Brain-derived Neurotrophic Factor System Research Articles

Brain-Derived Neurotrophic Factor Levels and Its Val66Met Gene Polymorphism Predict Tardive Dyskinesia Treatment Response to Ginkgo Biloba

Tardive dyskinesia (TD) has no well-accepted treatments or known pathophysiology, but low brain-derived neurotrophic factor (BDNF) may play an important role in its pathophysiology. Ginkgo biloba (EGb-761) is a potent antioxidant that has neuroprotective effects mediated through enhancing BDNF levels. We hypothesized that treatment with EGb-761 would increase serum BDNF levels and reduce TD, particularly among schizophrenia patients who have the BDNF valine 66 to methionine (Val66Met) genotype (Val/Val). Serum BDNF levels and genotyping for the BDNF gene Val66Met polymorphism were assessed in Chinese schizophrenic patients with (n = 368) and without (n = 563) TD as well as healthy control subjects (n = 546). About half of the TD patients (n = 157) then participated in a double-blind, randomized, placebo-control 12-week treatment with 240 mg per day of EGb-761. Serum BDNF levels were measured again at posttreatment. Clinical efficacy was determined using the Abnormal Involuntary Movement Scale (AIMS). TD patients had lower BDNF levels than the non-TD patients and healthy controls. EGb-761 treatment improved symptoms of TD and increased BDNF levels compared with placebo treatment. Moreover, the improvement of AIMS total score correlated with the increase in BDNF levels. Furthermore, improvement in the AIMS score was greatest in those with the Val/Val allele and lowest with the Met/Met allele. The BDNF system may be implicated in the pathophysiology of TD and its improvement with antioxidant treatment. Furthermore, patients with the genetic potential for greater BDNF release (Val/Val at 66) may obtain a greater reduction in TD from EGb-761 treatment.

Is BDNF biological link between depression and type 2 diabetes mellitus?

Epidemiological and clinical studies have demonstrated a strong association between depression and diabetes. Of note, depression is a risk factor for the development of type 2 diabetes mellitus (T2DM), while most patients with T2DM also have depression. Despite the abundance of evidence showing an epidemiological link between depression and T2DM, the cause of this association is still unknown. Brain-derived neurotrophic factor (BDNF) is widely expressed in the brain. Biological and clinical studies have repeatedly shown that BDNF is important in the pathogenesis of depression and T2DM. Therefore, we propose that BDNF may play an important role linking depression and T2DM. Studies examining the components of the BDNF system in patients with T2DM and depression may provide new understanding into the link between depression and T2DM. Such studies might also help us to identify potential treatment targets for these two common disorders.

Physical activity level in Achilles tendinosis is associated with blood levels of pain‐related factors: a pilot study

Physical activity affects the pain symptoms for Achilles tendinosis patients. Brain-derived neurotrophic factor (BDNF), tumor necrosis factor-alpha (TNF-α) and their receptors have been detected in human Achilles tendon. This pilot study aimed to compare serum BDNF and soluble tumor necrosis factor receptor I (sTNFRI) levels in Achilles tendinosis patients and healthy controls and to examine the influence of physical activity, and BMI and gender, on these levels. Physical activity was measured with a validated questionnaire, total physical activity being the parameter analyzed. Physical activity was strongly correlated with BDNF among tendinosis women [Spearman's rho (ρ)=0.90, P<0.01] but not among control women (ρ=-0.08, P=0.83), or among tendinosis and control men. Physical activity was significantly correlated with sTNFRI in the entire tendinosis group and among tendinosis men (ρ=0.65, P=0.01), but not in the entire control group or among control men (ρ=0.04, P=0.91). Thus, the physical activity pattern is related to the TNF and BDNF systems for tendinosis patients but not controls, the relationship being gender dependent. This is new information concerning the relationship between physical activity and Achilles tendinosis, which may be related to pain for the patients. This aspect should be further evaluated using larger patient materials.

Abstract 4337: Interactions of brain-derived neurotrophic factor (BDNF) and neuropeptide Y (NPY) systems in neuroblastoma: New insight into mechanisms of BDNF's pro-survival effects

Abstract BDNF is a known survival factor for neuroblastomas (NB) and is implicated in the development of their chemoresistance. NPY, on the other hand, is a sympathetic neurotransmitter, which is highly released from NB tumors. The elevated NPY levels in NB patients are associated with poor clinical outcome, which is in agreement with its Y2 receptor (Y2R)-mediated proliferative effects on NB cells and pro-angiogenic activities. In normal sympathetic neurons, BDNF has been shown to up-regulate NPY expression, while NPY itself has been implicated in promoting their survival. Therefore, we sought to determine if similar interactions between BDNF and NPY systems occur in NB cells. We have found that BDNF up-regulates expression of both NPY and its Y2Rs in native NB cells, as well as SH-SY5Y cells transfected with BDNF receptor – TrkB (SH-SY5Y/TrkB). However, even more dramatically, BDNF induces expression of another NPY receptor – Y5R, which is not detectable in most NB cell lines under basal conditions. In agreement with this, expression of Y5Rs correlated with TrkB and BDNF expression in human NB samples. In addition, Y5R seems to be directly involved in BDNF signaling. In SH-SY5Y/TrkB cells, BDNF-induced activation of p44/42 MAPK is significantly reduced by selective Y5R antagonist, CGP 71683, but not by Y2R antagonist, BIIE 0246. Interestingly, the Y5R antagonist had no effect on Akt activation stimulated by BDNF. Thus, these data suggest specific cross-talk between TrkB and Y5R signaling leading to activation of p44/42 MAPK pathway. Since BDNF is a known survival factor for NB cells, we sought to determine if pro-survival activity of BDNF is mediated by NPY. Chemotherapy was found to up-regulate the expression of both BDNF and NPY systems. This was further supported by elevated expression of NPY and its Y5Rs in cells derived from a chemotherapy-treated patient (CHLA-20, SMS-KANR) as compared to cells derived from primary tumors of the same patient (CHLA-15, SMS-KAN). In the functional studies, NPY mimicked the anti-apoptotic effect of BDNF in chemotherapy-treated NB cells. Moreover, as observed with MAPK activation, blocking Y5Rs, but not Y2Rs, reduced the pro-survival activity of BDNF in these cells. In summary, while Y2R is the main NPY R constitutively expressed in NBs and responsible for its proliferative effect, expression of Y5R is induced by BDNF and chemotherapy, subsequently enhancing the pro-survival functions of NPY. These anti-apoptotic actions of NPY can additionally augment the known direct survival effects of BDNF. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4337. doi:10.1158/1538-7445.AM2011-4337

P02-226 - BDNF Val66Met modulates 5-HTTLPR for develop neuroticism in borderline personality disorder

Brain derived neurotrophic factor (BDNF) is the most widely distributed and highly expressed neurotrophin in the CNS. BDNF gene have been associated with increased risk psychiatric disorders. It has been described interaction between BDNF and serotonin system at a neural and genetic level. Neuroticism as a personality trait relevant in borderline personality disorder (BPD) has genetic inheritance and is associated with serotonergic dysfunction. Has been reported that BDNF Val66Met variant is associated with neuroticism in general population. The aim of this study is to test the association between Val66Met and neuroticism and evaluate if the presence of Val66Met allele interacts with polymorphism in promoter region of serotonin transporter gene (5-HTTLPR) for develop neuroticism in BPD. We evaluate personality with NEO PI R in 104 BPD subjects that did not meet criteria for axis I diagnoses and other personality disorders. Genetic analysis of BDNF was performed determining the presence of Val/Val Val/Met and Met/Met BDNF variants. 5-HTTLPR was performed determining the presence of L and S 5-HTTLPR alleles. Statistical analysis were tested with parametric and correlation method with Stata10. We did not found differences in neuroticism between BDNF variants, but when controlled by BDNF alleles we found that Met/Met modulate the expression of 5-HTTLPR, with S-carriers (LS+SS) having higher neuroticism than LL (F = 6.36, p = 0.0031). We found no differences in expression of 5-HTTLPR in other BDNF variants. We conclude that BDNF have a differential modulating effect of 5-HTTLPR in neuroticism in BPD.

Role of BDNF val66met polymorphism on the association between physical activity and incident dementia

Increased physical activity may have beneficial effects on cognitive outcomes; a role of brain-derived neurotrophic factor (BDNF) has been suggested in animal models but not yet tested in humans. This study investigated modification by BDNF val66met polymorphism of the association between physical activity, incident dementia and other cognitive outcomes. Of 732 community elders, 107 had dementia at baseline, and 518 (83%) of the remainder were followed over 2.4 years. Cognitive impairment and decline were defined from Mini-Mental State Examination scores. Self-reported level of physical activity was recorded on a 4-point scale. BDNF val66met and apolipoprotein E genotypes were ascertained. Covariates included age, sex, education, depression, vascular risk factors, and instrumental activities of daily living. Baseline lower physical activity was significantly associated with incident dementia as well as with baseline dementia and cognitive impairment and incident cognitive decline. BDNF val66met polymorphism itself was not associated with any cognitive outcome. However, the strength of association between lower activity and all cognitive outcomes increased incrementally with the number of met alleles, and was strongest in those with the met/met genotype. BDNF×activity interaction terms were stronger for prospective outcomes (incident dementia, cognitive decline) compared to cross-sectional outcomes (prevalent dementia, cognitive impairment no dementia). This study supports a previously suggested neurobiological basis for the effects of physical activity on dementia involving the BDNF system since the met allele is recognised to be associated with lower activity-dependent secretion of BDNF.

Glutamatergic and dopaminergic system genes polymorphism in prefrontal tests performance in schizophrenia, bipolar disorders and in healthy subjects

Prefrontal functions impairment in schizophrenia and bipolar disorder are are markers of vulnerability to the diseases. Our previous data showed association between Wisconsin Card Sorting Test (WCST) performance in schizophrenia with the polymorphism of dopaminergic genes)COMT, DRD 1) and with polymorphism of Brain-derived neurotrophic factor (BDNF) in bipolar disorders. The Src-family tyrosine kinase Fyn plays important role in the interaction between BDNF and glutamatergic receptor NMDA in prefrontal cortex. The possible association between the polymorphisms of BDNF and Fyn genes and performance on WCST and N-back tests in healthy subjects were assessed in 200 healthy persons, genotyped for the two polymorphism of BDNF gene (C/T, Val66Met) and three polymorphisms of the Fyn gene (-93 A/G, IVS10+37T/C, Ex12+894T/G). In the whole group, the T/T genotype of C-270T BDNF polymorphism was associated with higher percentage of conceptual responses on WCST. Male subjects with C/T genotype obtained better results on percentage of correct reactions in N-back test. No significant differences between any of Fyn gene polymorphisms and WCST performance were found. Better results on percentage of correct reactions in N-back test were obtained by subjects with G/G genotype of 93A/G polymorphism and with G/G genotype of FYN T/G polymorphism. Female subjects having T/T polymorphism of T/C polymorphism performed better as to percentage of correct reactions in N-back test. The results obtained may suggest a contribution of BDNF and glutamatergic system genes to working memory efficiency in healthy subjects and bipolar disorder, while in schizophrenia with dopaminergic system genes.

Central and Medial Amygdaloid Brain-Derived Neurotrophic Factor Signaling Plays a Critical Role in Alcohol-Drinking and Anxiety-Like Behaviors

Brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor family of neurotrophins and plays a vital role in synaptic plasticity. This study investigated the involvement of the amygdaloid BDNF system in molecular mechanisms underlying anxiety and alcohol-drinking behaviors. Male Sprague Dawley rats were cannulated targeting central amygdala (CeA), medial amygdala (MeA), or basolateral amygdala (BLA), and BDNF expression was manipulated using an antisense oligodeoxynucleotide (ODN) strategy. Anxiety-like and alcohol-drinking behaviors were measured after infusion of BDNF sense and antisense ODNs with or without BDNF coinfusion, using the elevated plus-maze test and two-bottle free-choice paradigm, respectively. Here we report that BDNF antisense ODN infusions into the CeA and MeA, but not BLA, provoked anxiety-like behaviors in rats, which were rescued by BDNF coinfusion. The levels of BDNF, p-ERK1/2 (phosphorylated extracellular signal-regulated kinases 1/2), and p-CREB (phosphorylated cAMP responsive-element binding protein) were decreased by BDNF antisense, but not by sense, ODN infusions, which were restored to normal after BDNF coinfusions. Furthermore, BDNF antisense ODN infusions into the CeA or MeA, but not into BLA, increased alcohol intake, which was attenuated by BDNF coinfusions. These novel results suggest that decreased BDNF levels in the CeA and MeA, but not in the BLA, are crucial in regulating alcohol-drinking and anxiety-like behaviors in rats.

Chronic corticosterone decreases brain-derived neurotrophic factor (BDNF) mRNA and protein in the hippocampus, but not in the frontal cortex, of the rat

This study examined the effects of chronic corticosterone (32 mg/kg/day, s.c., 21 days) on brain-derived neurotrophic factor (BDNF) mRNA and protein in the frontal cortex and hippocampus of the rat. Because evidence suggests that BDNF is an important determinant of the function of the 5-hydroxytryptamine (5-HT) system, we also quantified tissue levels of 5-HT and its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA), to investigate if changes in BDNF mRNA and protein paralleled changes in the 5-HT system. Corticosterone modestly decreased BDNF protein (− 16.6%) in whole hippocampus and BDNF mRNA (− 19%) in the CA3 area. In contrast, BDNF mRNA and protein in the frontal cortex were unchanged. In both the frontal cortex and hippocampus, tissue levels of 5-HT and 5-HIAA were increased and decreased, respectively. Combined, these data suggests that the effects of corticosterone on the BDNF system are not linked to the effects on the 5-HT systems. However, our findings do suggest that chronic corticosterone impairs hippocampal BDNF function, a finding with potential relevance for the hippocampal atrophy reported in major depression. Additionally, as inferred from the alterations in tissue levels of 5-HT and 5-HIAA, chronic corticosterone may influence the function of the 5-HT system.

Prefrontal cognition in schizophrenia and bipolar illness in relation to Val66Met polymorphism of the brain‐derived neurotrophic factor gene

The measures of prefrontal cognition have been used as endophenotype in molecular-genetic studies. Brain-derived neurotrophic factor (BDNF) has been implicated in cognitive functions and in the pathogenesis of major psychoses. This study investigates the relationship between Val66Met polymorphisms of the BDNF gene and prefrontal cognitive function in 129 patients with schizophrenia and 111 patients with bipolar mood disorder. Cognitive tests included the Wisconsin Card Sorting Test (WCST), with such domains as number of perseverative errors, non-perseverative errors, completed corrected categories, conceptual level responses, and set to the first category, and the N-back test, where mean reaction time and percent of correct reactions were measured. Genotyping for Val66Met BDNF polymorphism was done by polymerase chain reaction method. In schizophrenia, no relationship between Val66Met polymorphism of the BDNF gene and the results of the WCST was observed. Patients with Val/Val genotype had a higher percentage of correct reactions in the N-back test than those with the remaining genotypes. Bipolar patients with Val/Val genotype obtained significantly better results on three of five domains of the WCST. No relationship between BDNF polymorphism and the results of the N-back test was found in this group. A limitation to the results could be variable psychopathological state and medication during cognitive testing and lack of Hardy-Weinberg equilibrium in schizophrenia group. Val66Met polymorphism of the BDNF gene may be associated with cognitive performance on the WCST in bipolar mood disorder but not in schizophrenia. An association of this polymorphism with performance on the N-back test in schizophrenia and not in bipolar illness may suggest that in schizophrenia, the BDNF system may be connected with early phases of information processing.

A “deficient environment” in prenatal life may compromise systems important for cognitive function by affecting BDNF in the hippocampus

The intrauterine environment has the capacity to mold the prenatal nervous system. Particularly, recent findings show that an adverse prenatal environment produces structural defects of the hippocampus, a critical area sub-serving learning and memory functions. These structural changes are accompanied by a disruption in the normal expression pattern of brain-derived neurotrophic factor (BDNF) and its cognate tyrosine kinase B (TrkB) receptor. The important role that the BDNF system plays in neural modeling and learning and memory processes suggests that fetal exposure to unfavorable intrauterine conditions may compromise proper cognitive function in adult life. These findings have implications for disorders that involve a dysfunction in the BDNF system and are accompanied by cognitive deficits.

Differential regulation by exercise of BDNF and NT-3 in rat spinal cord and skeletal muscle.

We have investigated the impact of neuromuscular activity on the expression of neurotrophins in the lumbar spinal cord region and innervating skeletal muscle of adult rats. Rats were exercised on a treadmill for 1 day or 5 consecutive days and euthanized at 0, 2 or 6 h after the last bout of exercise. By Day 1, there was no clear evidence of an increase in brain-derived neurotrophic factor (BDNF) mRNA in the spinal cord or the soleus muscle. By Day 5, there was a significant increase in BDNF mRNA in the spinal cord at 2 h post-training, and the soleus muscle showed a robust increase between 0 and 6 h post-training. Immunoassays showed significant increases in BDNF protein in the soleus muscle by training Day 5. Immunohistochemical analyses showed elevated BDNF levels in motoneuron cell bodies and axons in the ventral horn. Neurotrophin-3 (NT-3) mRNA was measured to determine whether selected neurotrophins respond with a selective pattern of induction to neuromuscular activity. In the spinal cord, there was a progressive post-training decrease in NT-3 mRNA following a single bout of training, while there was a significant increase in NT-3 mRNA at 2 h post-training by Day 5. The soleus muscle showed a progressive increase in NT-3 mRNA by Days 1 and 5 following training. These results show that neuromuscular activity has specific effects on the BDNF and NT-3 systems, and that repetitive exercise affects the magnitude and stability of these responses.