Reduction Of Brain-derived Neurotrophic Factor Research Articles

Environmental enrichment improves long-term memory impairment and aberrant synaptic plasticity by BDNF/TrkB signaling in nerve-injured mice

Nerve injury can induce memory impairment in mice. The aim of this research is to study the effect of environmental enrichment (EE) on long-term memory impairment in nerve-injured mice and the underlying mechanisms. Adult male C57BL/6 mice were received sham or chronic constriction injury (CCI) operation and reared in a standard environment (SE) or EE for 4 weeks after the operation. The pain threshold, long-term memory, expression of brain-derived neurotrophic factor (BDNF) and synaptic plasticity in hippocampus were determined. The results showed that CCI can induce the reduction in the mechanical and thermal pain thresholds, which were accompanied by long-term memory deficits in mice. CCI also induced the reduction of BDNF expression and synaptic plasticity impairments in the hippocampus, as represented by the dendritic spine density and postsynaptic density protein (PSD)-95 reduction, and long-term potential (LTP) dysfunction. Notably, EE can ameliorate the pain threshold and BDNF reduction, long-term memory deficits, and synaptic plasticity impairments in nerve-injured mice. However, the tropomyosin receptor kinase (Trk) B antagonist, ANA-12, blocked the EE-induced improvement in the long-term memory and synaptic plasticity impairment in nerve-injured mice. In conclusion, EE improved the pain threshold reduction, long-term memory and synaptic plasticity deficits in nerve-injured mice; BDNF / Trk B signaling may contribute to the relief of long-term memory and synaptic plasticity deficits induced by EE in nerve-injured mice.

Changes in exercise capacity and serum BDNF following long-term sprint interval training in well-trained cyclists.

The study determined the effects of sprint interval training on the acute and chronic changes of serum brain-derived neurotrophic factor (BDNF) and aerobic capacity. Twenty-six cyclists were divided into experimental (E) and control groups. Both groups executed a 6-month exercise intervention involving high-intensity interval training (HIIT) and continuous endurance training (CET) with group E replacing HIIT and CET sessions with sprint interval training (SIT) that was executed twice a week. Two exercise tests were administered prior to the intervention and at 2 and 6 months after study outset. Incremental exercise test assessed aerobic capacity by measuring maximal oxygen uptake and work output; the sprint interval exercise test (SIXT) comprises 3 sets of four 30-s all-out repetitions interspersed with 90 s of rest with sets separated by 25-40 min of active recovery. Oxygen uptake, work output, BDNF, and vascular endothelial growth factor A (VEGF-A) concentrations (baseline, 10 min after first set, and 10 and 60 min after third SIXT set) were taken during the SIXT. Significant decreases in BDNF relative to baseline values were observed 10 min after the first set and 60 min after the third set in group E at the 2- and 6-month assessments. Increases in baseline VEGF-A after 2 and 6 months of training and increases in maximal oxygen uptake after 2 months of training were also observed only in group E. The inclusion of SIT with HIIT and CET shows positive long-term effects, including increased maximal oxygen uptake and baseline VEGF-A and a reduction in BDNF below baseline levels during and after SIXT.

Research on changes in cognitive function, β-amyloid peptide and neurotrophic factor in stroke patients.

To investigate the changes as well as the related mechanism in cognitive function and levels of serum β-amyloid peptide (Aβ) and brain-derived neurotrophic factor (BDNF) in stroke patients. A total of 30 patients with acute stroke treated in our hospital from June 2015 to September 2016 were selected as stroke group, while 30 volunteers during the same period were enrolled as control group. Changes in cognitive function of patients were evaluated using the Montreal Cognitive Assessment (MoCA) and mini-mental state examination (MMSE) before and after the treatment. At the same time, the concentrations of serum Aβ1-40 and BDNF were detected, and their correlations with the MMSE score were analyzed. Finally, levels of serum cyclic adenosine monophosphate (cAMP) and phosphorylated-cAMP-response element binding protein (p-CREB), and the phosphorylation level of Tau protein were detected by Western blotting. MoCA and MMSE scores of patients in stroke group were significantly lower than those in control group (p < 0.01), and the scores were significantly higher in stroke patients after treatment than those before treatment (p < 0.01). Compared with those in control group, the serum Aβ1-40 concentration in patients in stroke group was significantly increased (p < 0.01), but the BDNF level was significantly decreased (p < 0.01). Compared with those before treatment, the serum Aβ1-40 concentration in patients was significantly decreased after treatment (p < 0.01), but the BDNF concentration was significantly increased (p < 0.01). Correlation analysis showed that the MMSE score was negatively correlated with the concentration of Aβ1-40 (r2 = 0.764, p < 0.01), but positively related to the level of BDNF (r2 = 0.827, p < 0.01). Compared with those in control group, the content of serum cAMP and p-CREB in stroke patients was significantly decreased (p < 0.01), but the expression of p-Tau was statistically increased (p < 0.01). The cognitive function in stroke patients is impaired, with the rising content of serum Aβ1-40 and reduction of BDNF, the mechanism of which is related to the decrease of cAMP and p-CREB and the increase of p-Tau. This provides a theoretical basis for searching the new therapeutic targets and new drugs for stroke.

Carob (Ceratonia siliqua L.) Prevents Short-Term Memory Deficit Induced by Chronic Stress in Rats.

Long-term exposure to stressful conditions could impair the normal brain structure and function, specifically the hippocampus-dependent memory. This impairment could be attributed to a decrease in brain-derived neurotrophic factor (BDNF) levels during chronic stress. Knowing that carob [Ceratonia siliqua L. (Fabaceae)] is rich in a wide variety of polyphenols with a high antioxidant value, we hypothesized that the methanolic carob extract (C. siliqua) pods will prevent stress-induced memory impairment. Hence, the methanolic extract of carob pods was investigated for its ability to enhance learning and memory as well as to protect from memory impairment in normal stressed animals. Rats were chronically stressed for 7weeks via the intruder stress model. Carob extract was administered to animals via intraperitoneal (i.p.) route at a daily dose of 50mg/kg. Radial arm water maze (RAWM) was utilized to test for spatial learning and memory. In addition, brain tissues were dissected to determine BDNF levels. Chronic stress (CS) impaired short-term spatial memory (number of committed errors: P < 0.05, days to criterion (DTC): P < 0.001). Animal treatment with carob pod extract prevented the short-term memory impairment induced by CS (P < 0.05), while such treatment showed no effect on memory functions of unstressed rats. Moreover, carob pod extract prevented the reduction in the hippocampal BDNF (P < 0.05) induced by chronic stress exposure. In conclusion, CS impaired short-term memory function, while methanolic extract of carob pods prevented this impairment, probably as a result of preventing reduction in BDNF levels in the hippocampus.

Brain-Derived Neurotrophic Factor Levels are Lower in Chronic Stroke Patients: A Relation with Manganese-dependent Superoxide Dismutase ALA16VAL Single Nucleotide Polymorphism through Tumor Necrosis Factor-α and Caspases Pathways

The manganese-dependent superoxide dismutase (MnSOD) Ala16Val single nucleotide polymorphism (SNP) has shown to be associated to risk factors of vascular diseases. Brain-Derived Neurotrophic Factor (BDNF) plays an essential role in the plasticity and neuronal regeneration of the brain after vascular injuries. However, little is known about interaction between MnSOD Ala16Val SNP on stroke, a frequent neurologic disease that involves various interacting pathways, such as vascular dysfunctions, inflammation, and neurotrophic factors. In this sense, the objective of this study was to investigate the relationship between MnSOD Ala16Val SNP with BDNF levels on stroke and also its influence on nitrosative stress, inflammatory, apoptotic, and DNA damage parameters. For this, 88 subjects were investigated, 44 subjects poststroke and 44 healthy controls. Questionnaires were applied to clinical characteristics and after laboratorial exams were collected. We analyzed levels of oxidative/nitrosative stress, inflammatory, apoptotic, and DNA damage markers. We showed a higher proportion of VV genotype in poststroke as compared to healthy subjects. Nitrite/nitrate, Tumor Necrosis Factor-α, Caspase 3 (CASP 3) and 8 (CASP 8) activation, Acethylcholinesterase (AChE), and Picogreen levels were higher in VV poststroke group, as well as BDNF and ACh levels were lower in VV and AV poststroke. We may suggest that V allele carries a worse outcome profile after stroke, relating to nitrosative stress, inflammatory, and apoptotic response. These events associated to a BDNF reduction, probably, contribute to the appearance or reincidence of stroke.

Association between Obesity and Circulating Brain-Derived Neurotrophic Factor (BDNF) Levels: Systematic Review of Literature and Meta-Analysis.

Reduction in brain-derived neurotrophic factor (BDNF) expression in the brain as well as mutations in BDNF gene and/or of its receptor are associated to obesity in both human and animal models. However, the association between circulating levels of BDNF and obesity is still not defined. To answer this question, we performed a meta-analysis carrying out a systematic search in electronic databases. Ten studies (307 obese patients and 236 controls) were included in the analysis. Our data show that obese patients have levels of BDNF similar to those of controls (SMD: 0.01, 95% CI: −0.28, 0.30, p = 0.94). The lack of difference was further confirmed both in studies in which BDNF levels were assessed in serum (MD: −0.93 ng/mL, 95% CI: −3.34, 1.48, p = 0.45) and in plasma (MD: 0.15 ng/mL, 95% CI: −0.09, 0.39, p = 0.23). Data evaluation has shown that some bias might affect BDNF measurements (e.g., subject recruitment, procedures of sampling, handling, and storage), leading to a difficult interpretation of the results. Standardization of the procedures is still needed to reach strong, affordable, and reliable conclusions.

Antidepressant-like Effects of p-Coumaric Acid on LPS-induced Depressive and Inflammatory Changes in Rats

Depression causes mental and physical changes which affect quality of life. It is estimated to become the second most prevalent disease, but despite its commonness, the pathophysiology of depression remains unclear and medicine is not sufficiently protective. p-Coumaric acid (p-CA) is a dietary phenolic acid which has been proven to have antifungal, anti-HIV, anti-melanogenic, antioxidant and anti-inflammatory effects. Considering these effects, we investigated whether p-CA can prevent depressive symptoms by reducing inflammatory cytokines in animals injected with lipopolysaccharide (LPS). Changes in despair-related behaviors, inflammatory cytokines, neurotrophic factors and synaptic activity were measured. In these animals, p-CA improved despair-related behavioral symptoms induced by LPS in the forced swim test (FST), tail suspension test (TST) and sucrose splash test (SST). p-CA also prevented the increase of inflammatory cytokines in the hippocampus such as cycloxigenase-2 and tumor necrosis factor-α due to LPS. Similarly, it prevented the reduction of brain-derived neurotrophic factor (BDNF) by LPS. Electrophysiologically, p-CA blocked the reduction of long-term depression in LPS-treated organotypic tissue slices. In conclusion, p-CA prevented LPS-induced depressive symptoms in animals, as determined by behavioral, biochemical and electrophysiological measures. These findings suggest the potential use of p-CA as a preventive and therapeutic medicine for depression.

Early Downregulation of p75NTR by Genetic and Pharmacological Approaches Delays the Onset of Motor Deficits and Striatal Dysfunction in Huntington's Disease Mice.

Deficits in striatal brain-derived neurotrophic factor (BDNF) delivery and/or BDNF/tropomyosin receptor kinase B (TrkB) signaling may contribute to neurotrophic support reduction and selective early degeneration of striatal medium spiny neurons in Huntington's disease (HD). Furthermore, we and others have demonstrated that TrkB/p75NTR imbalance in vitro increases the vulnerability of striatal neurons to excitotoxic insults and induces corticostriatal synaptic alterations. We have now expanded these studies by analyzing the consequences of BDNF/TrkB/p75NTR imbalance in the onset of motor behavior and striatal neuropathology in HD mice. Our findings demonstrate for the first time that the onset of motor coordination abnormalities, in a full-length knock-in HD mouse model (KI), correlates with the reduction of BDNF and TrkB levels, along with an increase in p75NTR expression. Genetic normalization of p75NTR expression in KI mutant mice delayed the onset of motor deficits and striatal neuropathology, as shown by restored levels of striatal-enriched proteins and dendritic spine density and reduced huntingtin aggregation. We found that the BDNF/TrkB/p75NTR imbalance led to abnormal BDNF signaling, manifested as a diminished activation of TrkB-phospholipase C-gamma pathway but upregulation of c-Jun kinase pathway. Moreover, we confirmed the contribution of the proper balance of BDNF/TrkB/p75NTR on HD pathology by a pharmacological approach using fingolimod. We observed that chronic infusion of fingolimod normalizes p75NTR levels, which is likely to improve motor coordination and striatal neuropathology in HD transgenic mice. We conclude that downregulation of p75NTR expression can delay disease progression suggesting that therapeutic approaches aimed to restore the balance between BDNF, TrkB, and p75NTR could be promising to prevent motor deficits in HD.

AMPA Receptor Activation–Independent Antidepressant Actions of Ketamine Metabolite (S)-Norketamine

BackgroundKetamine, an N-methyl-D-aspartate receptor antagonist, exerts robust antidepressant effects in patients with treatment-resistant depression. The precise mechanisms underlying ketamine’s antidepressant actions remain unclear, although previous research suggests that alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) activation plays a role. We investigated whether (S)-norketamine and (R)-norketamine, the two main metabolites of (R,S)-ketamine, also play a significant role in ketamine’s antidepressant effects and whether the effects are mediated by AMPAR. MethodsCellular mechanisms of antidepressant action of norketamine enantiomers were examined in mice. Results(S)-Norketamine had more potent antidepressant effects than (R)-norketamine in inflammation and chronic social defeat stress models. Furthermore, (S)-norketamine induced more beneficial effects on decreased dendritic spine density and synaptogenesis in the prefrontal cortex and hippocampus compared with (R)-norketamine. Unexpectedly, AMPAR antagonists did not block the antidepressant effects of (S)-norketamine. The electrophysiological data showed that, although (S)-norketamine inhibited N-methyl-D-aspartate receptor–mediated synaptic currents, (S)-norketamine did not enhance AMPAR-mediated neurotransmission in hippocampal neurons. Furthermore, (S)-norketamine improved reductions in brain-derived neurotrophic factor–tropomyosin receptor kinase B signaling in the prefrontal cortex of mice susceptible to chronic social defeat stress, whereas the tropomyosin receptor kinase B antagonist and a mechanistic target of rapamycin inhibitor blocked the antidepressant effects of (S)-norketamine. In contrast to (S)-ketamine, (S)-norketamine did not cause behavioral abnormalities, such as prepulse inhibition deficits, reward effects, loss of parvalbumin immunoreactivity in the medial prefrontal cortex, or baseline gamma-band oscillation increase. ConclusionsOur data identified a novel AMPAR activation–independent mechanism underlying the antidepressant effects of (S)-norketamine. (S)-Norketamine and its prodrugs could be novel antidepressants without the detrimental side effects of (S)-ketamine.

The miR206-JunD Circuit Mediates the Neurotoxic Effect of Methylmercury in Cortical Neurons

Methylmercury (MeHg) causes neuronal death through different pathways. Particularly, we found that in cortical neurons it increased the expression of Repressor Element-1 Silencing Transcription Factor (REST), histone deacetylase (HDAC)4, Specificity Protein (Sp)1, Sp4, and reduced the levels of brain-derived neurotrophic factor (BDNF). Herein, in rat cortical neurons we investigated whether microRNA (miR)206 can modulate MeHg-induced cell death by regulating REST/HDAC4/Sp1/Sp4/BDNF axis. MeHg (1 µM) reduced miR206 expression after both 12 and 24 h and miR206 transfection prevented MeHg-induced neuronal death. Furthermore, miR206 reverted MeHg-induced REST and Sp4 increase and BDNF reduction at gene and protein level, and reverted HDAC4 protein increase, but not HDAC4 mRNA upregulation. Moreover, since no miR206 seed sequences were identified in the 3'-untranslated regions (3'-UTRs) of REST and SP4, we investigated the role of JunD, that presents a consensus motif on REST, Sp4, and BDNF promoters. Indeed, MeHg increased JunD mRNA and protein levels, and JunD knockdown counteracted MeHg-induced REST, Sp4 increase, but not BDNF reduction. Furthermore, we identified a miR206 binding site in the 3'-UTR of JunD mRNA (miR206/JunD) and mutagenesis of miR206/JunD site reverted JunD luciferase activity reduction induced by miR206. Finally, miR206 prevented MeHg-increased JunD binding to REST and Sp4 promoters, and MeHg-reduced BDNF expression was determined by the increase of HDAC4 binding on BDNF promoter IV. Collectively, these results suggest that miR206 downregulation induced by MeHg exposure determines an upregulation of HDAC4, that in turn downregulated BDNF, and the activation of JunD that, by binding REST and Sp4 gene promoters, increased their expression.

Abstract WP418: Mineralocorticoid Receptor Signaling is Associated With Neuroinflammation and Changes in Cognitive Function in Angiotensin II-Induced Hypertension

Introduction: Mineralocorticoid receptor (MR) activation facilitates hypertension-associated cerebral artery dysfunction and reduced perfusion that may increase the risk for vascular dementia. Hypothesis: Angiotensin II (AngII)-hypertension results in neuroinflammation and oxidative stress that will impair cognition in a MR-dependent manner. Methods: 16-17 week old male C57bl/6 mice were treated with AngII (800ng/kg/min) ± the MR antagonist, eplerenone (EPL;100mg/kg/day) for 4 weeks; Sham mice served as control. Data are presented as mean ± SEM; n=4-12 per group *=different from Sham. Results: AngII reduced astrocyte density and increased microglial density; the changes in microglia were prevented by EPL. AngII reduced the mRNA expression of brain-derived neurotrophic factor (BDNF), doublecortin, glial fibrillary acidic protein (GFAP), and synaptophysin (SYP); the reductions in BDNF, GFAP and SYP mRNA expression were prevented by EPL. We assessed cognitive function using the Barnes maze; AngII treated mice spent less time in the target quadrant than the sham or AngII+EPL mice. There was a trend toward there being an increase in the latency to reach the target quadrant in the AngII mice but the changes were not significant. Changes in nest building are associated with cognitive decline, nest building was impaired in AngII mice and these changes were prevented by EPL. There was a trend for oxidized proteins to be increased in AngII mice that may be prevented by EPL but these changes were not significant. Preliminary studies suggest that AngII changes the morphology of cortical neurons suggesting that the increased blood pressure may lead to unhealthy neurons. Conclusion: AngII-hypertension results in neuroinflammation and creates an environment where markers for neuronal support and synapse formation are impaired. These changes are regulated by MR signaling and may be associated with the declined cognitive function.

Both Ketamine and NBQX Attenuate Alcohol-Withdrawal Induced Depression in Male Rats.

The co-morbidity between heavy drinking and depression can negatively influence successful cessation of alcohol use. Since ketamine, a glutamatergic NMDA receptor antagonist, has shown promise as a quick-acting antidepressant, we studied its effects specifically on alcohol withdrawal-induced depression. We also evaluated the effects of NBQX an AMPA/kainate receptor antagonist, because some of the effects of ketamine are proposed to be indirectly mediated through these receptors. Adult male Wistar rats were exposed daily to ethanol via inhalation chambers 4 h/day for 7 days (blood alcohol concentration=160 mg%), followed by daily intraperitoneal injections of ketamine (2.5 mg/kg), NBQX (5mg/kg), alone or in combination. Eighteen hours later, open field locomotor activity (OFLA) followed by forced swim test (FST) were performed. The animals were sacrificed 2 h later for evaluation of brain-derived neurotrophic factor (BDNF) in the hippocampus. Alcohol withdrawal did not affect OFLA, but caused an increase in immobility in FST, suggesting induction of “depressive-like” helplessness. Both ketamine and NBQX normalized the swimming score in FST. The combination of the two drugs, however, cancelled each other’s effect. Parallel to these behavioral observations, both ketamine and NBQX normalized the reduction in hippocampal BDNF caused by alcohol withdrawal. Here also, the combination of the two drugs cancelled each other’s effect. These results suggest that either NMDA or AMPA/kainate receptor antagonists, acting at least partially through hippocampal BDNF, may be of therapeutic potential in alcohol use disorder.

Vitamin D is associated with metabotropic but not neurotrophic effects of exercise in ovariectomized rats

PurposeHere, we studied the beneficial effects of aerobic exercise on metabolic syndrome components, cognitive performance, brain derived neurotrophic factor (BDNF) and irisin in ovariectomized rats with different serum vitamin D (Vit D) status.MethodsEighty female wistar rats were divided into 2 groups of sham operated (sham, n = 8), and ovariectomized (OVX, n = 72). Then OVX were divided into 9 groups of receiving combination of exercise protocol with low dose of Vit D (OVX + EXE + LD), high dose of Vit D (OVX + EXE + HD), Vit D deficiency (OVX + EXE − D), and (OVX + EXE + Veh). Also non exercised groups of OVX receiving high dose of Vit D (OVX + HD), low dose of Vit D (OVX + LD), Vit D deficiency (OVX − D), and Veh (OVX + Veh) were included. After 2 months of related interventions, spatial memory was assessed using Morris water maze (MWM), and then metabolic syndrome components were measured.ResultsHigh dose of Vit D supplementation showed significant reduction in weight (p = 0.001), lipid profiles (p = 0.001), visceral fat (p = 0.001) and waist circumference (p = 0.001) regardless of exercising or not, with no change in cognitiive function. Serum BDNF level was significantly higher in Vit D deficient group (p = 0.001), and was decreased in the OVX + HD. In contrary, irisin did not show any significant relationship with serum concentration of Vit D, while it was significantly elevated in the exercised groups compared with non-exercised counterparts.ConclusionVit D insufficiency deteriorates metabolic syndrome components, and elevates serum BDNF as a compensatory metabotropic factor, and further supplementation significantly attenuates these components parallel with reduction in BDNF. In addition, aerobic exercise successfully induces various metabolic benefits, provided optimum serum level of Vit D.

Distinct modifications of hippocampal glucocorticoid receptor phosphorylation and FKBPs by lipopolysaccharide in depressive female and male rats.

Inflammation plays a critical role in pathogenesis of depression and can affect the hypothalamic-pituitary-adrenal axis activity. Accordingly, in this study we investigated the role of hippocampal glucocorticoid receptor in mediating the effects of inflammation on behaviour of female and male Wistar rats. We studied the effects of lipopolysaccharide on the levels of glucocorticoid receptors and its co-chaperones FK506 binding protein 52 and FK506 binding protein 51, the levels of glucocorticoid receptor phospho-isoforms, pGR-232 and pGR-246, and glucocorticoid receptor up-stream kinases. In order to assess transcriptional activity of glucocorticoid receptor, we measured mRNA levels of several glucocorticoid receptor-regulated genes. We demonstrated that lipopolysaccharide induced depressive-like behaviour and elevated serum corticosterone in both sexes. However, it affected glucocorticoid receptor signalling in the nucleus of females and males differently - in females it elevated levels of glucocorticoid receptors, pGR-246 and FK506 binding protein 52, while in males it decreased levels of glucocorticoid receptor, both co-chaperons and pGR-246. Alterations in pGR-246 were associated with alterations of c-Jun N-terminal kinases. Altered nuclear levels of total glucocorticoid receptors and pGR-246 were accompanied by sex-specific reduction in brain-derived neurotrophic factor and cyclooxygenase-2 mRNA and sex-unspecific reduction in the expression of p11 and glucocorticoid receptor genes. These alterations may ultimately affect different glucocorticoid receptor -associated processes involved in depressive-like behaviour in males and females.

Long-term voluntary exercise prevents post-weaning social isolation-induced cognitive impairment in rats

This study aimed to determine the effect of exercise on locomotion, anxiety-related behavior, learning, and memory in socially isolated post-weaning rats, as well as the correlation between exercise and the concentration of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the hippocampus. Rats were randomly assigned to three groups: the control group; the social isolation group; the social isolation plus exercise (SIE) group. Social isolation conditions, with or without exercise were maintained for 90d, and then multiple behavioral tests, including the open-field test, elevated plus maze test, and Morris water maze (MWM) test were administered. Following behavioral assessment, hippocampal tissue samples were obtained for measurement of BDNF and NGF. There wasn’t a significant difference in locomotor activity between the groups (P>0.05). Anxiety scores were higher in the socially isolated group (P<0.05) than in the SIE group (P<0.05). According to the probe trial session of the MWM test results, exercise training improved platform crossings’ number in the socially isolated rats (P<0.05). Exercise training ameliorated social isolation-induced reduction in hippocampal BDNF and NGF content (P<0.05). These findings suggest that exercise training improves cognitive functions via increasing hippocampal BDNF and NGF concentrations in socially isolated post-weaning rats.

Harmine produces antidepressant-like effects via restoration of astrocytic functions

Depression is a world-wide disease with no effective therapeutic methods. Increasing evidence indicates that astrocytic pathology contributes to the formation of depression. In this study, we investigated the effects of harmine, a natural β-carboline alkaloid and potent hallucinogen, known to modulate astrocytic glutamate transporters, on chronic unpredictable stress (CUS)-induced depressive-like behaviors and astrocytic dysfunctions. Results showed that harmine treatment (10, 20mg/kg) protected the mice against the CUS-induced increases in the immobile time in the tail suspension test (TST) and forced swimming test (FST), and also reversed the reduction in sucrose intake in the sucrose preference experiment. Harmine treatment (20mg/kg) prevented the reductions in brain-derived neurotrophic factor (BDNF) protein levels and hippocampal neurogenesis induced by CUS. In addition, harmine treatment (20mg/kg) increased the protein expression levels of glutamate transporter 1 (GLT-1) and prevented the CUS-induced decreases in glial fibrillary acidic protein (GFAP) protein expressions in the prefrontal cortex and hippocampus, suggesting that restoration of astrocytic functions may be a potential mechanism underlying the antidepressant-like effects of harmine. This opinion was proved by the results that administration of mice with l-Alpha-Aminoadipic Acid (L-AAA), a gliotoxin specific for astrocytes, attenuated the antidepressant-like effects of harmine, and prevented the improvement effects of harmine on BDNF protein levels and hippocampal neurogenesis. These results provide further evidence to confirm that astrocytic dysfunction contributes critically to the development of depression and that harmine exerts antidepressant-like effects likely through restoration of astrocytic functions.

Effect of Melatonin and Resveratrol against Memory Impairment and Hippocampal Damage in a Rat Model of Vascular Dementia

Objectives: This study was intended to investigate whether treatment with resveratrol and melatonin alone or in combination can exert neurorestorative effects in a rat model of vascular dementia. Methods: Briefly, male Wistar rats were subjected to permanent bilateral common carotid artery occlusion (BCCAO) by surgery. After 4 weeks, the cognitive deficits were assessed using the Morris water maze and novel object recognition tests. The biochemical parameters of oxidative stress and inflammation were also assessed. Results: Rats in the BCCAO group showed cognitive deficits, accompanied by oxidonitrosative stress, neuroinflammation, and a reduction in brain-derived neurotrophic factor (BDNF) in the hippocampus region. Moreover, the acetylcholinesterase activity in the hippocampus was found to be increased in the BCCAO group compared to the sham group. The 4-week treatment with melatonin (10 mg/kg) and resveratrol (20 mg/kg) alone and in combination (melatonin 5 mg/kg and reseveratrol 10 mg/kg) caused a significant improvement in the cognitive deficits induced by BCCAO, accompanied by a reversal of oxidonitrosative stress, neuroinflammation, and BDNF depletion in the hippocampus region. Additionally, the treatment with melatonin and resveratrol significantly decreased acetylcholinesterase activity compared to in the BCCAO group. Melatonin and resveratrol ameliorated the BDNF expression of hippocampal protein. Conclusion: These results emphasize that coadministration of melatonin and resveratrol can be beneficial in BCCAO-induced vascular dementia through changes in BDNF expressions.

Anxiolytic effects of muscarinic acetylcholine receptors agonist oxotremorine in chronically stressed rats and related changes in BDNF and FGF2 levels in the hippocampus and prefrontal cortex.

In depressive disorders, one of the mechanisms proposed for antidepressant drugs is the enhancement of synaptic plasticity in the hippocampus and cerebral cortex. Previously, we showed that the muscarinic acetylcholine receptor (mAChR) agonist oxotremorine (Oxo) increases neuronal plasticity in hippocampal neurons via FGFR1 transactivation. Here, we aimed to explore (a) whether Oxo exerts anxiolytic effect in the rat model of anxiety-depression-like behavior induced by chronic restraint stress (CRS), and (b) if the anxiolytic effect of Oxo is associated with the modulation of neurotrophic factors, brain-derived neurotrophic factor (BDNF) and fibroblast growth factor-2 (FGF2), and phosphorylated Erk1/2 (p-Erk1/2) levels in the dorsal or ventral hippocampus and in the medial prefrontal cortex. The rats were randomly divided into four groups: control unstressed, CRS group, CRS group treated with 0.2mg/kg Oxo, and unstressed group treated with Oxo. After 21days of CRS, the groups were treated for 10days with Oxo or saline. The anxiolytic role of Oxo was tested by using the following: forced swimming test, novelty suppressed feeding test, elevated plus maze test, and light/dark box test. The hippocampi and prefrontal cortex were used to evaluate BDNF and FGF2 protein levels and p-Erk1/2 levels. Oxo treatment significantly attenuated anxiety induced by CRS. Moreover, Oxo treatment counteracted the CRS-induced reduction of BDNF and FGF2 levels in the ventral hippocampus and medial prefrontal cerebral cortex CONCLUSIONS: The present study showed that Oxo treatment ameliorates the stress-induced anxiety-like behavior and rescues FGF2 and BDNF levels in two brain regions involved in CRS-induced anxiety, ventral hippocampal formation, and medial prefrontal cortex.

BDNF concentrations and daily fluctuations differ among ADHD children and respond differently to methylphenidate with no relationship with depressive symptomatology.

Brain-derived neurotrophic factor (BDNF) enhances the growth and maintenance of several monoamine neuronal systems, serves as a neurotransmitter modulator and participates in the mechanisms of neuronal plasticity. Therefore, BDNF is a good candidate for interventions in the pathogenesis and/or treatment response of attention deficit hyperactivity disorder (ADHD). We quantified the basal concentration and daily fluctuation of serum BDNF, as well as changes after methylphenidate treatment. A total of 148 children, 4-5years old, were classified into groups as follows: ADHD group (n=107, DSM-IV-TR criteria) and a control group (CG, n=41). Blood samples were drawn at 2000 and 0900 hours from both groups, and after 4.63±2.3months of treatment, blood was drawn only from the ADHD group for BDNF measurements. Factorial analysis was performed (Stata software, version 12.0). Morning BDNF (36.36±11.62ng/ml) in the CG was very similar to that in the predominantly inattentive children (PAD), although the evening concentration in the CG was higher (CG 31.78±11.92 vs PAD 26.41±11.55ng/ml). The hyperactive-impulsive group, including patients with comorbid conduct disorder (PHI/CD), had lower concentrations. Methylphenidate (MPH) did not modify the concentration or the absence of daily BDNF fluctuations in the PHI/CD children; however, MPH induced a significant decrease in BDNF in PAD and basal day/night fluctuations disappeared in this ADHD subtype. This profile was not altered by the presence of depressive symptoms. Our data support a reduction in BDNF in untreated ADHD due to the lower concentrations in PHI/CD children, which is similar to other psychopathologic and cognitive disorders. MPH decreased BDNF only in the PAD group, which might indicate that BDNF is not directly implicated in the methylphenidate-induced amelioration of the neuropsychological and organic immaturity of ADHD patients.

The potential therapeutic effect of BDNF on GABAergic neuroplasticity dysfunction in late-life anxiety

Late-life anxiety has a high prevalence and usually co-morbidity with cerebral- and cardiovascular diseases which in turn increases the disability and mortality in old people. The pathology of late-life anxiety is difference from adult with the character of GABAergic neuroplasticity dysfunction. The therapeutic strategy presently can only alleviate the anxious symptom but not ameliorate the neuroplasticity. Brain-derived neurotrophic factor (BDNF) is a critical signaling molecule which regulates the GABAergic neuroplasticity, reduction of BDNF along with aging can induce GABAergic dysfunction which contributes to late-life anxiety. BDNF may exert anxiolytic effects by restoring the GABAergic plasticity and can be a potential therapeutic strategy of late-life anxiety. Key words: Late-life anxiety; Dysfunction of neuroplasticity; Neurotrophic mechanism; GABA; BDNF