used to treat perimenopausal syndrome in women. It is also used clinically to treat depression, but the mechanism remains unknown.Objectives: To investigate the neuroprotective effect of EXD, and its antidepressant potential.Materials and methods: ICR mice were treated with EXD (0.5, 1.5 and 4.5 g/kg i.g.) and fluoxetine (6.0 mg/kg i.g.) for 10 days. On day 10 of the treatment, depression-like behaviour was induced by reserpine (2.5 mg/kg injected i.p.), and after 24 h of reserpine administration, it was assessed using the tail suspension and forced swimming tests. MTT assay, lactate dehydrogenase test, flow cytometry analysis, Hoechst staining and western blotting were used to assess the apoptosis of PC12 cells. Apoptosis proteins and neurotransmitter were tested in vitro and in vivo, respectively.Results: MTT assay results showed corticosterone prevented cell growth, but EXD at concentrations of 100, 200 and 400 µg/mL restored cell viability (EC50: 204.016 µg/mL). EXD decreased lactate dehydrogenase leakage from 63.48 to 43.60 U/L, and upregulated expression of Bcl-2 while the expression of Bax, caspase-3 and caspase-8 were decreased in vivo and in vitro. Moreover, EXD improved depression-like behaviour in mice, and 4.5 g/kg EXD treatment increased the secretion of serotonin, dopamine and norepinephrine by 67.44, 28.12 and 42.12 pg/mg, respectively, in hypothalamus compared to that of reserpine group.Discussion and conclusions: EXD demonstrated neuroprotective effects and improved depression-like behaviour in mice. Further research should be focussed on the mechanism of the active components in EXD.

Safety evaluation and protective effects of ethanolic extract from maca (Lepidium meyenii Walp.) against corticosterone and H2O2 induced neurotoxicity.

Maca has been traditionally used to enhance sexual behavior and fertility. Recently, maca's neuroprotective effects have been reported. The purpose of this study was to investigate whether the ethanol extract of maca (EEM) (100 mg/kg/bw, 200 mg/kg/bw, 400 mg/kg/bw, p.o.) exerted neuroprotective effects in corticosterone (CORT)-induced (40 mg/kg/bw, s.c.) rats, to determine the neuroprotective effects of EEM (12.5, 25, 50 µg/ml) and macamides in H2O2-induced (50 µM) PC12 cells. The acute toxicity (2000 mg/kg/bw, p.o.) and subacute toxicity (200 mg/kg/bw, 500 mg/kg/bw, 1000 mg/kg/bw, p.o.) of EEM were evaluated by mouse models. EEM reversed CORT-induced abnormal behaviors, reduced the contents of TNF-α, IL-6 in hippocampi, and increased the positive cells of doublecortin (DCX), bromodeoxyuridine (BrdU) and DCX + BrdU in the hippocampus of rats. Moreover, EEM and 4 macamides remarkably increased the cell viability in H2O2-induced PC12 cells. EEM promoted the phosphorylation of IκBα and p65, suppressed the NF-κB activation, and inhibited the levels of pro-inflammatory cytokines such as TNF-α, IL-6 and their mRNA levels in H2O2-induced PC12 cells. In conclusion, EEM could exert neuroprotective effects in CORT-induced rats and in H2O2-induced PC12 cells. Moreover, EEM did not present relevant toxicity after exposure to single and repeated doses.

Involvement of mitochondrial apoptotic pathway and MAPKs/NF-κ B inflammatory pathway in the neuroprotective effect of atractylenolide III in corticosterone-induced PC12 cells.

Atractylenolide III (ATL-III), a sesquiterpene compound isolated from Rhizoma Atractylodis Macrocephalae, has revealed a number of pharmacological properties including anti-inflammatory, anti-cancer activity, and neuroprotective effect. This study aimed to evaluate the cytoprotective efficiency and potential mechanisms of ATL-III on corticosterone injured rat phaeochromocytoma (PC12) cells. Our results demonstrate that ATL-III increases cell viability and reduces the release of lactate dehydrogenase (LDH). The results suggest that ATL-III protects PC12 cells from corticosterone-induced injury by inhibiting the intracellular Ca2+ overloading, inhibiting the mitochondrial apoptotic pathway and modulating the MAPK/NF-ΚB inflammatory pathways. These findings provide a novel insight into the molecular mechanism by which ATL-III protected the PC12 cells against corticosterone-induced injury for the first time. Our results provide the evidence that ATL-III may serve as a therapeutic agent in the treatment of depression.

Camellia euphlebia protects against corticosterone-induced apoptosis in differentiated PC12 cells by regulating the mitochondrial apoptotic pathway and PKA/CREB/BDNF signaling pathway.

Camellia euphlebia is a Chinese folk medicine, known for its multiple pharmacological properties. Our previous studies have demonstrated its antidepressant activity by several animal models of depression. The possible underlying mechanism was further explored by investigating the neuroprotective effect of Camellia euphlebia extract (CEE) on corticosterone-induced apoptosis in neuronally differentiated PC12 cells. The results of methyl-thiazolyl-tetrazolium assay, lactate dehydrogenase release assay, Hoechst 33342 staining, propidium iodide staining, AV-FITC/PI double staining and DNA fragmentation analysis consistently indicated that pretreatment of PC12 cells with CEE at 20-80 µg/mL significantly reversed 300 µmol/L corticosterone-induced apoptosis in a dose dependent manner. Furthermore, intracellular mitochondrial membrane potential, reactive oxygen species accumulation, calcium level, Bcl-2/Bax ratio, caspase activity were assessed, and the results indicated that CEE exhibited its anti-apoptotic effect through the regulation of mitochondrial apoptosis pathway. Additionally, CEE increased the cyclic adenosine monophosphate-dependent protein kinase (PKA) level, which phosphorylated cAMP response element binding protein (CREB), and finally elevated the mRNA expression of brain-derived neurotrophic factor (BDNF) gene. It is speculated that the antidepressant effect of CEE in vivo may be associated with the cytoprotection of neuron damaged by corticosterone, and the cellular mechanism involves the mitochondrial-mediated apoptosis and PKA-CREB-BDNF signaling pathway.

Active fraction combination from Liuwei Dihuang decoction (LW-AFC) ameliorates corticosterone-induced long-term potentiation (LTP) impairment in mice in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: Liuwei Dihuang decoction (LW), a classic formula in Traditional Chinese medicine (TCM), has been used for nearly one thousand years for various diseases with characteristic features of kidney yin deficiency. LW consists of 6 herbs including Dihuang (prepared root of Rehmannia glutinosa (Gaertn.) DC.), Shanyao (rhizome of Dioscorea polystachya Turcz.), Shanzhuyu (fruit of Cornus officinalis Siebold & Zucc.), Mudanpi (root bark of Paeonia × suffruticosa Andrews), Zexie (rhizome of Alisma plantago-aquatica L.) and Fuling (scleorotia of Wolfiporia extensa (Peck) Ginns). LW-active fraction combination (LW-AFC) is extracted from LW, it is effective for the treatment of kidney yin deficiency in many animal models. Recent researches indicate that the "kidney deficiency" is related to a disturbance in the neuroendocrine immunomodulation (NIM) network, and glucocorticoids play an important role in kidney deficiency. AIM OF THE STUDY: This study evaluated the effects of LW-AFC and the active fractions (polysaccharide, LWB-B; glycoside, LWD-b; oligosaccharide, CA-30) on corticosterone (Cort)-induced long-term potentiation (LTP) impairment in vivo. MATERIALS AND METHODS: In this study, LTP was used to evaluate the synaptic plasticity. LW-AFC was orally administered for seven days. The active fractions were given by either chronic administration (i.g., i.p., 7 days) or single administration (i.c.v., i.g., i.p.). Cort was injected subcutaneously 1 h before the high-frequency stimulation (HFS) to induce LTP impairment. Moreover, in order to research on the possible effective pathways, an antibiotic cocktail and an immunosuppressant were also used. RESULTS: Chronic administration (i.g.) of LW-AFC and its three active fractions could ameliorate Cort-induced LTP impairment. Single administration (i.c.v., i.g., i.p.) of any of the active fractions had no effect on Cort-induced LTP impairment, while chronic administration (i.g., i.p.) of LWB-B or LWD-b showed positive effects against Cort. Interestingly, CA-30 only showed protective effects via i.g. administration, and there was little effect when CA-30 was administered i.p. In addition, when the intestinal microbiota was disrupted by application of the antibiotic cocktail, CA-30 showed little protective effects against Cort. The effects of LW-AFC were also abolished when the immune function was inhibited. In the hippocampal tissue, Cort treatment increased corticosterone and glutamate, and LW-AFC could inhibit the Cort-induced elevation of corticosterone and glutamate; there was little change in D-serine in Cort-treated animals, but LW-AFC could increase the D-serine levels. CONCLUSION: LW-AFC and its three active fractions could ameliorate Cort-induced LTP impairment. Their protective effects are unlikely by a direct way, and immune modulation might be the common pathway. CA-30 could protect LTP from impairment via modulating the intestinal microbiota. Decreasing corticosterone and glutamate and increasing D-serine in the Cort-treated animals' hippocampal tissue might be one of the mechanisms for the neural protective effects of LW-AFC. Further study is needed to understand the underlying mechanisms.

Antioxidant and antidepressant-like effects of Eugenia catharinensis D. Legrand in an animal model of depression induced by corticosterone.

This work investigated the antioxidant and antidepressant-like effects of ethyl acetate extract from Eugenia catharinensis in mice treated with corticosterone (20 mg/Kg). The animals received saline or corticosterone (21 days) and, in the last 7 days, they were treated with the extract (50, 125, 200 or 250 mg/Kg) or vehicle. After 24 h, the mice were submitted to the open field and forced swimming tests, after which the hippocampus and cerebral cortex were removed. Our results showed that the extract decreased the immobility time of mice in the forced swimming test and that the extract was able to reverse the effect caused by corticosterone. Corticosterone pre-treatment generated oxidative stress, altering antioxidant enzymes in the nervous tissue. The extract increased the catalase and superoxide dismutase activities and reversed the effects of corticosterone. In the hippocampus, the extract increased superoxide dismutase activity and reversed the increase in catalase activity elicited by corticosterone. We propose that the effects elicited by the Eugenia catharinensis are dependent on the presence of phenolic compounds (gallic acid, protocatechuic acid, syringic acid, 4-hydroxy methylbenzoic acid, chlorogenic acid, salicylic acid, caffeic acid, vanillic acid, p-coumaric acid, isoquercetin, rutin, ferulic acid, aromadendrin, galangin and apigenin) in this extract, as demonstrated by HPLC-ESI-MS/MS.

Isobutylhydroxyamides from Sichuan Pepper and Their Protective Activity on PC12 Cells Damaged by Corticosterone.

The pericarp of Zanthoxylum bungeanum Maxim., commonly known as Sichuan pepper, is a widely used spice to remove fishy odor and add palatable taste. A phytochemical investigation of the 95% ethanol extract of Sichuan pepper resulted in the isolation of 21 isobutylhydroxyamides, including 8 new ones named ZP-amides G-N, among which the chiral resolution of racemic ZP-amide A and ZP-amide B was successfully accomplished. The protective activity on corticosterone-treated PC12 cells of the isolated isobutylhydroxyamides was also evaluated. The new compounds 3-5 and the known compounds 1, 1a, 2, 2a, 11, and 15 improved the survival rate of PC12 cells. The bioactivity studies disclosed the potential of Sichuan pepper to be developed as new neuroprotective functional food.

Targeting the Endocannabinoid/CB1 Receptor System For Treating Major Depression Through Antidepressant Activities of Curcumin and Dexanabinol-Loaded Solid Lipid Nanoparticles.

BACKGROUND/AIMS: This study investigated the underlying mechanisms of the antidepressant effects of curcumin and dexanabinol-loaded solid lipid nanoparticles in corticosterone-induced cell and mice depression models. METHODS: Curcumin and dexanabinol-loaded solid lipid nanoparticles (Cur/SLNs-HU-211) were synthesized via an emulsifcation and low-temperature solidification method. Antidepressant activities of nanoparticles in a corticosterone-induced major depression model were investigated by MTT assay, cellular uptake by flow cytometry, behaviour by Forced Swimming Test and rotarod test, neurotransmitters by High Performance Liquid Chromatography, Western blotting, qPCR and immunofluorescence. RESULTS: Treatment with Cur/SLNs-HU-211 induced greater dopamine (DA)/5-hydroxytryptamine (5-HT) release with reduced corticosterone-induced apoptotic cell death in PC12 cells. Additionally, in vivo Cur/SLNs-HU-211 significantly induced recovery from depressive behaviour with increased DA/5-HT levels, CB1 mRNA levels and CB1, p-MEK1 and p-ERK1/2 protein expression levels in the hippocampus and striatum. Cur/SLNs-HU-211 improved CB1 expression and inspired the proliferation of astrocytes in the hippocampus and striatum, exerted neuroprotective effects by preventing corticosterone -induced BDNF/NeuN expression reduction. CONCLUSION: Our study implies that Cur/SLNs-HU-211 may be a useful approach for treatment of major depression.

Corticosterone and exogenous glucose alter blood glucose levels, neurotoxicity, and vascular toxicity produced by methamphetamine.

Our previous studies have raised the possibility that altered blood glucose levels may influence and/or be predictive of methamphetamine (METH) neurotoxicity. This study evaluated the effects of exogenous glucose and corticosterone (CORT) pretreatment alone or in combination with METH on blood glucose levels and the neural and vascular toxicity produced. METH exposure consisted of four sequential injections of 5, 7.5, 10, and 10 mg/kg (2 h between injections) D-METH. The three groups given METH in combination with saline, glucose (METH+Glucose), or CORT (METH+CORT) had significantly higher glucose levels compared to the corresponding treatment groups without METH except at 3 h after the last injection. At this last time point, the METH and METH+Glucose groups had lower levels than the non-METH groups, while the METH+CORT group did not. CORT alone or glucose alone did not significantly increase blood glucose. Mortality rates for the METH+CORT (40%) and METH+Glucose (44%) groups were substantially higher than the METH (< 10%) group. Additionally, METH+CORT significantly increased neurodegeneration above the other three METH treatment groups (≈ 2.5-fold in the parietal cortex). Thus, maintaining elevated levels of glucose during METH exposure increases lethality and may exacerbate neurodegeneration. Neuroinflammation, specifically microglial activation, was associated with degenerating neurons in the parietal cortex and thalamus after METH exposure. The activated microglia in the parietal cortex were surrounding vasculature in most cases and the extent of microglial activation was exacerbated by CORT pretreatment. Our findings show that acute CORT exposure and elevated blood glucose levels can exacerbate METH-induced vascular damage, neuroinflammation, neurodegeneration and lethality. Cover Image for this issue: doi. 10.1111/jnc.13819.

The Role of Nitric Oxide in the Antidepressant Actions of 5-Aminoimidazole-4-Carboxamide-1-ß-D-Ribofuranoside in Insulin-Resistant Mice.

OBJECTIVE: Depression and Type 2 diabetes mellitus are interrelated conditions, but the underlying neurobiology is insufficiently understood. The current study compared the effects of a pharmacological manipulation with 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside (AICAR) that targets neurobiological processes by adenosine 5'-monophosphate-activated protein kinase activation versus exercise on depression-like behavior and nitric oxide (NO)-related measures. METHODS: A mouse model of a depression-like and insulin-resistant state, induced by the co-treatment of high-fat diet and corticosterone administration, was used to examine the antidepressant action of AICAR and exercise. RESULTS: Data showed that AICAR was a putative antidepressant in the depression-like and insulin-resistant mice (total ambulatory distance in the open-field test was 5120.69 ± 167.47 cm, mobility duration in the forced swim test was 17.61 ± 1.54 seconds, latency to feed in the novelty suppressed feeding test was 255.67 ± 37.80 seconds; all p values < .05). Furthermore, the antidepressant actions of AICAR required endothelial nitric oxide synthase activity with increased NO production in the prefrontal cortex, whereas corticosterone-induced expression of neuronal nitric oxide synthase and NO production may increase the risk of depression. In contrast to the traditional antidepressants such as ketamine and imipramine, AICAR interfered with the effects of insulin in skeletal muscle in the context of high-fat diet, consistent with the potential antidepressant effects of AICAR. Exercise also resulted in activation of adenosine 5'-monophosphate-activated protein kinase, nitric oxide synthase, and NO production (all p values < .01), which in turn may be implicated in the antidepressant effects of exercise. CONCLUSIONS: These findings suggest that NO is an essential signal mediating the antidepressant actions of AICAR. Ultimately, the concurrent effects of AICAR on brain insulin action and mitochondrial function suggest a potential of neural insulin resistance, which may contribute to our understanding of the comorbidity of depression and Type 2 diabetes.

Effects of brief pulse and ultrabrief pulse electroconvulsive stimulation on rodent brain and behaviour in the corticosterone model of depression.

Brief pulse electroconvulsive therapy (BP ECT; pulse width 0.5-1.5 ms) is the most effective treatment available for severe depression. However, its use is associated with side-effects. The stimulus in ultrabrief pulse ECT (UBP ECT; pulse width 0.25-0.3 ms) is more physiological and has been reported to be associated with less cognitive side-effects, but its antidepressant effectiveness is not yet well established. Using electroconvulsive stimulation (ECS), the animal model of ECT, we previously reported UBP ECS to be significantly less effective than well-established BP ECS in eliciting behavioural, molecular and cellular antidepressant-related effects in naïve rats. We have now compared the effects of BP and UBP ECS in an animal model of depression related to exogenous supplementation with the stress-induced glucocorticoid hormone, corticosterone. Corticosterone administration resulted in an increase in immobility time in the forced swim test (FST) (p < 0.01) and decreases in the expression of brain-derived neurotrophic factor (BDNF) (p < 0.05) and glial fibrillary acidic protein (GFAP) (p < 0.001) in the hippocampus and frontal cortex. There was no significant difference in the duration or type of seizure induced by BP (0.5 ms) or UBP (0.3 ms) ECS. UBP ECS proved to be as effective as BP ECS at inducing a behavioural antidepressant response in the FST with a significant decrease (p < 0.001) in immobility seen following administration of ECS. Both forms of ECS also induced significant increases in BDNF protein (p < 0.01) expression in the hippocampus. BP ECS (p < 0.05) but not UBP ECS induced a significant increase in GFAP levels in the hippocampus and frontal cortex. Overall, UBP ECS effectively induced antidepressant-related behavioural and molecular responses in the corticosterone supplementation model, providing the first preclinical data on the potential role of this form of ECS to treat a depression phenotype related to elevated corticosterone.

Neonatal tryptophan depletion and corticosterone supplementation modify emotional responses in adult male mice.

The serotonergic system and the hypothalamic-pituitary-adrenal (HPA) axis are crucially involved in the regulation of emotions. Specifically, spontaneous and/or environmentally mediated modulations of the functionality of these systems early in development may favour the onset of depressive- and anxiety-related phenotypes. While the independent contribution of each of these systems to the emergence of abnormal phenotypes has been detailed in clinical and experimental studies, only rarely has their interaction been systematically investigated. Here, we addressed the effects of reduced serotonin and environmental stress during the early stages of postnatal life on emotional regulations in mice. To this aim, we administered, to outbred CD1 mouse dams, during their first week of lactation, a tryptophan deficient diet (T) and corticosterone via drinking water (C; 80µg/ml). Four groups of dams (animal facility rearing, AFR; T treated, T; C treated, C; T and C treated, TC) and their male offspring were used in the study. Maternal care was scored throughout treatment and adult offspring were tested for: anhedonia (progressive ratio schedule); anxiety-related behaviour (approach-avoidance conflict paradigm); BDNF, dopamine and serotonin concentrations in selected brain areas. T, C and TC treatments reduced active maternal care compared to AFR. Adult TC offspring showed significantly increased anxiety- and anhedonia-related behaviours, reduced striatal and increased hypothalamic BDNF and reduced dopamine and serotonin in the prefrontal cortex and their turnover in the hippocampus. Thus, present findings support the view that neonatal variations in the functionality of the serotonergic system and of HPA axis may jointly contribute to induce emotional disturbances in adulthood.

Synaptic plasticity, but not hippocampal neurogenesis, mediated the counteractive effect of wolfberry on depression in rats(1).

Depression is a life-threatening psychiatric disorder characterized with a long-term hypercortisolemia in depressed patients. Based on this clinical feature, hypercortisolemia was mimicked in experimental animals to understand the neuropathogy of depression and to explore new therapeutic strategies. Wolfberry, also known as Lycium barbarum, is a type of common fruit produced in mainland China. Accumulated evidence has shown that the extracts from Lycium barbarum (LBP) had a wide range of neuroprotective effects in various neurogenerative models. However, the antidepressant effect of LBP on depression and its mechanism has not yet been explored. In the present study, we investigated the effects of LBP on counteracting depression using an animal model injected with moderate dose (40 mg/kg) or severe dose (50 mg/kg) of corticosterone (CORT) treatments for 14 days. The results showed that CORT significantly increased immobility time and decreased hippocampal cell proliferation. LBP treatment significantly decreased the immobility time in forced swimming test, a test for the intensity of depressive behaviors, both in 40 and 50 mg/kg CORT stressed rats. Moreover, LBP treatment restored the reduced proliferation of neuroprogentior cells in the hippocampus in 40 mg/kg CORT stressed rats and the neuronal differentiation but not the proliferation in 50 mg/kg CORT stressed rats. After ablation of adult neurogenesis with Ara-c infusion, the beneficial effect of LBP treatment in reducing immobility time was not affected in 40 and 50 mg/kg CORT stressed rats. Golgi staining and Western blotting detection showed that LBP treatment restored the reduced spine density and the decreased level of PSD-95 in the hippocampus caused by 40 and 50 mg/kg CORT, respectively, indicating enhanced synaptic plasticity in the hippocampus. The data showed a novel effect of LBP on reducing depression-like behavior and its antidepressant effect may be mediated by enhanced synaptic plasticity, but not hippocampal neurogenesis.

[Neuroprotective effect of longistyline A against corticosterone-induced neurotoxicity in PC12 cells].

This study is to investigate the protective effect of longistyline A against corticosterone-induced neurotoxicity in PC12 cells. While PC12 cells were exposed to 100 micromol x L(-1) corticosterone for 48 h, cell survival rate was reduced and lactate dehydrogenase (LDH) release increased. In parallel, corticosterone caused significant elevations of DNA fragmentation, [Ca2+]i and caspase-3 activity. However, when the PC12 cells were incubated with longistyline A (4.0, 8.0 and 16.0 micromol x L(-1)) in the presence of 100 micromol x L(-1) corticosterone for 48 h, the effects were evidently alleviated, but dose-dependent manner was not obvious. In summary, longistyline A could generate a neuroprotective effect against corticosterone-induced neurotoxicity in PC12 cells possibly by decreasing [Ca2+]i and caspase-3 activity.