CREB-BDNF Pathway Research Articles

Procyanidins Extracted from the Lotus Seedpod Ameliorate Cognitive Impairment through CREB-BDNF Pathway Mediated LTP in APP/PS1 Transgenic Mice.

Alzheimer's disease (AD) is an age-related neurodegenerative disease and is featured by cognitive impairment. Procyanidins have been shown to have a potential protective effect against neurodegenerative diseases, but the underlying mechanism is not comprehensive enough. To further investigate the effects of procyanidins from lotus seedpod (LSPC) on cognition in AD. The APP/PS1 transgenic mice were administered with LSPC (100 mg/kg body weight) for five months. The Morris water maze test was used to assess learning and memory function, the long-term potentiation (LTP) was measured, and the expressions of Aβ, pCREB/CREB and BDNF were quantified by western blot. LSPC significantly ameliorated cognitive dysfunction, reduced Aβ deposition and reversed the remarkable reduction of the phosphorylation of CREB and the expression of BDNF, and then enhanced the effect of LTP in APP/PS1 mice. These results revealed that LSPC could ameliorate cognitive impairment through the CREB-BDNF pathway that mediates the enhancement of LTP in APP/PS1 transgenic mice.

The Anxiolytic Effect of Polysaccharides from Stellariae Radix through Monoamine Neurotransmitters, HPA Axis, and ECS/ERK/CREB/BDNF Signaling Pathway in Stress-induced Male Rats

BackgroundStellaria dichotoma L. var. lanceolata Bge. is renowned for its efficacy in "clearing deficiency heat" and represents a significant traditional Chinese medicine (TCM) resource. Modern pharmacology has demonstrated the anti-anxiety effects of Stellaria dichotoma L. var. lanceolata Bge. polysaccharides (SDPs). SDPs are one of the active constituents of Stellaria dichotoma L. var. lanceolata Bge. This study presents the first extraction of SDPs and investigates their potential molecular mechanisms and anxiolytic effects that are not previously reported. MethodsFirst, SDPs were obtained by water extraction and alcohol precipitation and analyzed for their monosaccharide composition by high performance liquid chromatography (HPLC). Male SD rats were subjected to a two-week indeterminate empty bottle stress procedure and a three-day acute restraint stress procedure, during which diazepam (DZP) (1 mg/kg) and SDPs (50, 100 and 200 mg/kg, intragastrically) were administered. A number of behavioral tests, including the elevated plus maze test (EPM), the open field test (OFT) and the light/dark box test (LDB), were used to assess the anti-anxiety potential of SDPs. Serum levels of Corticosterone (CORT) and Adrenocorticotropic hormone (ACTH), as well as the levels of Dopamine (DA) and serotonin (5-HT) found in the hippocampus and frontal cortex, were quantified using commercially available enzyme-linked immunosorbent assay (ELISA) kits. In addition, protein levels of key proteins cAMP-response element binding protein (CREB), phospho-CREB (p-CREB), brain-derived neurotrophic factor (BDNF), ERK½, p-ERK½, and GAPDH expression in rat hippocampus were measured by Western blot analysis, and modulation of the endocannabinoid system was assessed by immunohistochemistry. ResultsFollowing administration of SDPs (50, 100, 200 mg/kg) and diazepam 1 mg/kg, anxiolytic activity was exhibited through an increase in the percentage of arm opening times and arm opening time of rats in the elevated plus maze. Additionally, there was an increase in the number of times and time spent in the open field center, percentage of time spent in the open box, and shuttle times in the LDB. Furthermore, tissue levels of DA and 5-HT were increased in the hippocampus and frontal cortex of rats after treatment with SDPs. In addition, SDPs significantly decreased serum levels of CORT and ACTH in rats. SDPs also effectively regulated the phosphorylation of the extracellular regulated protein kinases (ERK) and CREB-BDNF pathway in the hippocampus. Moreover, the expression levels of CB1 and CB2 proteins were heightened due to SDPs treatment in rats. ConclusionsThe study verified that SDPs alleviate anxiety in the EBS and ARS. The neuroregulatory behavior is accomplished by regulating the Monoamine neurotransmitter, HPA axis, and ECB-ERK-CREB-BDNF signaling pathway.

IL-1ra treatment prevents chronic social defeat stress-induced depression-like behaviors and glutamatergic dysfunction via the upregulation of CREB-BDNF

BackgroundProinflammatory cytokines IL-1β has been proposed to be a key mediator in the pathophysiology of mood-related disorders. However, the IL-1 receptor antagonist (IL-1ra) is a natural antagonist of IL-1 and plays a key role in the regulation of IL-1-mediated inflammation, the effects of IL-1ra in stress-induced depression has not been well elucidated. MethodsChronic social defeat stress (CSDS) and lipopolysaccharide (LPS) were used to investigate the effects of IL-1ra. ELISA kit and qPCR were used to detect IL-1ra levels. Golgi staining and electrophysiological recordings were used to investigate glutamatergic neurotransmission in the hippocampus. Immunofluorescence and western blotting were used to analyze CREB-BDNF pathway and synaptic proteins. ResultsSerum levels of IL-1ra increased significantly in two animal models of depression, and there was a significant correlation between serum IL-1ra levels and depression-like behaviors. Both CSDS and LPS induced the imbalance of IL-1ra and IL-1β in the hippocampus. Furthermore, chronic intracerebroventricular (i.c.v.) infusion of IL-1ra not only blocked CSDS-induced depression-like behaviors, but also alleviated CSDS-induced decrease in dendritic spine density and impairments in AMPARs-mediated neurotransmission. Finally, IL-1ra treatment produces antidepressant-like effects through the activation of CREB-BDNF in the hippocampus. LimitationFurther studies need to investigate the effect of IL-1ra in the periphery in CSDS-induced depression. ConclusionOur study suggests that the imbalance of IL-1ra and IL-1β reduces the expression of the CREB-BDNF pathway in the hippocampus, which dysregulates AMPARs-mediated neurotransmission, ultimately leading to depression-like behaviors. IL-1ra could be a new potential candidate for the treatment of mood disorders.

Activation of CREB-BDNF Pathway in Pyramidal Neurons in the Hippocampus Improves the Neurological Outcome of Mice with Ischemic Stroke.

Cerebral ischemia is characterized by several pathological reaction evolving over time. Hyperactivation of glutamatergic neurons is the main factor leading to excitotoxicity which potentiates oxidative stress and triggers the mechanisms of neural apoptosis after cerebral ischemia. However, it is unclear whether glutamate in the ventral hippocampal Cornus Ammonis 1 (vCA1) acts a part in neurological deficits, pain perception, anxiety, and depression induced by ischemic stroke. We investigated the effects of chemogenetic inhibition or activation of vCA1 pyramidal neurons which are mainly glutamatergic neurons on sequelae induced by cerebral ischemia. Our results revealed that inhibition of vCA1 pyramidal neurons by chemogenetics alleviated neurological deficits, pain perception, anxiety, and depression caused by cerebral ischemia in mice, but activation of vCA1 pyramidal neurons had limited effects. Moreover, we found that stroke was accompanied by decreased levels of cAMP-response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in vCA1, which are modulated by glutamate. In this study, overexpression of CREB protein in pyramidal neurons in vCA1 by AAV virus significantly upregulated the content of BDNF and ameliorated the dysfunction induced by ischemic stroke. Our results demonstrated activation of the CREB-BDNF pathway in vCA1 pyramidal neurons significantly improved neurological deficits, pain perception, anxiety, and depression induced by ischemic stroke.

Abstract P234: Arterial Hypertension, Insulin Resistance And Depressive-like Behavior In Crtc1 -deficient Mice

Background: Epidemiological evidence has demonstrated a link between cardiovascular disease, metabolic syndrome and depression. Whether this association is causal and what mechanisms may be involved is still unknown. Studies in humans and mice suggest that alterations of the CREB-BDNF pathway can contribute to the development of both, eating disorders and major depressive disorders. Mice deficient in the CREB-regulated transcriptional coactivator 1 (Crtc1) have been shown to become overweight and display depressive-like behavior. Here, we investigated whether Crtc1 -deficient mice concomitantly exhibit a hypertensive, insulin resistant and depression-like phenotype. Methods: Mean arterial blood pressure and heart rate were measured by radiotelemetry in unrestrained Crtc1 -deficient mice (KO) and wildtype littermates (WT). Renal renin expression was quantified by qPCR. Insulin resistance was determined by the i.p. glucose tolerance test, and depressive-like behavior was assessed by the soiled bedding preference test. Results: Crtc1 -deficient mice had higher arterial blood pressures (dark: KO 117±2 mm Hg, WT 107±2 mm Hg, p<0.05; light: KO 102±2 mm Hg, WT 94±2 mm Hg, p<0.05, 1-way ANOVA, n=8-11) and heart rates (dark: KO 593±11 bpm, WT 596±7 bpm; light: KO 529±12 bpm, WT 494±8 bpm, p<0.05, 1-way ANOVA, n=8-11). Relative renin mRNA expression was not different between genotypes (KO 0.86±0.07, WT 1.00±0.10, n=10). Glucose tolerance was significantly impaired in Crtc1 -deficient mice (maximum plasma glucose concentrations KO 423±27 mg/dl, WT 295±27 mg/dl, p<0.0001, 2-way ANOVA, n=9). In the soiled bedding preference test, male Crtc1 -deficient mice exhibited a lack of preference for female-soiled bedding over clean bedding (female vs. clean KO 75.3±11.2 s vs 79.0±11.0 s, WT 119.5±13.5 s vs. 51.5±10.5 s, n=2-3). Conclusions: Crtc1 might be a molecular component of a pathway that connects arterial hypertension, metabolic syndrome and depression.

The combination of HT-ac and HBET improves the cognitive and learning abilities of heat-stressed mice by maintaining mitochondrial function through the PKA-CREB-BDNF pathway.

The aim was to investigate whether the combination of hydroxytyrosol acetate (HT-ac) and ethyl β-hydroxybutyrate (HBET) can improve the cognition of heat-stressed mice, meanwhile exploring the mechanism of action. Mice were divided into 5 groups: control, heat-stressed, HT-ac, HBET, and HT-ac + HBET. Mice were gavaged for 21 days and exposed to heat (42.5 ± 0.5 °C, RH 60 ± 10%, 1 h day-1) on days 15-21, except for the control group. Results showed that the combination of HT-ac + HBET improved the cognitive and learning abilities of heat-stressed mice, which were tested by Morris water maze, shuttle box, and jumping stage tests. The combination of HT-ac + HBET maintained the integrity of neurons and mitochondria of heat-stressed mice. Likewise, this combination increased the mitochondrial membrane potential, the ATP content, the expression of phosphorylated PKA, BDNF, phosphorylated CREB and Bcl-2, and decreased the expression of Bax, caspase-3, and intracytoplasmic Cyt C in heat-stressed mice.

Role of the cAMP–PKA–CREB–BDNF pathway in abnormal behaviours of serotonin transporter knockout mice

Serotonin transporter gene-linked polymorphic region polymorphisms are associated with anxiety, neuroticism, affective disorders and vulnerability to stressful life events; however, the relevant physiological mechanisms are not well understood. Serotonin transporter knockout mice have been widely used as a model of allelic variation of serotonin transporter function in humans; herein, wild-type mice and heterozygous and homozygous knockout mice models were established to explore the behavioural changes related to different genotypes and the possible physiological mechanisms. Behavioural changes were assessed using behavioural tests, namely, elevated plus maze, open field, Morris water maze and rotarod tests. Serum indicators were detected using the enzyme-linked immunosorbent assay. Compared with wild-type mice, homozygous mice showed significant anxiety-like behaviours in the plus maze and open field tests; conversely, anxiety-like behaviours in heterozygous mice were less pronounced. Homozygous mice also showed cognitive impairment and motor inhibition in the Morris water maze and rotarod tests. Serotonin levels decreased in both heterozygous and homozygous mice, and 5-hydroxytryptophan, protein kinase A, adenylyl cyclase, cyclic adenosine monophosphate response element-binding protein and brain-derived neurotrophic factor levels were lower in homozygous mice than in wild-type and heterozygous mice, whereas no statistical differences were found between wild-type and heterozygous mice. Additionally, there was a correlation between serological and behavioural indicators. This study provided experimental evidence that the cyclic adenosine monophosphate–protein kinase A–cyclic adenosine monophosphate response element-binding protein–brain-derived neurotrophic factor pathway may be involved in the regulation of polymorphism to stress and enriched the behavioural and physiological characteristics of serotonin transporter knockout mice.

1,3-Dicaffeoylquinic Acid as an Active Compound of Arctium lappa Root Extract Ameliorates Depressive-Like Behavior by Regulating Hippocampal Nitric Oxide Synthesis in Ovariectomized Mice.

Menopause is a risk factor for depression. Although 1,3-dicaffeoylquinic acid (1,3-diCQA), a phenolic compound in Arctium lappa (A. lappa) root, has various health benefits, its effects on menopausal depression remain to be determined. Therefore, this study investigates the antidepressant-like effects of 1,3-diCQA from an A. lappa root extract (AE) and the associated molecular mechanisms. Ovariectomized (OVX) mice were orally administered AE for 20 weeks, following which depression-like behaviors were assessed. Although the mice exhibited depression-like behaviors, AE administration mitigated these symptoms by activating the ERK–CREB–BDNF pathway and increasing nNOS levels in the hippocampus. Similarly, a significant increase in nNOS-derived NO production and activation of the ERK–CREB–BDNF pathway was observed in the primary hippocampal neurons. Although this stimulatory effect of 1,3-diCQA was not significantly affected by treatment with estrogen receptor agonist or antagonist, it was inhibited by 7-NI, an nNOS inhibitor. Moreover, mice treated with 1,3-diCQA exhibited a marked improvement in their forced swimming test and tail suspension test immobility, while pretreatment with 7-NI reversed the antidepressant-like effects of 1,3-diCQA. Our results suggest that 1,3-diCQA regulates nNOS in an estrogen recepters-independent manner to increase NO production in OVX mice.

Lindera glauca Blume ameliorates amyloid-β1-42-induced memory impairment in mice with neuroprotection and activation of the CREB-BDNF pathway

BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder presenting cognitive decline accompanied by deposits of amyloid-β (Aβ) and tau hyperphosphorylation. Without current treatment to AD, many studies suggested diverse approaches, one of which was herbal medicine and its active compounds. Very few studies have examined the effect of Lindera glauca Blume (L. glauca) in models of degenerative disease despite the attention that it received as a novel potential treatment source. We examined the efficacy of L. glauca in a mouse model of AD, which was induced by intrahippocampal injection of Aβ1–42. MethodsMice were intrahippocampally infused with Aβ1–42 and were orally administered ethanolic extract of L.glauca before and after infusion for 21 days. Y-maze test and Morris water maze was conducted to assess memory impairment. Immunohistochemistry and western blot analysis were performed to assess the effect of L. glauca administration on pathological changes in mice. ResultsL. glauca exhibited beneficial effects in spatial and reference learning as shown in increased time spent in the target quadrant in Morris water maze and increased spontaneous alternation in Y-maze. At the same time, decline of Aβ burden and phosphorylated tau were observed in the hippocampus of L. glauca-treated mouse under intrahippocampal injection of Aβ1–42. The results corresponded with amelioration of the decreased neuronal marker, neuronal-specific nuclear protein (NeuN) and attenuation of the increased reactive astrocyte marker, glial fibrillary acidic protein (GFAP) levels in hippocampus. Additionally, 21-day treatment with L. glauca inhibited downregulation of phosphorylated cAMP response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) levels. ConclusionL. glauca improves behavioral deficits induced by Aβ1–42 and inhibits both Aβ- and tau-related pathological changes, stimulating neuroprotection mediated by CREB activation. L. glauca can be suggested as a new candidate for treatment of AD.

Scrophularia buergeriana Extract (Brainon) Improves Scopolamine-Induced Neuronal Impairment and Cholinergic Dysfunction in Mice through CREB-BDNF Signaling Pathway

We evaluated the effectiveness of Scrophularia buergeriana extract (Brainon) on cognitive dysfunction and determined its underlying mechanisms in a scopolamine (SCO)-treated mouse model of memory impairment. Brainon treatment for 28 days ameliorated the symptoms of memory impairment as indicated by the results of both passive avoidance performance and the Morris water mazes. Brainon lowered acetylcholinesterase activity and raised acetylcholine levels in the hippocampus. The treatment elevated the protein levels of brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP response element-binding (CREB). Additionally, the excessive generation of SCO-induced reactive oxygen species (ROS) and subsequent oxidative stress were suppressed by the enhancement of superoxide dismutase (SOD)-1 and SOD-2 proteins. mRNA levels of upregulated interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, as well as the apoptotic protein Bcl-2-associated X protein (Bax), cleaved caspase-9, and cleaved poly adenosine diphosphate-ribose polymerase (PARP) expression after SCO injection were downregulated by Brainon treatment. Collectively, these findings suggested that Brainon possesses anti-amnesic effects through the CREB-BDNF pathway. Moreover, it exerted antioxidant, anti-inflammatory, and anti-apoptotic effects in SCO-induced mice exhibiting cognitive impairment and memory loss.

Hesperidin Interacts With CREB-BDNF Signaling Pathway to Suppress Pentylenetetrazole-Induced Convulsions in Zebrafish.

Hesperidin (3,5,7-trihydroxyflavanone 7-rhamnoglucoside) is a β-7-rutinoside of hesperetin (4′-methoxy-3′,5,7-trihydroxyflavanone), abundantly found in citrus fruits and known to interact with various cellular pathways to show a variety of pharmacological effects. The present study was envisaged to understand the anticonvulsant effect of hesperidin in a zebrafish model of pentylenetetrazole (PTZ)-induced convulsions, with the support of in silico docking. Healthy zebrafish larvae were preincubated with hesperidin (1, 5, and 10 µM) for 1 h, before PTZ exposure. Hesperidin treatment significantly increased the seizure latency and minimized PTZ-induced hyperactive responses. A significant reduction in c-fos expression further supported the suppression of neuronal excitation following hesperidin incubation in the larvae exposed to PTZ. The treatment also modulated larval bdnf expression and reduced the expression of il-10. The results of in vivo studies were further supported by in silico docking analysis, which showed the affinity of hesperidin for the N-methyl-d-aspartate receptor, the gamma-aminobutyric acid receptor, Interleukin 10 and the TrkB receptor of brain-derived neurotrophic factor. The results concluded that hesperidin suppresses PTZ-mediated seizure in zebrafish larvae through interaction with the central CREB–BDNF pathway.

Effect of Puyu Capsules on behavior,HPA axis and CREB-BDNF pathway expression in hippocampus of depressed mice

This study aimed to investigate the antidepressant effects of Puyu Capsules and its potential mechanism. The antidepressant activity of Puyu Capsules was evaluated by forced swimming test(FST) and tail suspension test(TST) after subchronic administration in mice. Next, the mice were subjected to a chronic unpredictable stress(CUS) protocol for a period of 28 d to induce depressive-like behaviors. Then, a sucrose preference test, open-field test and novelty-suppressed feeding test were performed to evaluate the antidepressant effect of Puyu Capsules. After the behavioral test, the adrenal index was calculated; the levels of serum corticosterone(CORT) and adrenocorticotropic hormone(ACTH) were detected by enzyme-linked immunosorbent assay(ELISA); the levels of glucocorticoid receptor(GR), protein expression of brain-derived neurotrophic factor(BDNF), and the ratio of phosphorylated cAMP response element binding protein(CREB) to total CREB were detected by Western blot to explore the antidepressant function and mechanism of Puyu Capsules. The results suggested that Puyu Capsules had significant antidepressant effects on both the depression model and CUS model. At the same time, the drug could prevent the change of adrenal index induced by CUS and reverse the abnormal activation of CORT and ACTH in the serum of depressed mice. Finally, Puyu Capsules could also reverse the lower expression of pCREB, BDNF and GR in the hippocampus of CUS mice. In conclusion, Puyu Capsules produced significant antidepressant effects, and the mechanism was closely related to hypothalamic pituitary adrenal(HPA) axis activity, GR and CREB-BDNF pathway expression.

Dietary supplementation with Salvia officinalis L. and aerobic training attenuates memory deficits via the CREB-BDNF pathway in amyloid beta- injected rats

Dietary supplementation with Salvia officinalis L. and aerobic training attenuates memory deficits via the CREB-BDNF pathway in amyloid beta- injected rats

Dietary Flavonoids Interaction with CREB-BDNF Pathway: An Unconventional Approach for Comprehensive Management of Epilepsy

cAMP response element binding protein (CREB) is a key transcriptional regulator that regulates the transcription of genes related with neuronal differentiation, synaptic plasticity, learning and memory. Brain derived neurotrophic factor (BDNF), is a CREB dependent gene which plays a pivotal role in the pathogenesis of epilepsy and central comorbid condi-tions associated with epilepsy. However, the beneficial or detrimental consequences of CREB-BDNF activation on the in-duction and/or progression of seizures depend specifically on the region of brain involved and the time of activation. The bi-oactive molecules that alter the activity of CREB in a way to have specialized effects in different brain regions and neural cir-cuits involved could potentially be utilized for therapeutic purposes. Flavonoids are the polyphenolic compounds which lead to phosphorylation of CREB in the hippocampus, followed by increase in extracellular signal regulated kinase (ERK) and BDNF. Several members of flavonoid family have also showed suppression of epileptic seizures via interaction with CREB/BDNF pathway. Moreover, epilepsy is often accompanied by a number of behavioural and psychological comorbid conditions that further gets aggravated by the use of conventional antiepileptic drug therapy. Multiple studies have also sup-ported the beneficial effects of flavonoids in cognitive and memory impairments by upregulation of CREB-BDNF pathway. The current review is an attempt to collate the available preclinical and clinical studies to establish the therapeutic potential of various dietary flavonoids in comprehensive management of epilepsy with relation to CREB-BDNF pathway.

P1‐207: NEUROPROTECTIVE EFFECT OF POLYPHENOLIC RICH EXTRACT OF AEGLE MARMELOS IN ALZHEIMER'S DISEASE LIKE PATHOLOGY VIA MAINTAINING OXIDATIVE BALANCE AND ACETYLCHOLINE LEVEL

Alzheimer's disease (AD) is a progressive neurodegenerative mental disorder amongst aging people which is associated with impairment in cognitive functions. Free radicals as well as cholinergic deficit neuron within nucleus basalis magnocellularis further attributed with aggregation of β amyloid contributes as an essential hallmark in AD. Hydroethanolic extract of Aegle marmelos (HEAM) fruit pulp was quantitatively estimated for individual polyphenolic compounds by HPLC-DAD analysis which exhibited the presence of rich amount of chlorogenic acid, protocatechuic acid and caffeic acid. In present study we estimated the neuropharmacological potential of HEAM on hippocampal memory deficit induced by scopolamine injection in rodents. Swiss albino mice were orally preadministered with HEAM (200, 400, and 600 mg/kg) and Donepezil (1mg/kg) for 21days. To assess cognitive function, Elevated plus maze and Hebbs William maze task were performed for consecutively 2 days. Homogenized brain hippocampus was used for enzymatic antioxidant level, AChE inhibitory activity determination as well as gene expression determination. Scopolamine injection elevated the TL (transfer latency) and TRC (Time taken to reach the reward chamber), which were significantly reversed by pretreatment with HEAM in a dose dependent manner. In addition, acetylcholinesterase activity, enzymatic and nonenzymatic oxidant-antioxidant balance level, neurogenesis and their concerning pathways were markedly distorted by scopolamine in hippocampal region, whereas those impairments were significantly ameliorated with HEAM pretreatment. Brain derived neurotrophic factor (BDNF) and phosphorylated cAMP response element-binding protein (pCREB) gene expression were accelerated by HEAM preadminstration. Molecular docking studies exhibited the highest binding affinity of chlorogenic acid towards acetylcholinesterase receptor with docking score -8.13. The current findings advocates that HEAM could be a strong neuroprotective agent against cognitive deficit associated with AD and its possible underlying mechanism might be improving brain cholinergic status through CREB-BDNF pathway as well as oxidative balance.

Additive antidepressant-like effects of fasting with β-estradiol in mice.

Our recent study has shown that acute fasting produces antidepressant‐like effects in male mice. However, there is little evidence regarding the antidepressant‐like effects of acute fasting in female mice. Moreover, it is not yet clear whether estrogen produces additive effects with acute fasting. Therefore, this study aims to investigate the antidepressant‐like effects of acute fasting plus estrogen treatment. In this study, the acute fasting produced antidepressant‐like effects in female mice and the antidepressant‐like effects of 9 hours fasting with those of β‐estradiol (E2) were additive. Activity of the cyclic adenosine monophosphate (cAMP) response element‐binding protein (CREB)‐brain‐derived neurotrophic factor (BDNF) pathway in the prefrontal cortex (PFC) and hippocampus (HP) was increased, as well as neurogenesis in the subgranular zone of the hippocampus. Serum ghrelin and estrogen were also increased by fasting plus E2. Furthermore, RNA‐seq analysis indicated that fasting and E2 co‐regulate similar gene expression pathways, underlying similar neurological functions. Taken together, these data suggest that E2 produces additive antidepressant‐like effects with fasting by activating the CREB‐BDNF pathway in the PFC and HP. Genome‐wide transcriptome mapping suggests that fasting may be used as an adjunct to estrogen replacement therapy for the treatment of depression associated with reduced estrogen function.

Inhibition of Necroptosis Rescues SAH-Induced Synaptic Impairments in Hippocampus via CREB-BDNF Pathway.

Subarachnoid hemorrhage (SAH) is a devastating form of stroke that leads to incurable outcomes. Increasing evidence has proved that early brain injury (EBI) contributes mostly to unfavorable outcomes after SAH. A previously unknown mechanism of regulated cell death known as necroptosis has recently been reported. Necrostatin-1 (nec-1), a specific and potent inhibitor of necroptosis, can attenuate brain impairments after SAH. However, the effect of nec-1 on the hippocampus and its neuroprotective impact on synapses after SAH is not well understood. Our present study was designed to investigate the potential effects of nec-1 administration on synapses and its relevant signal pathway in EBI after SAH. Nec-1 was administrated in a rat model via intracerebroventricular injection after SAH. Neurobehavior scores and brain edema were detected at 24 h after SAH occurred. The expression of the receptor-interacting proteins 1 and 3 (RIP1and3) was examined as a marker of necroptosis. We used hematoxylin and eosin staining, Nissl staining, silver staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) to observe the morphological changes in hippocampus. The protective effect of nec-1 on synapses was evaluated using western blotting and electron microscopy and Western blotting was used to detect the cAMP responsive element binding (CREB) protein and brain-derived neurotrophic factor (BDNF), and we used transmission electron microscopy and TUNEL to detect the protective effects of nec-1 when a specific inhibitor of CREB, known as 666-15, was used. Our results showed that in the SAH group, RIP1, and RIP3 significantly increased in the hippocampus. Additionally, injection of nec-1 alleviated brain edema and improved neurobehavior scores, compared with those in the SAH group. The damage to neurons was attenuated, and synaptic structure also improved in the Sham+nec-1 group. Furthermore, nec-1 treatment significantly enhanced the levels of phospho-CREB and BDNF compared with those in the SAH group. The protective effect of nec-1 could hindered by 666-15. Thus, nec-1 mitigated SAH-induced synaptic impairments in the hippocampus through the inhibition of necroptosis in connection with the CREB-BDNF pathway. This study may provide a new strategy for SAH patients in clinical practice.

Ingestion of Bifidobacterium longum subspecies infantis strain CCFM687 regulated emotional behavior and the central BDNF pathway in chronic stress-induced depressive mice through reshaping the gut microbiota.

Increasing evidence points to the effect of the gut microbiota on central nervous system functions. Supplementation of certain microbial strains has been demonstrated to alleviate depressive behaviors and neurological abnormalities. This study took the approach to screen for an anti-depressive Bifidobacterium longum strain from fourteen candidates and systematically verified its effect in a chronic stress-induced depression mice model. B. longum subsp. infantis strain CCFM687 could significantly enhance the biosynthesis of 5-hydroxytryptamine (5-HTP) in vitro in RIN14B cells through up-regulation of the Tph1 gene expression. Administration of CCFM687 in mice significantly improved the scores in behavioral tests and increased the level of 5-HTP and serotonin (5-HT) in the prefrontal cortex (PFC) of the brain. The brain-derived neurotrophic factor (BDNF) in the PFC was also increased, possibly through the 5-HT1A-CREB-BDNF pathway. In addition, CCFM687 alleviated the hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis response and accordingly reversed the peripheral inflammation status. Moreover, the stress-induced structural and functional dysbiosis of the gut microbiome was improved by CCFM687, through increased alpha diversity and abundance of butyrate-producing bacteria, in conjunction with inhibition of pathogenic gene expression. In summary, these results indicate that supplementation of B. longum subsp. infantis strain CCFM687 may prevent the onset of depression from chronic stress, and RIN14B could serve as an efficient cell model for rapid screening of anti-depressive probiotics.

NNOS-CAPON interaction mediates amyloid-β-induced neurotoxicity, especially in the early stages.

SummaryIn neurons, increased protein–protein interactions between neuronal nitric oxide synthase (nNOS) and its carboxy‐terminal PDZ ligand (CAPON) contribute to excitotoxicity and abnormal dendritic spine development, both of which are involved in the development of Alzheimer's disease. In models of Alzheimer's disease, increased nNOS–CAPON interaction was detected after treatment with amyloid‐β in vitro, and a similar change was found in the hippocampus of APP/PS1 mice (a transgenic mouse model of Alzheimer's disease), compared with age‐matched background mice in vivo. After blocking the nNOS–CAPON interaction, memory was rescued in 4‐month‐old APP/PS1 mice, and dendritic impairments were ameliorated both in vivo and in vitro. Furthermore, we demonstrated that S‐nitrosylation of Dexras1 and inhibition of the ERK–CREB–BDNF pathway might be downstream of the nNOS–CAPON interaction.

MAP kinase p38 is a novel target of CacyBP/SIP phosphatase

Mitogen-activated protein (MAP) kinases are important players in cellular signaling pathways. Recently, it has been shown that CacyBP/SIP serves as a phosphatase for one of the MAP kinases, ERK1/2. Through dephosphorylation of this kinase CacyBP/SIP modulates the transcriptional activity of Elk-1 and the activity of the CREB-BDNF pathway. In this work, using NB2a cell lysate and recombinant proteins, we show that CacyBP/SIP binds and dephosphorylates another member of the MAP kinase family, p38. Analysis of recombinant full-length CacyBP/SIP and its three major domains, N-terminal, middle CS and C-terminal SGS, indicates that the middle CS domain is responsible for p38 dephosphorylation. Moreover, we show that CacyBP/SIP might be implicated in response to oxidative stress. Dephosphorylation of phospho-p38 by CacyBP/SIP in NB2a cells treated with hydrogen peroxide is much more effective than in control ones. In conclusion, involvement of CacyBP/SIP in the regulation of p38 kinase activity, in addition to that of ERK1/2, might point to the function of CacyBP/SIP in pro-survival and pro-apoptotic pathways.