S-Nitrosoglutathione Attenuates Oxidative Stress and Improves Retention Memory Dysfunctions in Intra-Cerebroventricular-Streptozotocin Rat Model of Sporadic Alzheimer's Disease via Activation of BDNF and Nuclear Factor Erythroid 2-Related Factor-2 Antioxidant Signaling Pathway.

INTRODUCTION: The brain-derived neurotrophic factor (BDNF) and transcription nuclear factor erythroid 2-related factor-2 (NRF-2) play an important role in Alzheimer's disease (AD). However, the interactive involvement of BDNF and NRF-2 in respect to antioxidant mechanisms in different parts of the AD brain is still unclear. Considering the above condition, used S-nitrosoglutathione (GSNO) to examine whether it modulates the BDNF and NRF-2 levels to activate signaling pathway to promote antioxidant levels in AD brains. METHOD: AD was induced by intracerebroventricular infusion of streptozotocin (ICV-STZ, 3 mg/kg) in Wistar rats. The effect of GSNO was analyzed by evaluating the retention of memory in months 1, 2, and 3. After the behavior study, rats were sacrificed and accessed the amyloid beta (Aß)-40, Aß42, glutathione (GSH), BDNF, and NRF-2 levels in the hippocampus, cortex, and amygdala tissue. RESULTS: Pretreatment with GSNO (50 µg/kg/intraperitoneal/day) restored the BDNF, and NRF-2 levels toward normalcy as compared with ICV-STZ + saline-treated animals. Also, GSNO treatment reversed the oxidative stress and increased the GSH levels toward normal levels. Further, reduced Aß levels and neuronal loss in different brain regions. As a result, GSNO treatment improved the cognitive deficits in ICV-STZ-treated rats. CONCLUSION: The results showed that endogenous nitric oxide donor GSNO improved the cognitive deficits and ICV-STZ-induced AD pathological conditions, possibly via attenuating the oxidative stress. Hence, the above finding supported that GSNO treatment may activate BDNF and NRF-2 antioxidant signaling pathways in the AD brain to normalize oxidative stress, which is the main causative factor for ICV-STZ-induced AD pathogenesis.

Effects of carbamazepine on BDNF expression in trigeminal ganglia and serum in rats with trigeminal neuralgia. / å¡é©¬è¥¿å¹³å¯¹ä¸‰å‰ç¥žç»ç—›å¤§é¼ ä¸‰å‰ç¥žç»èŠ‚åŠè¡€æ¸ ä¸­BDNF表达变化的影响.

OBJECTIVES: Trigeminal neuralgia (TN) is a severe chronic neuropathic pain that mainly affects the distribution area of the trigeminal nerve with limited treating efficacy. There are numerous treatments for TN, but currently the main clinical approach is to suppress pain by carbamazepine (CBZ). Brain-derived neurotrophic factor (BDNF) is closely related to chronic pain. This study aims to determine the effects of CBZ treatment on BDNF expression in both the trigeminal ganglion (TG) and serum of TN via a chronic constriction injury of the infraorbital nerve (ION-CCI) rat model. METHODS: The ION-CCI models were established in male Sprague-Dawley rats and were randomly divided into a sham group, a TN group, a TN+low-dose CBZ treatment group (TN+20 mg/kg CBZ group), a TN+medium-dose CBZ treatment group (TN+40 mg/kg CBZ group), and a TN+high-dose CBZ treatment group (TN+80 mg/kg CBZ group). The mechanical pain threshold in each group of rats was measured regularly before and after surgery. The expressions of BDNF and tyrosine kinase receptor B (TrkB) mRNA in TGs of rats in different groups were determined by real-time PCR, and the expression of BDNF protein on neurons in TGs was observed by immunofluorescence. Western Blotting was used to detect the protein expression of BDNF, TrkB, extracellular regulated protein kinases (ERK), and phospho-extracellular regulated protein kinases (p-ERK) in TGs of rats in different groups. The expression of BDNF in the serum of rats in different groups was detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: The results of mechanical pain sensitivity showed that there was no significant difference in the mechanical pain threshold in the right facial sensory area of the experimental rats in each group before surgery (all P>0.05). From the 3rd day after operation, the mechanical pain threshold of rats in the TN group was significantly lower than that in the sham group (all P<0.01), and the mechanical pain threshold of rats in the TN+80 mg/kg CBZ group, the TN+40 mg/kg CBZ group, and the TN+20 CBZ mg/kg group was higher than that in the TN group (all P<0.05). The BDNF and TrkB mRNA and protein expressions in TGs of rats in the TN group were higher than those in the sham group (all P<0.05), and those in the TN+80 mg/kg CBZ group, the TN+40 mg/kg CBZ group, and the TN+20 mg/kg CBZ group were lower than the TN group (all P<0.05). The p-ERK levels in TG of rats in the TN+80 mg/kg CBZ group, the TN+40 mg/kg CBZ group, and the TN+20 mg/kg CBZ group were significantly decreased compared with the TN group (all P<0.05). The BDNF and neuron-specific nuclear protein (NeuN) were mainly co-expressed in neuron of TGs in the TN group and they were significantly higher than those in the sham group (all P<0.05). The co-labeled expressions of BDNF and NeuN in TGs of the TN+ 80 mg/kg CBZ group, the TN+40 mg/kg CBZ group, and the TN+20 mg/kg CBZ group were lower than those in the TN group (all P<0.05). The results of ELISA showed that the level of BDNF in the serum of the TN group was significantly higher than that in the sham group (P<0.05). The levels of BDNF in the TN+80 mg/kg CBZ group, the TN+40 mg/kg CBZ group, and the TN+20 mg/kg CBZ group were lower than those in the TN group (all P<0.05). Spearman correlation analysis showed that the BDNF level in serum was negatively correlated with mechanical pain threshold (r=-0.650, P<0.01). CONCLUSIONS: CBZ treatment can inhibit the expression of BDNF and TrkB in the TGs of TN rats, reduce the level of BDNF in serum of TN rats and the phosphorylation of ERK signaling pathway, so as to inhibit TN. The serum level of BDNF can be considered as an indicator for the diagnosis and prognosis of TN.

Engeletin alleviates depression-like phenotype by increasing synaptic plasticity via the BDNF-TrkB-mTORC1 signalling pathway.

Major depressive disorder (MDD) is a severe mental disorder associated with high rates of morbidity and mortality. Current first-line pharmacotherapies for MDD are based on enhancement of monoaminergic neurotransmission, but these antidepressants are still insufficient and produce significant side-effects. Consequently, the development of novel antidepressants and therapeutic targets is desired. Engeletin, a natural Smilax glabra rhizomilax derivative, is a compound with proven efficacy in treating ischemic stroke, yet its therapeutic effects and mechanisms for depression remain unexplored. The effects of engeletin were assessed in the forced swimming test (FST) and tail suspension test (TST) in mice. Engeletin was also investigated in the chronic restraint stress (CRS) mouse model of depression with fluoxetine (FLX) as the positive control. Changes in prefrontal cortex (PFC) spine density, synaptic plasticity-linked protein expressions and the brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB)- mammalian target of rapamycin complex 1 (mTORC1) signalling pathway after chronic stress and engeletin treatment were then investigated. The TrkB and mTORC1 selective inhibitors, ANA-12 and rapamycin, respectively, were utilized to assess the engeletin's antidepressive mechanisms. Our data shows that engeletin exhibited antidepressant-like activity in the FST and TST in mice without affecting locomotor activity. Furthermore, it exhibited efficiency against the depression of CRS model. Moreover, it enhanced the BDNF-TrkB-mTORC1 pathway in the PFC during CRS and altered the reduction in dendritic spine density and levels of synaptic plasticity-linked protein induced by CRS. In conclusion, engeletin has antidepressant activity via activation of the BDNF-TrkB-mTORC1 signalling pathway and upregulation of PFC synaptic plasticity.

7,8-Dihydroxyflavone protects retinal ganglion cells against chronic intermittent hypoxia-induced oxidative stress damage via activation of the BDNF/TrkB signaling pathway.

PURPOSE: Chronic intermittent hypoxia (CIH) plays a key role in the complications of obstructive sleep apnea (OSA), which is strongly associated with retinal and optic nerve diseases. Additionally, the brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling pathway plays an important protective role in neuronal injury. In the present study, we investigated the role of 7,8-dihydroxyflavone (7,8-DHF) in regulating CIH-induced injury in mice retinas and rat primary retinal ganglion cells (RGCs). METHODS: C57BL/6 mice and in vitro primary RGCs were exposed to CIH or normoxia and treated with or without 7,8-DHF. The mice eyeballs or cultured cells were then taken for histochemistry, immunofluorescence or biochemistry, and the protein expression of the BDNF/TrkB signaling pathway analysis. RESULTS: Our results showed that CIH induced oxidative stress (OS) in in vivo and in vitro models and inhibited the conversion of BDNF precursor (pro-BDNF) to a mature form of BDNF, which increased neuronal cell apoptosis. 7,8-DHF reduced the production of reactive oxygen species (ROS) caused by CIH and effectively activated TrkB signals and downstream protein kinase B (Akt) and extracellular signal-regulated kinase (Erk) survival signaling pathways, which upregulated the expression of mature BDNF. ANA-12 (a TrkB specific inhibitor) blocked the protective effect of 7,8-DHF. CONCLUSION: In short, the activation of the BDNF/TrkB signaling pathway alleviated CIH-induced oxidative stress damage of the optic nerve and retinal ganglion cells. 7,8-DHF may serve as a promising agent for OSA related neuropathy.

Ghrelin treatment leads to dendritic spine remodeling in hippocampal neurons and increases the expression of specific BDNF-mRNA species.

Ghrelin (Gr) is an orexigenic peptide that acts via its specific receptor, GHSR-1a distributed throughout the brain, being mainly enriched in pituitary, cortex and hippocampus (Hp) modulating a variety of brain functions. Behavioral, electrophysiological and biochemical evidence indicated that Gr modulates the excitability and the synaptic plasticity in Hp. The present experiments were designed in order to extend the knowledge about the Gr effect upon structural synaptic plasticity since morphological and quantitative changes in spine density after Gr administration were analyzed "in vitro" and "in vivo". The results show that Gr administered to hippocampal cultures or stereotactically injected in vivo to Thy-1 mice increases the density of dendritic spines (DS) being the mushroom type highly increased in secondary and tertiary extensions. Spines classified as thin type were increased particularly in primary extensions. Furthermore, we show that Gr enhances selectively the expression of BDNF-mRNA species.

Antidepressant-like effect of guanosine involves activation of AMPA receptor and BDNF/TrkB signaling.

Guanosine is a purine nucleoside that has been shown to exhibit antidepressant effects, but the mechanisms underlying its effect are not well established. We investigated if the antidepressant-like effect induced by guanosine in the tail suspension test (TST) in mice involves the modulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, voltage-dependent calcium channel (VDCC), and brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) pathway. We also evaluated if the antidepressant-like effect of guanosine is accompanied by an acute increase in hippocampal and prefrontocortical BDNF levels. Additionally, we investigated if the ability of guanosine to elicit a fast behavioral response in the novelty suppressed feeding (NSF) test is associated with morphological changes related to hippocampal synaptogenesis. The antidepressant-like effect of guanosine (0.05 mg/kg, p.o.) in the TST was prevented by DNQX (AMPA receptor antagonist), verapamil (VDCC blocker), K-252a (TrkBantagonist), or BDNF antibody. Increased P70S6K phosphorylation and higher synapsin I immunocontent in the hippocampus, but not in the prefrontal cortex, were observed 1 h after guanosine administration. Guanosine exerted an antidepressant-like effect 1, 6, and 24 h after its administration, an effect accompanied by increased hippocampal BDNF level. In the prefrontal cortex, BDNF level was increased only 1 h after guanosine treatment. Finally, guanosine was effective in the NSF test (after 1 h) but caused no alterations in dendritic spine density and remodeling in the ventral dentate gyrus (DG). Altogether, the results indicate that guanosine modulates targets known to be implicated in fast antidepressant behavioral responses (AMPA receptor, VDCC, and TrkB/BDNF pathway).

Opium Effect in Pregnancy on the Dynamics of Maternal Behavior: Testing a Neurochemical Model.

BACKGROUND: Investigations into neurochemical mechanisms of opioid addiction are difficult due to the complexity of behavior and multiplicity of involved neurotransmitter and hormonal systems. The aim of this study was to examine the benefits of structured analysis of these mechanisms using the framework of the neurochemical model Functional Ensemble of Temperament (FET) and the example of maternal behavior under the condition of opium consumption in pregnancy. The FET differentiates between (a) endurance, (b) speed of integration, and (c) emotionality aspects of behavior suggesting that these systems are differentially regulated by (a) serotonin-neuropeptides-brain-derived neurotrophic factor (BDNF), (b) dopamine-GABA, and (c) opioid receptor systems, correspondingly. The FET also suggests that mu-opioid receptors (MORs) binding the endorphines (including opium's ingredient morphine) have a stronger association with regulation endurance, whereas delta-OR have a stronger association with integration of behavior and kappa-OR - with the perceptual mobilization seen in anxiety. To test the predictions of this model, we compared the impact of massive MOR dysregulation on 3 behavioral aspects of behavior and on serotonin, BDNF, and corticosterone levels. METHODS: The study used 24 female white Wistar rats which were randomly divided into (1) control group: pregnant rats without any intervention; (2) opium-exposed group: animals that were exposed to opium during pregnancy and after the delivery until the end of the study. At the end of the study, the levels of BDNF, serotonin (5-HT) in the hippocampus of the mother's brain, and serum corticosterone, as well as 12 aspects of the maternal behavior were evaluated. The differences between control and experimental groups were assessed using the t test for independent samples. RESULTS: The BDNF and serotonin concentrations in the hippocampus of the mother rats which were exposed to opium were lower than in the control group; the mean corticosterone in exposed mothers was higher than in the control group. Behaviorally, opium-consuming mothers showed lower endurance in 4 distinct behavioral categories (nesting, feeding, grooming, and retrieval) than the mothers in the control group. Ease of integration of behavior was affected to a lesser degree, showing a significant effect only in 1 out of 5 applied measures. Self-grooming, seen as an emotionality-related aspect of behavior, was not affected. CONCLUSION: Opium exposure during pregnancy in our experiment primarily reduced the endurance of rat's maternal behavior, but the speed of integration of behavioral acts was less affected. This negative impact of opium on endurance was associated with a decrease of BDNF and serotonin levels in the hippocampus and an increase in corticosterone level in opium-consuming mothers. There is no effect of opium exposure on self-grooming behavior. This pattern supports the FET hypothesis about the role of 5-HT and BDNF in endurance, differential regulation of endurance, integrative and emotionality aspects of behavior, and differential association of the MOR system with endurance aspects, in comparison with kappa- and delta opioid receptors.

Impact of intradetrusor botulinum toxin A injections on serum and urinary concentrations of nerve growth factor and brain-derived neurotrophic factor in patients with multiple sclerosis and neurogenic detrusor overactivity.

AIMS: To evaluate the practical relevance of changes in serum and urinary neurotrophins levels in patients with multiple sclerosis (MS) and neurogenic lower urinary tract dysfunction (NLUTD) after intradetrusor injections of botulinum toxin A (BoNTA). METHODS: The study included 36 patients with MS and NLUTD and 20 controls. The patients with NLUTD received intradetrusor injection of BoNTA (200 U). The nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) levels were measured in serum and urine at baseline and then at 1, 3, and 6 months by enzyme-linked immunosorbent assay. Urinary NGF and BDNF were normalized to creatinine (NGF/Cr, BDNF/Cr). Patients' assessment included urodynamic examination and Neurogenic Bladder Symptom Score (NBSS). RESULTS: After BoNTA injections, no significant changes were observed in the serum NGF and BDNF or the urinary BDNF/Cr. The urinary NGF/Cr was significantly higher in MS patients (1.23 ± 0.34) at baseline compared with controls (0.084 ± 0.02; p = .021). The urinary NGF/Cr decreased to 0.51 ± 0.12 (p = .001) and 0.53 ± 0.32 (p = .005) at 1 and 3 months, increasing to 1.12 ± 0.49 (p = .003) at 6 months. The urinary NGF/Cr level at baseline demonstrated a low diagnostic accuracy in predicting a better response to the BoNTA treatment (area under the curve = 0.661; p = .047) and no correlation with the urodynamic parameters. CONCLUSIONS: The urinary NGF/Cr at baseline or its reduction at the first month following treatment does not serve as a predictor for the response to the BoNTA injections or for urodynamic changes.

Inhibition of Histone Deacetylase Reinstates Hippocampus-Dependent Long-Term Synaptic Plasticity and Associative Memory in Sleep-Deprived Mice.

Sleep plays an important role in the establishment of long-term memory; as such, lack of sleep severely impacts domains of our health including cognitive function. Epigenetic mechanisms regulate gene transcription and protein synthesis, playing a critical role in the modulation of long-term synaptic plasticity and memory. Recent evidences indicate that transcriptional dysregulation as a result of sleep deprivation (SD) may contribute to deficits in plasticity and memory function. The histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA), also known as Vorinostat, a clinically approved drug for human use, has been shown to ameliorate cognitive deficits in several neurological disease models. To further explore the therapeutic effect of SAHA, we have examined its potential role in improving the SD-mediated impairments in long-term plasticity, associative plasticity, and associative memory. Here we show that SAHA preserves long-term plasticity, associative plasticity, and associative memory in SD hippocampus. Furthermore, we find that SAHA prevents SD-mediated epigenetic changes by upregulating histone acetylation, hence preserving the ERK-cAMP-responsive element-binding protein (CREB)/CREB-binding protein-brain-derived neurotrophic factor pathway in the hippocampus. These data demonstrate that modifying epigenetic mechanisms via SAHA can prevent or reverse impairments in long-term plasticity and memory that result from sleep loss. Thus, SAHA could be a potential therapeutic agent in improving SD-related memory deficits.

The effect of geniposide on chronic unpredictable mild stress-induced depressive mice through BTK/TLR4/NF-κB and BDNF/TrkB signaling pathways.

The purpose of this study was to estimate the pharmacological effect of geniposide (GEN) on depression, caused by chronic unpredictable mild stress (CUMS), and explore its potential mechanism. During the 6 week CUMS procedure, the mice were treated with GEN (10, 40 mg/kg) by gavage once daily for 3 weeks. As a result, the GEN treatment remarkably improved the behavioral manifestations and suppressed the generations of inflammatory cytokines both in vivo and in vitro. The MDA level was significantly increased, while the activities of SOD, GSH-PX were decreased in CUMS-challenged mice and corticosterone-stimulated PC12 cells. GEN administration significantly inhibited those changes. Moreover, GEN treatment could downregulate the expressions of p-BTK, TLR4, MyD88, p-NF-κB proteins, and upregulate BDNF, p-TrkB generations in CUMS-induced mice. Moreover, GEN administration inhibited the protein levels of p-BTK, TLR4, MyD88, p-NF-κB in corticosterone-induced PC12 cell. In summary, the results suggested that GEN exerted a therapeutic effect on CUMS-induced depressive mice possibly through the regulation of BTK/TLR4/NF-κB and BDNF/TrkB signaling pathways.

Analysis of Antidepressant-like Effects and Action Mechanisms of GSB-106, a Small Molecule, Affecting the TrkB Signaling.

Induction of BDNF-TrkB signaling is associated with the action mechanisms of conventional and fast-acting antidepressants. GSB-106, developed as a small dimeric dipeptide mimetic of BDNF, was previously shown to produce antidepressant-like effects in the mouse Porsolt test, tail suspension test, Nomura water wheel test, in the chronic social defeat stress model and in the inflammation-induced model of depression. In the present study, we evaluated the effect of chronic per os administration of GSB-106 to Balb/c mice under unpredictable chronic mild stress (UCMS). It was observed for the first time that long term GSB-106 treatment (1 mg/kg, 26 days) during ongoing UCMS procedure ameliorated the depressive-like behaviors in mice as indicated by the Porsolt test. In addition, chronic per os administration of GSB-106 resulted in an increase in BDNF levels, which were found to be decreased in the prefrontal cortex and hippocampus of mice after UCMS. Furthermore, prolonged GSB-106 treatment was accompanied by an increase in the content of pTrkB706/707 in the prefrontal cortex and by a pronounced increase in the level of pTrkB816 in both studied brain structures of mice subjected to UCMS procedure. In summary, the present data show that chronic GSB-106 treatment produces an antidepressant-like effect in the unpredictable chronic mild stress model, which is likely to be associated with the regulation of the BDNF-TrkB signaling.

Lutein/zeaxanthin isomers regulate neurotrophic factors and synaptic plasticity in trained rats

Background/aim: This study was conducted to elucidate the effects of lutein/zeaxanthin isomers (L/Zi) on lipid metabolism, oxidative stress, NF-κB/Nrf2 pathways, and synaptic plasticity proteins in trained rats. Materials and methods: Wistar rats were distributed into four groups: 1) control, 2) L/Zi: rats received L/Zi at the dose of 100 mg/kg by oral gavage, 3) exercise, 4) exercise+L/Zi: rats exercised and received L/Zi (100 mg/kg) by oral gavage. The duration of the study was eight weeks. Results: Exercise combined with L/Zi reduced lipid peroxidation and improved antioxidant enzyme activities of muscle and cerebral cortex in rats (p < 0.001). In the Exercise + L/Zi group, muscle and cerebral cortex Nrf2 and HO-1 levels increased, while NF-κB levels decreased (p <0.001). Also, L/Zi improved BDNF, synapsin I, SYP, and GAP-43 levels of the cerebral cortex of trained rats (p < 0.001). The highest levels of BDNF, synapsin SYP, and GAP-43 in the cerebral cortex were determined in the Exercise+L/Zi group. Conclusion: These results suggested that exercise combined with L/Zi supplementation might be effective to reduce neurodegeneration via improving neurotrophic factors and synaptic proteins, and oxidative capacity in the cerebral cortex.

Enhancement of BDNF Expression and Memory by HDAC Inhibition Requires BET Bromodomain Reader Proteins.

Histone deacetylase (HDAC) inhibitors may have therapeutic utility in multiple neurological and psychiatric disorders, but the underlying mechanisms remain unclear. Here, we identify BRD4, a BET bromodomain reader of acetyl-lysine histones, as an essential component involved in potentiated expression of brain-derived neurotrophic factor (BDNF) and memory following HDAC inhibition. In in vitro studies, we reveal that pharmacological inhibition of BRD4 reversed the increase in BDNF mRNA induced by the class I/IIb HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). Knock-down of HDAC2 and HDAC3, but not other HDACs, increased BDNF mRNA expression, whereas knock-down of BRD4 blocked these effects. Using dCas9-BRD4, locus-specific targeting of BRD4 to the BDNF promoter increased BDNF mRNA. In additional studies, RGFP966, a pharmacological inhibitor of HDAC3, elevated BDNF expression and BRD4 binding to the BDNF promoter, effects that were abrogated by JQ1 (an inhibitor of BRD4). Examining known epigenetic targets of BRD4 and HDAC3, we show that H4K5ac and H4K8ac modifications and H4K5ac enrichment at the BDNF promoter were elevated following RGFP966 treatment. In electrophysiological studies, JQ1 reversed RGFP966-induced enhancement of LTP in hippocampal slice preparations. Last, in behavioral studies, RGFP966 increased subthreshold novel object recognition memory and cocaine place preference in male C57BL/6 mice, effects that were reversed by cotreatment with JQ1. Together, these data reveal that BRD4 plays a key role in HDAC3 inhibitor-induced potentiation of BDNF expression, neuroplasticity, and memory.SIGNIFICANCE STATEMENT Some histone deacetylase (HDAC) inhibitors are known to have neuroprotective and cognition-enhancing properties, but the underlying mechanisms have yet to be fully elucidated. In the current study, we reveal that BRD4, an epigenetic reader of histone acetylation marks, is necessary for enhancing brain-derived neurotrophic factor (BDNF) expression and improved memory following HDAC inhibition. Therefore, by identifying novel epigenetic regulators of BDNF expression, these data may lead to new therapeutic targets for the treatment of neuropsychiatric disorders.

Hydrogen Sulfide Ameliorates Cognitive Dysfunction in Formaldehyde-Exposed Rats: Involvement in the Upregulation of Brain-Derived Neurotrophic Factor.

OBJECTIVE: To investigate whether hydrogen sulfide (H2S) counteracts formaldehyde (FA)-induced cognitive defects and whether the underlying mechanism is involved in the upregulation of hippocampal brain-derived neurotrophic factor (BDNF) expression. METHODS: The cognitive function of rats was evaluated by the Morris water maze (MWM) test and the novel object recognition test. The content of superoxide dismutase (SOD) and malondialdehyde (MDA) in the hippocampus were detected by enzyme-linked immunosorbent assay (ELISA). The neuronal apoptosis in the hippocampal CA1 region was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end (TUNEL) staining. The expression of the BDNF protein was detected by Western blot and immunohistochemistry. RESULTS: We found that sodium hydrosulfide (NaHS, a donor of H2S) significantly reversed the impairment in the function of learning and memory in the MWM test and the novel objective recognition task induced by intracerebroventricular injection of FA. We also showed that NaHS significantly reduced the level of MDA, elevated the level of SOD, and decreased the amount of TUNEL-positive neurons in the hippocampus of FA-exposed rats. Moreover, NaHS markedly increased the expression of hippocampal BDNF in FA-exposed rats. CONCLUSIONS: H2S attenuates FA-induced dysfunction of cognition and the underlying mechanism is involved in the reduction of hippocampal oxidative damage and apoptosis as well as upregulation of hippocampal BDNF.

Does ketamine ameliorate the social stress-related bladder dysfunction in mice?

AIMS: The aim of this study is to investigate whether ketamine could relieve the social stress (SS)-related bladder dysfunction in mice. MATERIALS AND METHODS: The FVB mice were randomly assigned to either undergo SS exposure for 60 minutes per day on seven consecutive days for 4 weeks (SS1) or control without SS (SS0). The SS0 were then allocated to single or no injection of ketamine (SS0K1 and SS0K0). In the group of SS1, the SS1 mice were allocated to receive single injection of saline (SS1K0), single dose (SS1K1) or five daily dose of (SS1K5) ketamine injection (25 mg/kg/day/ip) since day 22. In vivo cystometry and tissue bath wire myography were performed on day 29. Serum and urine level of brain-derived neurotrophic factor (BDNF) were measured with enzyme-linked immunosorbent assay. RESULTS: In mice without social stress exposure, ketamine administration did not significantly affect voiding frequency (P > .05). SS1 K0 , SS1 K1, and SS1 K5 had significantly lower voiding frequency than that of control (SS1 K0 ) (each n = 15, P < .05). Ketamine administration reversed the trend of decreased voiding frequency in SS1 mice. Stressed mice had significant higher serum level of BDNF that reduced by short-term ketamine. Stressed mice had detrusor overactivity and impaired detrusor contractility which were not reversed by short-term ketamine. CONCLUSIONS: Social stress leads to elevated serum BDNF, infrequent voiding, detrusor overactivity, and impaired contractility. Short-term administration of ketamine may improve SS-related infrequent voiding and elevated serum BDNF level. However, ketamine did not improve SS-related bladder dysfunction on urodynamic and myography studies.

Maternal Folic Acid Supplementation During Pregnancy Promotes Neurogenesis and Synaptogenesis in Neonatal Rat Offspring.

Maternal folic acid supplementation during pregnancy is associated with improved cognitive performances in offspring. However, the effect of supplementation on offspring's neurogenesis and synaptogenesis is unknown, and whether supplementation should be continued throughout pregnancy is controversial. In present study, 3 groups of female rats were fed a folate-normal diet, folate-deficient diet, or folate-supplemented diet from 1 week before mating until the end of pregnancy. A fourth group fed folate-normal diet from 1 week before mating until mating, then fed folate-supplemented diet for 10 consecutive days, then fed folate-normal diet until the end of pregnancy. Offspring were sacrificed on postnatal day 0 for measurement of neurogenesis and synaptogenesis by immunofluorescence and western blot. Additionally neural stem cells (NSCs) were cultured from offspring's hippocampus for immunocytochemical measurement of their rates of proliferation and neuronal differentiation. The results demonstrated that maternal folic acid supplementation stimulated hippocampal neurogenesis by increasing proliferation and neuronal differentiation of NSCs, and also enhanced synaptogenesis in cerebral cortex of neonatal offspring. Hippocampal neurogenesis was stimulated more when supplementation was continued throughout pregnancy instead of being limited to the periconceptional period. In conclusion, maternal folic acid supplementation, especially if continued throughout pregnancy, improves neurogenesis and synaptogenesis in neonatal offspring.

Dammarane sapogenins attenuates stress-induced anxiety-like behaviors by upregulating ERK/CREB/BDNF pathways.

Dammarane sapogenins (DS), an extract derived from ginseng by alkaline hydrolysis of total ginsenosides, possesses high pharmacological activity and higher bioavailability than ginsenosides. The present study was designed to investigate the anxiolytic-like effects of DS in a mouse model of chronic social defeat stress (CSDS). DS (40 and 80 mg/kg) significantly ameliorated social avoidance and anxiety-like behavior in four test models of CSDS, showing increased time in the interaction zone in the social interaction test and in the center of the field in the open field test, an increased percentage of entries and open arm time in the elevated plus maze, and reduced latency to eat in the novelty-suppressed feeding test. Biochemical analyses showed that DS significantly reduced serum corticosterone levels and increased brain concentration of neurotransmitter 5-HT and noradrenaline in CSDS mice. Treatment with DS significantly upregulated BDNF (brain-derived neurotrophic factor), p-CREB/CREB and p-ERK1/2/ERK1/2 protein expression in the hippocampus and prefrontal cortex of CSDS mice. Collectively, these results suggest that DS exerts anxiolytic-like effects in CSDS model mice and the action is mediated, at least in part, by modulating the HPA (hypothalamic-pituitary-adrenal) axis and monoamine neurotransmitter levels, and via ERK/CREB/BDNF signaling pathway.

Imperatorin ameliorates learning and memory deficits through BDNF/TrkB and ERK/CaMKIIα/CREB signaling in prenatally-stressed female offspring.

Prenatal stress (PS) can lead to impaired spatial learning and memory in offspring. Imperatorin (IMP) is a naturally occurring furanocoumarin with many pharmacological properties. However, the effects of IMP on cognitive impairment induced by PS and the underlying molecular mechanisms remain unclear. We investigated the protective effect of IMP treatment after PS on learning and memory deficits in female offspring at postnatal 60 days. After treating prenatally-stressed offspring with IMP (15 and 30 mg/kg) for 28 days, we found that IMP increased body weight and ameliorated spatial learning and memory and working memory deficits in female offspring rats. Meanwhile, hippocampal Glu and serum corticosterone levels in prenatally-stressed offspring were significantly decreased after IMP administration. Additionally, IMP treatment significantly increased BDNF, TrkB, CaMKII, and CREB mRNA expression in the hippocampus of offspring rats. Furthermore, PS-mediated induction of RKIP protein and mRNA expression and glucocorticoid receptor protein expression in the hippocampus of offspring rats were significantly decreased by IMP treatment, and the protein expression of BDNF and TrkB and relative levels of p-EKR/ERK, p-CaMKIIα/CaMKIIα, and p-CREB/CREB were remarkably increased after IMP treatment. Taken together, IMP can ameliorate PS-induced learning and memory deficits through BDNF/TrkB and ERK/CaMKIIα/CREB signaling pathway and hypothalamic-pituitary-adrenal axis.

The potential effects of anticonvulsant drugs on neuropeptides and neurotrophins in pentylenetetrazol kindled seizures in the rat.

Purpose: Neuropeptides and neurotrophic factors are thought to be involved in epileptogenesis. This study aims to investigate the potential effects of anticonvulsant drugs on neuropeptides (galanin and neuropeptide Y) and neurotrophic factors (BDNF and NGF) in pentylenetetrazol (PTZ)-kindled seizures in the rat.Methods: Forty-eight adult male Sprague-Dawley rats were included in the study. The animals were divided into 8 groups of six rats. Group 1 was defined as naïve control, and received no medication. Group 2 (PTZ + saline) was treated with sub-convulsive doses of PTZ (35 mg/kg) and saline i.p. for 14 days. For anticonvulsant treatments, Groups 3-8 were treated with 200 mg/kg levetiracetam (PTZ + LEV), 1 mg/kg midazolam (PTZ + MDZ), 80 mg/kg phenytoin (PTZ + PHT), 80 mg/kg topiramate (PTZ + TPR), 40 mg/kg lamotrigine (PTZ + LMT) and 50 mg/kg sodium valproate (PTZ + SV), respectively. All anticonvulsant drugs were injected 30 min prior to PTZ injection throughout 14 days. Following treatment period, behavioral, biochemical and immunohistochemical studies were performed.Results: PTZ + saline group revealed significantly decreased galanin, NPY, BDNF and NGF levels compared to control. PTZ + MDZ group had significantly increased galanin, BDNF and NGF levels compared to saline group. Also, PTZ + LEV group showed increased BDNF levels. PTZ + saline group revealed significantly lower neuron count and higher GFAP (+) cells in hippocampal CA1-CA3 regions. All anticonvulsants significantly reduced hippocampal astrogliosis whereas only midazolam, levetiracetam, sodium valproate and lamotrigine prevented neuronal loss.Conclusion: Our results suggested that anticonvulsant drugs may reduce the severity of seizures, and exert neuroprotective effects by altering the expression of neuropeptides and neurotrophins in the epileptogenic hippocampus.

Cardiac autonomic tone, plasma BDNF levels and paroxetine response in newly diagnosed patients of generalised anxiety disorder.

Objective: The study examined the effect on cardiac autonomic tone via heart rate variability (HRV), brain derived neurotrophic factor (BDNF) in newly diagnosed generalised anxiety disorder (GAD) cases with paroxetine-controlled release (PX) CR intervention.Methods: Fifty GAD cases using DSM-5 criteria, matched with healthy controls (HC) were assessed with clinical measures (Hamilton Anxiety Scale (HAM-A), Clinical Global Impression- Severity Scale (CGI-Severity), General Health Questionnaire -12 (GHQ-12), HRV, plasma BDNF levels initially and 6 weeks postintervention with paroxetine CR.Results: HRV parameters were significantly lower in GAD vs HC at baseline for standard deviation of normal to normal intervals (SDNN) and proportion of differences in consecutive NN intervals that are longer than 50 ms (pNN50). Significantly higher plasma BDNF levels were noted between HC versus GAD at baseline. Postintervention HAM-A, CGI scores, GHQ-12 item scores showed significant reduction. Significant differences also noted in square root of mean squared difference of successive NN intervals (RMSSD), (SDNN), pNN50 and in plasma BDNF levels after intervention within GAD group. Significant negative correlation observed between HAM-A scores and SDNN parameter after taking PX CR in GAD.Conclusion: GAD showed cardiac autonomic dysfunction, lowered plasma BDNF levels and their improvement with paroxetine CR.Key messageGAD is associated with significantly lower HRV, suggestive of cardiac autonomic dysfunction and lowered plasma BDNF levels, an indicator of stress.Therapeutic intervention with Paroxetine in GAD patients showed clinically significant improvement reflecting restoration of the cardiac autonomic tone and BDNF levels, thus implying their role as potential biomarkers.