Effect of electroacupuncture on proBDNF/mBDNF and synaptic plasticity in rats with learning and memory impairment after cerebral ischemia-reperfusion. / ç”µé’ˆå¯¹è„‘ç¼ºè¡€å†çŒæ³¨å­¦ä¹ è®°å¿†éšœç¢å¤§é¼ æµ·é©¬è„‘æºæ€§ç¥žç»è¥å »å› å­è½¬åŒ–å’Œçªè§¦å¯å¡‘æ€§çš„å½±å“.

OBJECTIVES: To observe the effect of electroacupuncture (EA) at "Baihui" (GV20) and "Shenting" (GV24) on the rats' behavior and the transforming precursor of brain-derived neurotrophic factor (proBDNF) into mature brain-derived neurotrophic factor (mBDNF) in the hippocampus of rats with learning and memory impairment induced by cerebral ischemia-reperfusion (IR), so as to explore its mechanisms underlying improvement of learning and memory ability. METHODS: SD rats were randomly divided into blank, sham operation, model, and EA groups, with 6 rats in each group. The model of IR was established by occlusion of the middle cerebral artery. EA (1 Hz/20 Hz) was applied to GV24 and GV20 for 30 min, once daily for 14 days. The neurological function was evaluated according to the Zea Longa's score criteria 24 h after modeling and after intervention. Morris water maze test was used to detect the learning and memory function of the rats. TTC staining was used to evaluate the cerebral infarction volume on the affected side. The protein expression levels of proBDNF, mBDNF, tissue plasminogen activator (tPA), tyrosine kinase receptor B (TrkB) and p75 neurotrophin receptor (p75NTR) in hippocampal tissue were detected by Western blot. RESULTS: Compared with the sham operation group, the neurological function score, the percentage of cerebral infarction volume and the expression levels of proBDNF and p75NTR protein in hippocampus were increased (P<0.01), while the times of crossing the original platform and the total distance in the target quadrant, the expression levels of mBDNF, TrkB and tPA protein and the ratio of mBDNF/proBDNF were decreased (P<0.01, P<0.05) in the model group. Compared with the model group, the neurological function score, the percentage of cerebral infarction volume, and the expression levels of proBDNF and p75NTR protein in hippocampus were decreased (P<0.01, P<0.05), while the times of crossing the original platform, the total distance in the target quadrant, and the expression levels of mBDNF, TrkB and tPA protein and the ratio of mBDNF/proBDNF were increased (P<0.05, P<0.01) in the EA group. CONCLUSIONS: EA can alleviate learning and memory impairment in IR rats, which may be related to its function in up-regulating the expression of tPA protein and promoting the transformation of proBDNF to mBDNF, thus improving the synaptic plasticity.

Deciphering the antidepressant effects of Rosa damascena essential oil mediated through the serotonergic synapse signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Rosa damascena is an ancient plant with significance in both medicine and perfumery that have a variety of therapeutic properties, including antidepressant, anti-anxiety, and anti-stress effects. Rose damascena essential oil (REO) has been used to treat depression, anxiety and other neurological related disorders in Iranian traditional medicine. However, its precise mechanism of action remains elusive. AIM OF THE STUDY: The aim of this study was to investigate the impact and mechanism underlying the influence of REO on chronic unpredictable mild stress (CUMS) rats. MATERIALS AND METHODS: Gas chromatography-mass spectrometry (GC-MS) technique coupling was used to analyze of the components of REO. A CUMS rat model was replicated to assess the antidepressant effects of varying doses of REO. This assessment encompassed behavioral evaluations, biochemical index measurements, and hematoxylin-eosin staining. For a comprehensive analysis of hippocampal tissues, we employed transcriptomics and incorporated weighting coefficients by means of network pharmacology. These measures allowed us to explore differentially expressed genes and biofunctional pathways affected by REO in the context of depression treatment. Furthermore, GC-MS metabolomics was employed to assess metabolic profiles, while a joint analysis in Metscape facilitated the construction of a network elucidating the links between differentially expressed genes and metabolites, thereby elucidating potential relationships and clarifying key pathways regulated by REO. Finally, the expression of relevant proteins in the key pathways was determined through immunohistochemistry and Western blot analysis. Molecular docking was utilized to investigate the interactions between active components and key targets, thereby validating the experimental results. RESULTS: REO alleviated depressive-like behavior, significantly elevated levels of the neurotransmitter 5-hydroxytryptamine (5-HT), and reduced hippocampal neuronal damage in CUMS rats. This therapeutic effect may be associated with the modulation of the serotonergic synapse signaling pathway. Furthermore, REO rectified metabolic disturbances, primarily through the regulation of amino acid metabolic pathways. Joint analysis revealed five differentially expressed genes (EEF1A1, LOC729197, ATP8A2, NDST4, and GAD2), suggesting their potential in alleviating depressive symptoms by modulating the serotonergic synapse signaling pathway and tryptophan metabolism. REO also modulated the 5-HT2A-mediated extracellular regulated protein kinases-cAMP-response element binding protein-brain-derived neurotrophic factor (ERK-CREB-BDNF) pathway. In addition, molecular docking results indicated that citronellol, geraniol and (E,E)-farnesol in REO may serve as key active ingredients responsible for its antidepressant effects. CONCLUSIONS: This study is the first to report that REO can effectively alleviate CUMS-induced depression-like effects in rats. Additionally, the study offers a comprehensive understanding of its intricate antidepressant mechanism from a multi-omics and multi-level perspective. Our findings hold promise for the clinical application and further development of this essential oil.

Effect of 2-Week Naringin Supplementation on Neurogenesis and BDNF Levels in Ischemia-Reperfusion Model of Rats.

BACKGROUND: Ischemic stroke is the leading cause of mortality and disability worldwide with more than half of survivors living with serious neurological sequelae; thus, it has recently attracted a lot of attention in the field of medical study. PURPOSE: The aim of this study was to determine the effect of naringin supplementation on neurogenesis and brain-derived neurotrophic factor (BDNF) levels in the brain in experimental brain ischemia-reperfusion. STUDY DESIGN: The research was carried out on 40 male Wistar-type rats (10-12 weeks old) obtained from the Experimental Animals Research and Application Center of Selçuk University. Experimental groups were as follows: (1) Control group, (2) Sham group, (3) Brain ischemia-reperfusion group, (4) Brain ischemia-reperfusion + vehicle group (administered for 14 days), and (5) Brain ischemia-reperfusion + Naringin group (100 mg/kg/day administered for 14 days). METHODS: In the ischemia-reperfusion groups, global ischemia was performed in the brain by ligation of the right and left carotid arteries for 30 min. Naringin was administered to experimental animals by intragastric route for 14 days following reperfusion. The training phase of the rotarod test was started 4 days before ischemia-reperfusion, and the test phase together with neurological scoring was performed the day before and 1, 7, and 14 days after the operation. At the end of the experiment, animals were sacrificed, and then hippocampus and frontal cortex tissues were taken from the brain. Double cortin marker (DCX), neuronal nuclear antigen marker (NeuN), and BDNF were evaluated in hippocampus and frontal cortex tissues by Real-Time qPCR analysis and immunohistochemistry methods. RESULTS: While ischemia-reperfusion increased the neurological score values, DCX, NeuN, and BDNF levels decreased significantly after ischemia in the hippocampus and frontal cortex tissues. However, naringin supplementation restored the deterioration to a certain extent. CONCLUSION: The results of the study show that 2 weeks of naringin supplementation may have protective effects on impaired neurogenesis and BDNF levels after brain ischemia and reperfusion in rats.

Interaction of aerobic exercise and crocin improves memory, learning and hypocampic tau and neurotrophins gene expression in rats treated with trimethytin as a model of Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is characterized by progressive cognitive decline and a reduction in hippocampal neurotrophins, in which trimethytin (TMT) infusion causes tangles and neuronal dysfunction, creating an AD-like model in rats. Previous studies have demonstrated that crocin, which has anti-inflammatory properties, can enhance learning, memory acquisition, and cognitive behavior. This study aimed to assess the combined impact of aerobic exercise and crocin on memory, learning, and hippocampal Tau and neurotrophins gene expression in AD-like model rats. METHODS: Forty male Sprague Dawley rats were randomly divided into five groups: (1) healthy control, (2) Alzheimer's control, (3) endurance training, (4) crocin consumption, and (5) endurance training + crocin. Alzheimer's induction was achieved in groups 2-5 through intraperitoneal injection of 8 mg/kg TMT. Rats in groups 3 and 5 engaged in treadmill running three sessions per week, 15-30 min per session, at a speed of 15-20 m/min for eight weeks, and groups 4 and 5 received daily crocin supplementation of 25 mg/kg. RESULTS: Alzheimer's induction with TMT showed significant reduction in memory, learning, NGF, BDNF, and TrkB gene expression, and increase in tau gene expression (all p < 0.05). Notably, endurance training and crocin consumption separately significantly increased memory, learning, NGF, BDNF, and TrkB gene expression while significantly decreasing tau gene expression (all p < 0.05). Importantly, combined endurance training with crocin yielded the most profound effects on memory (p = 0.001), NGF (p = 0.002), BDNF (p = 0.001), and TrkB (p = 0.003) gene expression (p < 0.005), as well as a reduction in tau gene expression (p = 0.001). CONCLUSION: These findings underscore the possible impact of endurance training, particularly when coupled with crocin, on enhancing memory, learning, and neurotrophin gene expression and reducing tau gene expression in Alzheimer's rats. These results highlight the possibility of synergistic interventions for improved therapeutic outcomes.

Environmental enrichment accentuates glucose-induced feeding suppression and glial cell line-derived neurotrophic factor gene expression in the hypothalamus of mice.

The hypothalamus controls food intake by integrating nutrient signals, of which one of the most important is glucose. Consequently, impairments in hypothalamic glucose-sensing mechanisms are associated with hyperphagia and obesity. Environmental enrichment (EE) is an animal housing protocol that provides complex sensory, motor, and social stimulations and has been proven to reduce adiposity in laboratory mice. However, the mechanism by which EE promotes adiposity-suppressing effect remains incompletely understood. Neurotrophic factors play an important role in the development and maintenance of the nervous system, but they are also involved in the hypothalamic regulation of feeding. Brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) are expressed in the hypothalamus and their expression is stimulated by glucose. EE is associated with increased expression of Bdnf mRNA in the hypothalamus. Therefore, we hypothesized that EE potentiates the anorectic action of glucose by altering the expression of neurotrophic factor genes in the hypothalamus. Male C57BL/6 mice were maintained under standard or EE conditions to investigate the feeding response to glucose and the associated expression of feeding-related neurotrophic factor genes in the hypothalamus. Intraperitoneal glucose injection reduced food intake in both control and EE mice with a significantly greater reduction in the EE group compared to the control group. EE caused a significantly enhanced response of Gdnf mRNA expression to glucose without altering basal Gdnf mRNA expression and Bdnf mRNA response to glucose. These findings suggest that EE enhances glucose-induced feeding suppression, at least partly, by enhancing hypothalamic glucose-sensing ability that involves GDNF.

Neuroprotective effect of isovaleraldehyde accompanied with upregulation of BDNF and CREB phosphorylation via the PKA pathway.

Recently, the number of patients diagnosed with dementia has increased. The World Health Organization (WHO) estimates that 50 million patients suffer from dementia. Although several therapeutic strategies have been proposed, currently, there is no curative approach for treating dementia. Neurodegeneration is an irreversible process. As this disease gradually progresses over 15-20 years, a low-cost and sustainable method for preventing these diseases is desired. Cacao nib is consumed in many countries, and a recent clinical study indicated that cocoa intake upregulates brain-derived neurotrophic factor (BDNF), which plays a significant role in memory formation and neuronal cell survival. In the present study, neural cells were treated with cacao nib extract or the 17 characteristic components of cacao nib. Treatment with Cacao nib extract upregulates BDNF mRNA expression. In addition, cacao nib extract elicits the phosphorylation of cAMP-response-element-binding protein (CREB), which regulates the transcription of BDNF. Among the 17 species screened, isovaleraldehyde (IVA), also known as an aroma component of cacao nibs extract, improved BDNF mRNA expression without SH-SY5Y cell toxicity. IVA also promoted CREB phosphorylation through a cAMP-dependent protein kinase (PKA)-dependent mechanism. In conclusion, IVA could be responsible for the BDNF upregulation effect of cacao nib, and IVA upregulated BDNF expression via the PKA-CREB axis.

Azadiradione up-regulates the expression of parvalbumin and BDNF via Ube3a.

Azadiradione is a small bioactive limonoid found in the seed of Azadirachta Indica, an Indian medicinal plant commonly known as Neem. Recently, it has been shown to ameliorate the disease pathology in fly and mouse model of Huntington's disease by restoring impaired proteostasis. Here we report that the azadiradione could be involved in modulating the synaptic function through increased expression of Ube3a, a dual function protein having ubiquitin ligase and co-activator functions and associated with Angelman syndrome and autism. Treatment of azadiradione to HT22 hippocampal cell line and in adult mice induced the expression of Ube3a as well as two important synaptic function and plasticity regulating proteins, parvalbumin and brain-derived neurotropic factor (BDNF). Interestingly, another synaptic plasticity modulating protein Arc (activity-regulated cytoskeletal associated protein) was down-regulated by azadiradione. Partial knockdown of Ube3a in HT22 cell abrogated azadiradione induced expression of parvalbumin and BDNF. Ube3a-maternal deficient mice also exhibited significantly decreased expression of parvalbumin and BDNF in their brain and treatment of azadiradione in these animals did not rescue the altered expression of either parvalbumin or BDNF. These results indicate that azadiradione-induced expression of parvalbumin and BDNF in the brain is mediated through Ube3a and suggest that azadiradione could be implicated in restoring synaptic dysfunction in many neuropsychiatric/neurodegenerative disorders.

Mechanism of effects of electroacupuncture on memory and cognitive impairment in offspring rats with perinatal nicotine exposure. / ç”µé’ˆå¯¹å›´äº§æœŸå°¼å¤ä¸æš´éœ²å­ä»£å¤§é¼ è®°å¿†å’Œè®¤çŸ¥æŸä¼¤å½±å“çš„æœºåˆ¶æŽ¢è®¨.

OBJECTIVES: To observe the effects of electroacupuncture(EA) on memory, cognitive impairment, and the brain-derived neurotrophic factor(BDNF)/N-methyl-D-aspartate receptor subtype 1(NMDAR1) pathway in the brains of offspring rat with intrauterine growth restriction(IUGR) induced by perinatal nicotine exposure(PNE), so as to explore the underlying mechanism. METHODS: SD rats were randomly divided into normal, model, and EA groups, with 4 mothers and 10 offspring rats of each mother in each group. The IUGR model was established by subcutaneous injection of nicotine during pregnancy and lactation. From the 6th day of pregnancy in the mothers until the 21st day after birth of the offspring rats, EA (2 Hz/15 Hz, 1 mA) was administered bilaterally at the "Zusanli"(ST36) of mothers, once daily for 20 min. The brain organ coefficient was used to evaluate the brain development of the offspring rats. The Y-maze test and novel object recognition experiments were performed to assess memory and cognitive function. HE staining was used to observe the development and cellular morphology of the hippocampus and prefrontal cortex in the offspring rats. UV spectrophotometry was used to measure the glutamate(Glu) content in the hippocampus. ELISA was used to detect the BDNF content in the hippocampus. Western blot was performed to measure the protein expression of NMDAR1 in the hippocampus. Immunohistochemistry was used to count the number of BDNF-positive cells in the hippocampus and prefrontal cortex. RESULTS: Compared with the normal group, the brain organ coefficient, exploration time of the novel arm, spontaneous alternation rate, and novel object recognition index, contents of BDNF and expression of NMDAR1 proteins in the hippocampus, the number of BDNF-positive cells in the CA1 and CA3 regions of the hippocampus and prefrontal cortex were significantly reduced(P<0.01), while the Glu content in the hippocampus was significantly increased(P<0.01) in the model group of offspring rats；decreased cell number, scattered arrangement, and disrupted cellular structure were observed in the hippocampus and prefrontal cortex of offspring rats in the model group. Compared with the model group, the brain organ coefficient, exploration time of the novel arm, spontaneous alternation rate, and novel object recognition index, the BDNF contents and NMDAR1 protein expression in the hippocampus, the number of BDNF-positive cells in the hippocampal CA1 and CA3 regions and prefrontal cortex significantly increased(P<0.01, P<0.05), while the Glu content in the hippocampus was significantly decreased (P<0.01) in offspring rats of the EA group；increased cell number, neat arrangement, and reduced cellular damage were observed in the hippocampus and prefrontal cortex in the EA group. CONCLUSIONS: EA has an improving effect on memory and cognitive function impairment in offspring rats with IUGR induced by PNE, and this mechanism may be associated with the regulation of BDNF/NMDAR1 pathway, thereby improving the neuronal quantity and structure of the hippocampus and prefrontal cortex in offspring rats.

Corydalis yanhusuo Polysaccharides Ameliorate Chronic Stress-Induced Depression in Mice through Gut Microbiota-Derived Short-Chain Fatty Acid Activation of 5-Hydroxytryptamine Signaling.

Depression, a prevalent psychiatric disorder, presents a serious health risk to humans. Increasing evidence suggested that the gut microbiota and the 5-hydroxytryptamine (5-HT) pathway both contribute significantly to depression. This research aimed to investigate how Corydalis yanhusuo polysaccharides (CYP) could potentially alleviate depression induced by chronic unpredictable mild stress in mice, as well as its underlying mechanism. The sucrose preference test, tail suspension test, and forced swimming test were employed to evaluate the behavior of mice. Enzyme-linked immunosorbent assay and PCR techniques were utilized to measure depression-related factors (dopamine [DA], 5-HT, norepinephrine [NE], brain-derived neurotrophic factor [BDNF], tryptophan hydroxylase 2 [TPH-2], 5-hydroxytryptophan [5-HTP], and tryptophan hydroxylase [TPH-1] levels). Hematoxylin and eosin staining and Nissl staining were conducted to observe histopathological changes in the hippocampus, the differences in the diversity of gut flora between groups were analyzed using 16S rRNA sequencing, and gas chromatography-mass spectrometry metabolomics was utilized to evaluate short-chain fatty acid (SCFA) concentrations. The findings indicated that CYP treatment increased the sucrose preference index, decreased the immobility time, and improved neuropathological injury. In depressed mice, CYP improved the dysregulation of the gut microbiota, and increased the SCFA levels. In addition, CYP enhanced the DA, 5-HT, NE, BDNF, and TPH-2 levels in the brain and the expression of 5-HTP and TPH-1 in the colon, while SCFAs were positively correlated with these levels. In summary, our study suggested that CYP may mitigate depression by ameliorating gut microbiota dysregulation, promoting the generation of SCFAs, and activation of 5-HT signaling expression.

The effects of Ellagic acid supplementation on neurotrophic, inflammation, and oxidative stress factors, and indoleamine 2, 3-dioxygenase gene expression in multiple sclerosis patients with mild to moderate depressive symptoms: A randomized, triple-blind, placebo-controlled trial.

BACKGROUND: Depression is one of the most common psychological disorders among multiple sclerosis (MS) patients that characterized as the first symptoms. Ellagic acid is a natural polyphenol that may have neuroprotective properties through antioxidant, anti-inflammatory, and immunomodulatory effects. PURPOSE: The aim of the present study was to investigate the effects of Ellagic acid on circulating levels of brain derived neurotrophic factor (BDNF), interferon-γ (IFN-Æ´), nitric oxide (NO), nuclear factor erythroid-2-related factor 2 (Nrf2), cortisol, serotonergic system, and indoleamine 2, 3-dioxygenase (IDO) gene expression in MS patients with mild to moderate depressive symptoms. STUDY DESIGN: A randomized triple-blind clinical trial. METHODS: The eligible patients according to the inclusion criteria were randomly divided into two groups: either 180 mg Ellagic acid (Axenic company) (n = 25) or 180 mg maltodextrin (n = 25) group for 12 weeks. The Ellagic acid supplement were identical to placebo in shape, color and odor. Serum BDNF, NO, Nrf2, cortisol, serotonin, and IFN-Æ´ were measured by ELISA kit in the baseline and end of the study. Also, demographic characteristics, anthropometric measurements, physical activity, food intake, Beck Depression Inventory-II (BDI-II) and expanding disability status scale (EDSS) questionnaires, as well as IDO gene expression were assessed. SPSS software version 24 was used for statistical analysis. RESULTS: Fifty patients were evaluated, and a significant decrease in BDI-II (p = 0.001), IFN-Æ´ (p = 0.001), NO (p = 0.004), cortisol (p = 0.015), IDO gene expression (p = 0.001) and as well as increased the level of BDNF (p = 0.006) and serotonin (p = 0.019) was observed among those who received 90 mg Ellagic acid twice a day for 12 weeks versus control group. However, there were no significant differences between groups for Nrf2 levels (p>0.05) at the end of study. CONCLUSION: The current study indicates that Ellagic acid intervention has a favorable effect on depression in MS patients. This is achieved by reducing BDI-II scores, as well as levels of NO, cortisol, IFN-Æ´, and IDO gene expression. Furthermore, we found a significant elevation in circulating levels of BDNF and serotonin.

Biochemical Mechanisms of Beneficial Effects of Beta-Alanine Supplements on Cognition.

Using nutritional interventions to cure and manage psychiatric disorders is a promising tool. In this regard, accumulating documents support strong relationships between the diet and brain health throughout the lifespan. Evidence from animal and human studies demonstrated that ß-alanine (Beta-alanine; BA), a natural amino acid, provides several benefits in fight against cognitive decline promoting mental health. This review summarizes and reports state-of-the-art evidence on how BA affects cognitive health and argues existence of potential unrevealed biochemical mechanisms and signaling cascades. There is a growing body of evidence showing that BA supplement has a significant role in mental health mediating increase of the cell carnosine and brain-derived neurotrophic factor (BDNF) content. BDNF is one of the most studied neurotrophins in the mammalian brain, which activates several downstream functional cascades via the tropomyosin-related kinase receptor type B (TrkB). Activation of TrkB induces diverse processes, such as programmed cell death and neuronal viability, dendritic branching growth, dendritic spine formation and stabilization, synaptic development, cognitive-related processes, and synaptic plasticity. Carnosine exerts its main effect via its antioxidant properties. This critical antioxidant also scavenges hypochlorous acid (HOCl), another toxic species produced in mammalian cells. Carnosine regulates transcription of hundreds of genes related to antioxidant mechanisms by increasing expression of the nuclear erythroid 2-related factor 2 (Nrf2) and translocating Nrf2 to the nucleus. Another major protective effect of carnosine on the central nervous system (CNS) is related to its anti-glycating, anti-aggregate activities, anti-inflammatory, metal ion chelator activity, and regulation of pro-inflammatory cytokine secretion. These effects could be associated with the carnosine ability to form complexes with metal ions, particularly with zinc (Zn2+). Thus, it seems that BA via BDNF and carnosine mechanisms may improve brain health and cognitive function over the entire human lifespan.

Limited Cheese Intake Paradigm Replaces Patterns of Behavioral Disorders in Experimental PTSD: Focus on Resveratrol Supplementation.

Currently, the efficacy of drug therapy for post-traumatic stress disorder or PTSD leaves much to be desired, making nutraceutical support a promising avenue for treatment. Recent research has identified the protective effects of resveratrol in PTSD. Here, we tested the behavioral and neurobiological effects of combining cheese consumption with resveratrol supplements in an experimental PTSD model. Using the elevated plus maze test, we observed that cheese intake resulted in a shift from anxiety-like behavior to depressive behavior, evident in increased freezing acts. However, no significant changes in the anxiety index value were observed. Interestingly, supplementation with cheese and resveratrol only led to the elimination of freezing behavior in half of the PTSD rats. We further segregated the rats into two groups based on freezing behavior: Freezing+ and Freezing0 phenotypes. Resveratrol ameliorated the abnormalities in Monoamine Oxidize -A and Brain-Derived Neurotrophic Factor gene expression in the hippocampus, but only in the Freezing0 rats. Moreover, a negative correlation was found between the number of freezing acts and the levels of Monoamine Oxidize-A and Brain-Derived Neurotrophic Factor mRNAs in the hippocampus. The study results show promise for resveratrol supplementation in PTSD treatment. Further research is warranted to better understand the underlying mechanisms and optimize the potential benefits of resveratrol supplementation for PTSD.

[Electroacupuncture improves learning and memory impairment and enhances hippocampal synaptic plasticity through BDNF/TRKB/CREB signaling pathway in cerebral ischemia-reperfusion injury rats].

OBJECTIVE: To observe the effect of electroacupuncture on brain-derived neurotrophin factor (BDNF) / tyrosine kinase receptor B (TRKB) / cyclic adenosine monophosphate response element binding protein (CREB) pathway, synaptic plasticity marker protein and synaptic ultrastructure in the hippocampus of rats with learning and memory impairment induced by cerebral ischemia reperfusion (IR), so as to explore its mechanisms underlying improvement of cognitive impairment after stroke. METHODS: SD rats were randomly divided into blank, sham operation, model, and EA groups, with 12 rats in each group. The model of IR was established by occlusion of the middle cerebral artery. EA (2 Hz/10 Hz, 1-3 mA) was applied to "Shenting" (GV24) and "Baihui" (GV20) for 30 min, once daily for 14 days. The neurological function was evaluated according to the Zea Longa's score criteria. Morris water maze test was used to detect the learning and memory function of the rats. Nissl staining was used to observe the pathological morphology of the hippocampus. Transmission electron microscopy was used to observe the ultrastructure of the syna-pse in the hippocampus, the synaptic gap width and postsynaptic dense substance (PSD) thickness were measured. Immunofluorescence staining was used to observe the positive expression levels of BDNF, PSD-95 and synaptophysin (SYN) in hippocampal CA1 region. The protein expression levels of BDNF, TRKB, CREB, PSD-95, and SYN in hippocampal tissue were detected by Western blot. RESULTS: Compared with the sham operation group, the neurological function score and escape latency (EL) were significantly increased (P<0.01), the times of crossing the original platform were decreased (P<0.01), the number of neurons in the CA1 area of the hippocampus was reduced, with incomplete morphology, widened synaptic gaps and significantly decreased PSD thickness (P<0.01), the positive expressions of BDNF, PSD-95, SYN and the protein expression levels of BDNF, TRKB, CREB, PSD-95, SYN were significantly decreased (P<0.01) in the model group. Compared with the model group, the neurological function scores and EL on the 12th and 13th day were decreased (P<0.01, P<0.05), the times of crossing the original platform were increased (P<0.01), the morphology of hippocampal CA1 neurons improved, the synaptic gaps was decreased (P<0.01), the PSD thickness was significantly increased (P<0.01), the positive expressions of BDNF, PSD-95, SYN, and the protein expression levels of BDNF, TRKB, CREB, PSD-95, SYN were increased (P<0.05, P<0.01) in the EA group. CONCLUSION: EA can alleviate cognitive impairment in IR rats, which may be related to its function in up-regulating the proteins of BDNF/TRKB/CREB pathway, promoting the expressions of synaptic plasticity marker proteins PSD-95 and SYN, thus improving the synaptic plasticity.

Efficacy of Laser Acupuncture for Children With Autism Spectrum Disorder: Clinical, Molecular, and Biochemical Study.

BACKGROUND: Low-level laser acupuncture (LLLA) biostimulation could contribute to improving the symptoms and communication of children manifesting autism spectrum disorder (ASD). Photobiomodulation might influence the level of brain-derived neurotrophic factor (BDNF) and miR-320 expression. The aim was to investigate the influence of LLLA biostimulation on the severity, language abilities, BDNF levels, and miR-320 in a sample of children with ASD. METHODS: The participants with ASD (N = 30) were randomly divided equally into groups: Group I received LLLA therapy twice a week for 12 sessions and Group II did not receive it. Assessments of the severity, language abilities, BDNF level by enzyme-linked immunosorbent assay, and miR-320 expression by reverse transcriptase quantitative polymerase chain reaction were performed before and after the intervention. A comparison between ASD cases (N = 30) before starting the therapy and neurotypical children (N = 15) regarding miR-320 expression was performed. RESULTS: Following the intervention, the severity of ASD was reduced and language performance was elevated in both groups. The improvement in Group I was higher with (P = 0.002; 0.03). The plasma BDNF level was reduced only in Group I (P < 0.001). The expression level of miR-320 in Group I did not show a change (P = 0.641). A significant difference in miR-320 expression between children with ASD and the neurotypical group (P = 0.000) was observed. CONCLUSION: This study introduces LLLA therapy as a safe and promising therapeutic procedure for improving the core manifestations and communication abilities and for modulating BDNF levels in children with ASD. The reduced expression of miR-320 showed a good diagnostic value in children with ASD.

Smilagenin induces expression and epigenetic remodeling of BDNF in alzheimer's disease.

BACKGROUND: Smilagenin (SMI) is a lipid-soluble steroidal sapogenin, extracted from traditional Chinses medicinal herbs Radix Asparagi, which is extracted from the dry root of Asparagus cochinchinensis (Lour.) Merr. We previously found that SMI significantly increased brain-derived neurotrophic factor (BDNF) expression in Aß-intoxicated SH-SY5Y cells. METHODS: In this study, we performed behavioral tests to analyze cognitive function of WT and APP/PS1 mice treated with or without SMI, and found that SMI could significantly improve the learning and memory ability of APP/PS1 mice. Moreover, immunofluorescence and ELISA results showed that SMI pretreatment could effectively reduce the deposition of ß-amyloid plaques in the cortex and hippocampus of APP/PS1 mice (26 mg/kg/day for 60 days) and inhibit the secretion of Aß1-42 in N2a/APPswe cells (10 µM concentration for 24 hours). RESULTS: Mechanistically, SMI enhanced BDNF mRNA expression, elevated the global level of H3AC and H4AC, and increased the expression of P300 in AD models. Furthermore, chromatin immunoprecipitation results showed that SMI could increase the levels of H3AC and H4AC at the promoter of BDNF promoter Ⅱ and Ⅳ, indicating that SMI epigenetically regulates BDNF expression through HAT enhancement. To further verify the critical role of P300 by which SMI upregulated histone acetylation in BDNF, AD mice were treated with SMI and C646 simultaneously. Behavioral experiments showed that the improvement effects of SMI on cognitive impairment were abolished after P300 inhibition in APP/PS1 mice. CONCLUSIONS: Our research for the first time demonstrated that SMI showed neuroprotective effects by increasing the expression of P300 protein, thus upregulating histone acetylation levels in the promoter region of BDNF and promoting its transcription. Our findings provide an important theoretical basis for the treatment of Alzheimer's disease with SMI extracted from Asparagus cochinchinensis (Lour.) Merr.

Analgesic efficacy of median nerve stimulation in mice with chemotherapy-induced peripheral neuropathymodulation of brain-derived neurotrophic factor expression.

OBJECTIVE: Chemotherapeutic agents such as docetaxel (DTX) can trigger chemotherapy-induced peripheral neuropathy (CIPN), which is characterized by unbearable pain. This study was designed to investigate the analgesic effect and related neuronal mechanism of low-frequency median nerve stimulation (LFMNS) on DTX-induced tactile hypersensitivity in mice. METHODS: To produce CIPN, DTX was administered intraperitoneally 4 times, once every 2 d, to male ICR mice. LFMNS was performed on the wrist area, and the pain response was measured using von Frey filaments on both hind paws. Western blot and immunofluorescence staining were performed using dorsal root ganglion and spinal cord samples to measure the expression of brain-derived neurotrophic factor (BDNF). RESULTS: Repeated LFMNS significantly attenuated the DTX-induced abnormal sensory response and suppressed the enhanced expression of BDNF in the DRG neurons and spinal dorsal area. CONCLUSIONS: LFMNS might be an effective non-pharmaceutical option for treating patients suffering from CIPN regulating the expression of peripheral and central BDNF.

Efficacy of electroacupuncture stimulating Shenmen (HT7), Baihui (GV20), Sanyinjiao (SP6) on spatial learning and memory deficits in rats with insomnia induced by para-chlorophenylalanine: a single acupoint combined acupoints.

OBJECTIVE: To investiage the effect of electroacupuncture (EA) at a single acupoint of Shenmen (HT7), Baihui (GV20), Sanyinjiao (SP6) and at combined acupoints of Shenmen (HT7) and Baihui (GV20) and Sanyinjiao (SP6) on the PKA/CREB and BDNF/TrkB signaling, as well as neuroapoptosis and neurogenesis in hippocampus and elucidate the underlying mechanism of single and combined acupoints on ameliorating spatial learning and memory deficits in a rat model of primary insomnia. METHODS: Primary insomnia was modeled by intraperitoneal injection of para-chlorophenylalanine (PCPA) once daily for 2 d. EA was applied at Shenmen (HT7), Baihui (GV20), Sanyinjiao (SP6), or Shenmen (HT7) + Baihui (GV20) + Sanyinjiao (SP6) (combined) for 30 min daily for 4 d. Spatial learning and memory function was evaluated by the Morris water maze (MWM) test. Protein expressions of hippocampal cAMP-dependent protein kinase (PKA)-Cß, phosphorylated cAMP-responsive element-binding protein (p-CREB), brain-derived neurotrophic factor (BDNF), and tyrosine kinase receptor B (TrkB) were evaluated by Western blotting. Neuronal apoptosis in the hippocampus was detected with the transferase-mediated dUTP-X nick end labeling assay. Endogenous neurogenesis was examined with bromodeoxyuridine staining. The MWM test and hippocampal p-CREB, BDNF, and TrkB protein levels in the combined acupoints group were evaluated after the administration of a PKA-selective inhibitor (H89). RESULTS: Spatial learning and memory were significantly impaired in rats with insomnia. The spatial learning deficits were ameliorated in the Shenmen (HT7), Baihui (GV20), Sanyinjiao (SP6), and combined groups; this improvement was significantly greater in the combined group than the single acupoint groups. The spatial memory impairment was improved in the combined, Baihui (GV20), and Shenmen (HT7) groups, but not the Sanyinjiao (SP6) group. The expressions of PKA-Cß, p-CREB, BDNF, and TrkB were decreased in rats with insomnia. All these proteins were significantly upregulated in the combined group. PKA/p-CREB protein levels were elevated in the Baihui (GV20) and Shenmen (HT7) groups, whereas BDNF/TrkB expression was upregulated in the Sanyinjiao (SP6) group. The staining results showed significant attenuation of hippocampal cell apoptosis and increased numbers of proliferating cells in the combined group, whereas the single acupoint groups only showed decreased numbers of apoptotic cells. In the combined group, the PKA inhibitor reversed the improvement of spatial memory and upregulation of p-CREB expression caused by EA, but did not affect its activation of BDNF/TrkB signaling. CONCLUSIONS: EA at the single acupoints Baihui (GV20), Shenmen (HT7), or Sanyinjiao (SP6) had an ameliorating effect on the spatial learning and memory deficits induced by insomnia. EA at combined acupoints exerted a synergistic effect on the improvements in spatial learning and memory impairment in rats with insomnia by upregulating the hippocampal PKA/CREB and BDNF/TrkB signaling, facilitating neurogenesis, and inhibiting neuronal apoptosis. These findings indicate that EA at combined acupoints [(Baihui (GV20), Shenmen (HT7), and Sanyinjiao (SP6)] achieves a more pronounced regulation of hippocampal neuroplasticity than EA at single acupoints, which may partly explain the underlying mechanisms by which EA at combined acupoints exerts a better ameliorative effect on the cognitive dysfunction caused by insomnia.

[Antidepressant mechanism of Shenling Kaixin Granules based on BDNF/TrkB/CREB pathway].

To investigate the antidepressant mechanism of Shenling Kaixin Granules(SLKX) in treating chronic unpredictable mild stress(CUMS) model rats. Ninety male SD rats were randomly divided into control group, model group, Shugan Jieyu Capsules(110 mg·kg~(-1)) group and SLKX low-(90 mg·kg~(-1)), medium-(180 mg·kg~(-1)), and high-dose(360 mg·kg~(-1)) groups. Depression rat model was replicated by CUMS method. After treatment, the behavioral changes of rats were evaluated by sugar preference, open field, elevated cross maze and forced swimming experiments. The contents of interleukin 1 beta(IL-1ß), tumor necrosis factor α(TNF-α), brain-derived neurotrophic factor(BDNF) and 5-hydroxytryptamine(5-HT) in serum were determined by enzyme linked immunosorbent assay(ELISA), and the activities of superoxide dismutase(SOD) and catalase(CAT) in hippocampal CA1 region were also detected. Pathological changes in hippocampal CA1 region were detected by hematoxylin-eosin(HE) staining, and Western blot was used to determine the expression of nerve growth factor(NGF), BDNF, phospho-tyrosine kinase receptor(p-TrkB)/TrkB, phospho-cAMP-response element binding protein(p-CREB)/CREB, nuclear factor E2 related factor 2(Nrf2), heme oxygenase 1(HO-1), B-cell lymphoma-2(Bcl-2)/Bcl-2 associated X protein(Bax) and caspase-3 in hippocampal CA1 region. RESULTS:: showed that compared with the control group, the model group had decreased sugar preference, reduced number of entries and time spent in the center of open field and shortened total distance of movement, reduced number of entries and proportion of time spent in open arm, and increased number and time of immobility in forced swimming experiment. Additionally, the serum contents of IL-1ß and TNF-α and the expression of caspase-3 were higher, while the contents of BDNF and 5-HT, the activities of SOD and CAT in hippocampal CA1 region, the expressions of NGF, BDNF, p-TrkB/TrkB, p-CREB/CREB, HO-1 and Bcl-2/Bax, and the Nrf2 nuclear translocation were lower in model group than in control group. Compared with the conditions in model group, the sugar preference, the number of entries and time spent in the center of open, total distance of movement, and the number of entries and proportion of time spent in open arm in treatment groups were increased while the number and time of immobility in forced swimming experiment were decreased; the serum contents of IL-1ß and TNF-α and the expression of caspase-3 were down regulated, while the contents of BDNF and 5-HT, the activities of SOD and CAT in hippocampal CA1 region, the expressions of NGF, BDNF, p-TrkB/TrkB, p-CREB/CREB, HO-1, Bcl-2/Bax, and Nrf2 nuclear translocation were enhanced. In conclusion, SLKX might regulate the Nrf2 nucleus translocation by activating BDNF/TrkB/CREB pathway, lower oxidative stress damage in hippocampus, inhibit caspase-3 activity, and reduce apoptosis of hippocampal nerve cells, thereby playing an antidepressant role.

N6-methyladenosine profiling reveals that Xuefu Zhuyu decoction upregulates METTL14 and BDNF in a rat model of traumatic brain injury.

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese herbal formula Xuefu Zhuyu decoction (XFZYD) is a classic formula in the category of invigorating blood circulation and resolving blood stasis. It has been proven to improve the neurological and ethological prognosis of traumatic brain injury. XFZYD promotes synaptic and axonal regeneration after traumatic brain injury, which is functionally modulated by the N6-methyladenosine (m6A) modification of RNA. However, the epigenetic effects of XFZYD on m6A modification remain unknown. AIM OF THE STUDY: To explore how XFZYD protects against traumatic brain injury induced by controlled cortical impact (CCI) injury by altering RNA m6A modification. MATERIALS AND METHODS: The modified neurological severity scoring and Morris water maze were performed to evaluate the neuroprotective effects of XFZYD for 14 days and screen the dose. Then, dot blot, western blotting, and methylated RNA immunoprecipitation sequencing (MeRIP-Seq) were used to explore changes in RNA m6A modification in the perilesional cortex. The Metascape platform was used to analyze the Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome pathway of the differential m6A-tagged genes. Furthermore, MeRIP-qPCR was conducted to quantify differences in the hub differential m6A modification gene brain-derived neurotrophic factor (Bdnf). RESULTS: XFZYD significantly ameliorated the neurological deficits, spatial learning, and memory impairments in rats post-CCI on day 14. XFZYD enhanced the m6A level, and the expression of METTL14 and YTHDC2 in the perilesional cortex of CCI rats. In all three groups, the 3'-untranslated regions and coding sequence were primarily enriched for m6A peaks. XFZYD reversed the increased proportion of 3'-untranslated regions, and the decreased proportion of coding sequence and 5'-untranslated regions post-CCI. Moreover, XFZYD markedly downregulated 41 elevated m6A-tagged transcripts and upregulated 119 decreased m6A-tagged transcripts following CCI. Gene ontology and KEGG pathway analysis revealed that XFZYD-regulated m6A-tagged transcripts were predominantly enriched in synapse assembly, synaptic plasticity, learning or memory, and MAPK signaling pathway. Then, the hub-regulated m6A-tagged gene BDNF was identified. Both the m6A methylation level and the protein level of BDNF were ascended by XFZYD treatment. CONCLUSION: XFZYD improves neurological deficits, spatial learning and memory impairments in rats post-TBI probably through increasing the expression of METTL14 and BDNF in the cortex. Our study highlights a novel post-transcriptional regulation mechanism mediated by herbal medicine for traumatic brain injury treatment.

Regulation of Satiety by Bdnf-e2-Expressing Neurons through TrkB Activation in Ventromedial Hypothalamus.

The transcripts for Bdnf (brain-derived neurotrophic factor), driven by different promoters, are expressed in different brain regions to control different body functions. Specific promoter(s) that regulates energy balance remain unclear. We show that disruption of Bdnf promoters I and II but not IV and VI in mice (Bdnf-e1-/-, Bdnf-e2-/-) results in obesity. Whereas Bdnf-e1-/- exhibited impaired thermogenesis, Bdnf-e2-/- showed hyperphagia and reduced satiety before the onset of obesity. The Bdnf-e2 transcripts were primarily expressed in ventromedial hypothalamus (VMH), a nucleus known to regulate satiety. Re-expressing Bdnf-e2 transcript in VMH or chemogenetic activation of VMH neurons rescued the hyperphagia and obesity of Bdnf-e2-/- mice. Deletion of BDNF receptor TrkB in VMH neurons in wildtype mice resulted in hyperphagia and obesity, and infusion of TrkB agonistic antibody into VMH of Bdnf-e2-/- mice alleviated these phenotypes. Thus, Bdnf-e2-transcripts in VMH neurons play a key role in regulating energy intake and satiety through TrkB pathway.