Lower Brain-derived Neurotrophic Factor Research Articles

Serum brain-derived neurotrophic factor reflects the lower inflammation, lipid level, and major adverse cardiac and cerebrovascular events risk in maintenance hemodialysis patients

Brain-derived neurotrophic factor (BDNF) serves an anti-inflammation and anti-atherosclerosis role in vitro and in vivo, which also acts as a biomarker for the prognosis of cardio/cerebral vascular diseases; however, its clinical value in maintenance hemodialysis (MHD) patients’ management is few reported. Hence, this study aimed to evaluate the role of BDNF in estimating the major adverse cardiac and cerebrovascular events (MACCE) risk in MHD patients. A total of 490 MHD patients and 100 healthy controls (HCs) were enrolled. Subsequently, their serum BDNF levels were assessed using an enzyme-linked immunosorbent assay. Our study shows that BDNF was notably (more than two folds) decreased in MHD patients compared with that in HCs (median (interquartile range) value: 5.5 (3.1–9.4) vs. 13.2 (9.4–19.1) ng/mL). BDNF negatively correlated with diabetes history, hemodialysis duration, C-reactive protein, total cholesterol, and low-density lipoprotein cholesterol in MHD patients. During a median follow-up period of 17.4 months, accumulating MACCE rate was calculated, which disclosed that high BDNF was correlated with decreased accumulating MACCE rate in MHD patients. In detail, the 1-year/2-year/3-year/4-year accumulating MACCE rates in MHD patients with low BDNF were 11.6%/24.9%/31.2%/50.3%, respectively, while these rates were 5.9%/12.7%/22.7%/37.6% in MHD patients with high BDNF, separately. Furthermore, the correlation between BDNF and accumulating MACCE risk was subsequently validated in a multivariate cox’s regression analysis (hazard ratio: 0.602, 95% confidential interval: 0.399–0.960). In conclusion, Serum BDNF decreases in MHD patients, which would reflect the lower inflammation, and lipid level, especially forecasting the decreased MACCE risk in those patients.

Chronic social comparison elicits depression- and anxiety-like behaviors and alterations in brain-derived neurotrophic factor expression in male rats.

Social comparison is a fundamental human characteristic; however, long-term social comparison may induce psychological stress and can lead to depression and anxiety. Recent studies have shown that nonhuman primates compare themselves with others; however, no studies have investigated whether social comparisons exist among rodents. In the present study, we established a rat model of social comparison. This model was subsequently used to examine the effects of the differential environment of a partner on depression- and anxiety-like behaviors in male rats, as well as to assess the changes in serum, medial prefrontal cortex (mPFC), and dorsal hippocampus brain-derived neurotrophic factor (BDNF) levels induced by long-term social comparison. Compared to rats whose partners were exposed to the same environment, rats whose partners were exposed to two combined enriched environmental stimuli for 14days showed significantly decreased social novelty preference and sucrose consumption. No anxiety-like behaviors were observed. Rats whose partners were exposed to one enriched environment for 31days showed significantly increased immobility time in the forced swimming test, and significantly decreased time spent in the center area in the open-field test. Further, rats whose partners were exposed to one enriched environment for 31days showed lower BDNF levels in the mPFC and dorsal hippocampus, but not following partner exposure for 14days. These results suggest that social comparisons exist in rats and can induce psychosocial stress and other negative affect. This model will not only provide the possibility to reveal the neurobiological basis of the emotional impact of social comparison, but could also be used to confirm the conservative evolutionary characteristics of social comparison as a behavioral attribute.

Spontaneously hypertensive rats vs. Wistar Kyoto and Wistar rats: An assessment of anxiety, motor activity, memory performance, and seizure susceptibility

Spontaneously hypertensive rats (SHRs) are widely accepted for modeling essential hypertension and Attention deficit hyperactivity disorder (ADHD). However, data concerning central nervous system changes associated with behavioral responses of this strain and usage of Wistar Kyoto (WKY) rats as controls are confounding. The objective of the present study was to assess the impact of anxiety and motor activity on the cognitive responses of SHRs compared to Wistar and WKY rats. In addition, the role of brain-derived neurotrophic factor (BDNF) in the hippocampus on cognitive behavior and seizure susceptibility in the three strains was evaluated. In Experiment#1, SHR demonstrated impulsive responses in the novelty suppression feeding test accompanied by impaired spatial working and associative memory in the Y maze and object recognition test compared with the Wistar rat but not WKY rats. In addition, the WKY rats exhibited diminished activity compared to Wistar rats in an actimeter. In Experiment#2, the seizure susceptibility was assessed by 3-min electroencephalographic (EEG) recording after two consecutive injections of pentylenetetrazol (PTZ) (20+40 mg/kg). The WKY rats were more vulnerable to rhythmic metrazol activity (RMA) than the Wistar rats. In contrast, Wistar rats were more prone to generalized tonic-clonic seizures (GTCS) than WKY rats and SHRs. Control SHR had lower BDNF expression in the hippocampus compared to Wistar rats. However, while the BDNF levels were elevated in the Wistar and WKY rats after PTZ injection, no change in this signaling molecule was observed in the SHR in the seizure condition. The results suggest Wistar rats as a more appropriate control of SHR than WKY rats for studying memory responses mediated by BDNF in the hippocampus. The higher vulnerability to seizures in Wistar and WKY rats compared to SHR might be linked to PTZ-induced decreased expression of BDNF in the hippocampus.

Impact of low-dose Brain-Derived Neurotrophic Factor (BDNF) on atrial fibrillation recurrence.

Atrial fibrillation is the most common arrhythmia worldwide and is associated with significant morbidity and mortality. Despite the effectiveness of catheter-based ablation, periprocedural complication and recurrences remain a concern. In this context, we aim to appraise the potential impact of brain-derived neurotrophic factor (BDNF) on reducing episodes of paroxysmal atrial fibrillation (PAF). 22 patients with an established diagnosis of PAF and without structural heart disease were considered. Every patient received 20 drops of GUNA-BDNF administered in the morning. During the 24 months of follow-up, the arrhythmic burden was measured by the average monthly duration of PAF episodes. At the end of the follow-up period (24 months), data from 22 patients, of whom 17 men and five women, were analyzed. The arrhythmic burden, measured in terms of average monthly duration of PAF episodes, was found significantly reduced after the administration of low dose BDNF (9.5 vs. 65.3 minutes per month, P<0.001). A total of 17 out of 22 patients saw their arrhythmic burden eliminated or consistently reduced, furthermore two patients underwent a drastic reduction of the average monthly duration of AF (more than 200 minutes compared to the baseline). Only four patients, despite the administration of BDNF, still experienced an arrhythmic burden of 20 minutes or more. Considering the age groups, the major reduction was observed in people aged 70 or more, who were also the most represented in the sample. These results are coherent with the poor literature currently available. BDNF low dose therapy has shown to have an impacting role in reducing the arrhythmic burden and recurrences of AF, with a particular effectiveness in patients over 70 and without structural heart disease. We should welcome this work, despite it limitations. Further clinical and molecular studies are needed before-considering BDNF low dose as a tool against PAF.

BDNF and KISS-1 Levels in Maternal Serum, Umbilical Cord, and Placenta: The Potential Role of Maternal Levels as Effect Biomarker

Brain-derived neurotrophic factor (BDNF) and kisspeptin-1 (KISS-1) regulate placental development and fetal growth. The predictive value of maternal serum BDNF and KISS-1 concentrations for placental and umbilical cord levels has not yet been explored. The influence of prenatal lead (Pb) and cadmium (Cd) exposure and maternal iron status on BDNF and KISS-1 levels is also unclarified and of concern. In a pilot cross-sectional study with 65 mother–newborn pairs, we analyzed maternal and cord serum levels of pro-BDNF, mature BDNF, and KISS-1, BDNF, and KISS-1 gene expression in placenta, Pb and Cd in maternal and umbilical cord blood (erythrocytes), and placenta. We conducted a series of in vitro experiments using human primary trophoblast cells (hTCs) and BeWo cells to verify main findings of the epidemiological analysis. Strong and consistent correlations were observed between maternal serum levels of pro-BDNF, mature BDNF, and KISS-1 and corresponding levels in umbilical serum and placental tissue. Maternal red blood cell Pb levels were inversely correlated with serum and placental KISS-1 levels. Lower expression and release of KISS-1 was also observed in Pb-exposed BeWo cells. In vitro Pb exposure also reduced cellular BDNF levels. Cd-treated BeWo cells showed increased pro-BDNF levels. Low maternal iron status was positively associated with low BDNF levels. Iron-deficient hTCs and BeWo cells showed a consistent decrease in the release of mature BDNF. The correlations between maternal BDNF and KISS-1 levels, placental gene expression, and umbilical cord serum levels, respectively, indicate the strong potential of maternal serum as predictive matrix for BDNF and KISS-1 levels in placentas and fetal sera. Pb exposure and iron status modulate BDNF and KISS-1 levels, but a clear direction of modulations was not evident. The associations need to be confirmed in a larger sample and validated in terms of placental and neurodevelopmental function.

The month of walking alone and BDNF level differ between drug-naive first-episode schizophrenia patients and healthy controls.

Schizophrenia is a neurodevelopmental disorder, characterized by impairment in reasoning, affectivity, and social relationships. Previous studies have shown delayed motor development and Brain-Derived Neurotrophic Factor (BDNF) level change in individuals with schizophrenia. We researched the month of walking alone (MWA) and BDNF level between drug-naive first-episode schizophrenia patients (FEP) and healthy control (HC), as well as how they behave in neurocognitive function and severity of symptoms. Predictors of schizophrenia were further explored too. We researched the MWA and BDNF levels between FEP and HCs in the Second Xiangya Hospital of Central South University from August 2017 to January 2020, as well as how they behave in neurocognitive function and the severity of symptoms. A binary logistic regression analysis was used to examine the risk factors affecting the onset and treatment outcome of schizophrenia. We find that FEP showed a walking delay and lower BDNF levels compared to HCs, which were associated with cognitive impairment and severity of symptoms. According to the difference and correlation analysis results, and combined with the appropriate application conditions for binary logistic regression, Wechsler Intelligence Scale Picture completion, Hopkins Verbal Learning Test-Revised, and Trail Making Test: part A were added to the binary logistic regression analysis to distinguish FEP and HCs. Our study has shown delayed motor development and changes in BDNF levels in schizophrenia, extending insight into the early identification of patients with schizophrenia versus healthy populations.

Brain Derived Neurotrophic Factor Interacts with White Matter Hyperintensities to Influence Processing Speed and Hippocampal Volume in Older Adults.

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays an important role in regulating synaptic activity and plasticity. Given that type-2 diabetes (T2DM) increases the risk of cognitive decline, and studies have suggested lower BDNF levels may be a risk factor of diabetic neurovascular complications, we sought to investigate total white matter hyperintensities (WMH) as a moderator of the effect of BDNF on hippocampal volume and cognition. Older adults without dementia from the Alzheimer's Disease Neuroimaging Initiative (N = 454 including 49 with T2DM and 405 without diabetes) underwent neuropsychological evaluation, magnetic resonance imaging to quantify hippocampal and WMH volumes, and blood draw to assess BDNF. Adjusting for age, sex, and APOE ɛ4 carrier status, there was a significant interaction between total WMH and BDNF on bilateral hippocampal volume in the non-T2DM group (t = 2.63, p = 0.009). Examination of main effect models with a dichotomous high/low BNDF group revealed a significant main effect for low BDNF (t = -4.98, p < 0.001), such that as WMH increased, bilateral hippocampal volume decreased. There was also a significant interaction between total WMH and BDNF on processing speed in the non-T2DM group (t = 2.91, p = 0.004). There was a significant main effect for low BDNF (t = -3.55, p < 0.001) such that as WMH increased, processing speed decreased. The interactions were not significant in the T2DM group. These results further elucidate the protective role that BDNF plays on cognition, as well as the cognitive effects of WMH.

Acute bouts of aerobic and resistance exercise similarly alter inhibitory control and response time while inversely modifying plasma BDNF concentrations in middle-aged and older adults with type 2 diabetes.

Impairments in several domains of cognitive functions are observed in people with Type 2 Diabetes Mellitus (T2DM), often accompanied by low Brain-derived neurotrophic factor (BDNF) concentrations. Although aerobic and resistance exercise enhances cognitive functions and raises BDNF concentrations in several populations, it remained uncertain in T2DM subjects. This study compared the effects of a single bout of aerobic (AER, 40min of treadmill walk at 90-95% of the maximum walk speed) or resistance (RES, 3 × 10 repetitions in eight exercises at 70% of 10-RM) exercise on specific cognitive domain performance and plasma BDNF concentrations of physically active T2DM subjects. Eleven T2DM subjects (9 women/2 men; 63 ± 7years) performed two counterbalanced trials on non-consecutive days. Stroop Color and Word (SCW) task [assessing the attention (congruent condition) and inhibitory control (incongruent condition)], Visual response time (assessing the response time), and blood collection (for plasma BDNF concentrations) were performed pre and post-exercise sessions. With distinct magnitude, both AER and RES improved the incongruent-SCW (d = -0.26 vs. -0.43 in AER and RES, respectively; p < 0.05), RT(best) (d = -0.31 vs. -0.52, p < 0.05), and RT(1-5) (d = -0.64 vs. -0.21, p < 0.05). The congruent-SCW and RT(6-10) were not statistically different. Plasma BDNF concentrations were elevated 11% in AER (d = 0.30) but decreased by 15% in RES (d = -0.43). A single session of aerobic or resistance exercise similarly improved the inhibitory control and response time of physically active T2DM subjects. Nevertheless, aerobic and resistance exercise sessions induced an opposite clinical effect in plasma BDNF concentrations.

Plasma brain derived neurotrophic factor level as a modifying factor for trans fat intake and hypertension

Long-term consumption of trans-fat has been linked with its incorporation in brain neural membrane that could lead into alteration of signalling pathways, including Brain Derived Neurotrophic Factor (BDNF). As an ubiquitous neurotrophin, BDNF is believed to play a role in the regulation of blood pressure yet prior studies shown conflicting results to its effect. Moreover, direct effect of trans fat intake to hypertension has not yet been elucidated. This study aimed to investigate the role of BDNF and its association between trans-fat intake and hypertension. We conducted a population study in Natuna Regency which once reportedly has the highest prevalence of hypertension from Indonesian National Health Survey. Subjects with hypertension and those without hypertension were recruited for the study. Demographic data, physical examination, and food recall were collected. The level of BDNF from all subjects were obtained through analysis of blood samples. A total of 181 participants were included in this study, comprising 134 (74%) hypertensive subjects and 47 (26%) normotensive subjects. Median of daily trans-fat intake of hypertensive subjects was higher compared to normotensive subjects (0,013 [0,0003-0,07] vs 0,010 [0,0006-0,06] % of total energy/day, p=0,021). Interaction analysis showed significant results for plasma BDNF level in relationship of trans-fat intake and hypertension (p=0,011). Trans-fat intake association to hypertension in overall subjects showed odds ratio (OR) of 1,85 95%CI 1,05-3,26 (p=0,034), while in those with low-middle tercile BDNF level the OR was 3,35 95%CI 1,46-7,68 (p=0,004). Plasma BDNF level has a modifying effect in the association between trans-fat intake and hypertension. Subjects with high trans-fat intake, while having low BDNF level, have the highest probability for hypertension.

BDNF is altered in a brain-region specific manner and rescues deficits in Spinocerebellar Ataxia Type 1

Spinocerebellar ataxia type 1 (SCA1) is an adult-onset, dominantly inherited neurodegenerative disease caused by the expanded polyQ tract in the protein ATAXIN1 (ATXN1) and characterized by progressive motor and cognitive impairments. There are no disease-modifying treatments or cures for SCA1. Brain-derived neurotrophic factor (BDNF) plays important role in cerebellar physiology and has shown therapeutic potential for cerebellar pathology in the transgenic mouse model of SCA1, ATXN1[82Q] line that overexpress mutant ATXN1 under a cerebellar Purkinje-cell-specific promoter. Here we demonstrate decreased expression of brain derived neurotrophic factor (BDNF) in the cerebellum and medulla of patients with SCA1. Early stages of disease seem most amenable to therapy. Thus, we next quantified Bdnf expression in Atxn1154Q/2Q mice, a knock-in mouse model of SCA1, during the early symptomatic disease stage in four clinically relevant brain regions: cerebellum, medulla, hippocampus and motor cortex. We found that during the early stages of disease, Bdnf mRNA expression is reduced in the hippocampus and cerebellum, while it is increased in the cortex and brainstem. Importantly, we observed that pharmacological delivery of recombinant BDNF improved motor and cognitive performance, and mitigated pathology in the cerebellum and hippocampus of Atxn1154Q/2Q mice. Our findings demonstrate brain-region specific deficiency of BDNF in SCA1 and show that reversal of low BDNF levels offers the potential for meaningful treatment of motor and cognitive deficits in SCA1.

Nickel and aluminium mixture elicit memory impairment by activation of oxidative stress, COX-2, and diminution of AChE, BDNF and NGF levels in cerebral cortex and hippocampus of male albino rats

This study evaluated nickel and aluminium-induced neurotoxicity, as a binary metal mixture. Twenty-eight male Sprague Dawley albino rats were weight-matched and divided into four groups. Group 1 (control) received deionized water. Group 2 and 3 received Aluminium (1 mg/kg) and Nickel (0.2 mg/kg) respectively, while Group 4 received Ni and Al mixture HMM three times a week orally for 90 days. Barnes maze tests was performed. Rats were sacrificed under pentobarbital anaesthesia, cerebral cortex and hippocampus were separated, and metal levels were measured using Atomic Absorption Spectroscopy (AAS). Malondialdehyde (MDA), catalase (CAT), glutathione content (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), Brain Derived Neurotrophic Factor (BDNF), Nerve growth factor NGF, cyclo-oxygenase COX-2 and Acetylcholinesterase (AChE) were assayed using ELISA kits. Ni/Al binary mixture exposed rats showed a shorter latency period (though not significant) of 3.21 ± 1.40 s in comparison to 3.77 ± 1.11 (Ni only) and 3.99 ± 1.16(Al only). Ni/Al mixture gp had the lowest levels of Mg in both the hippocampus and frontal cortex when compared with the individual metals. In the hippocampus Al only exposed rats significantly showed p < 0.05 higher iron and Ca levels in comparison to Ni/Al mixture. Al alone significantly showed p < 0.05 lower levels of Fe but higher Ca than the Ni/Al mixture group. Exposure to Al only showed lower levels of BDNF in comparison to Ni/Al combination, whereas Ni/Al mixture gp had lower levels of NGF in comparison to the individual metals in the hippocampus. In the frontal cortex Ni only, group showed significantly lower BDNF in comparison to Ni/Al mixture whereas the mixture showed significantly lower NGF when compared with Al only group. There were higher levels of COX-2 in the Ni/Al mixture than individual metal treated rats in both hippocampus and frontal cortex. AChE levels in the Ni/Al mixture group was higher than Ni or Al only gps in the hippocampus whereas in the frontal cortex, Ni/Al exposed rats showed significantly lower AChE levels in comparison to Al only group. Ni, Al and Ni/Al mixture exhibited memory impairment by activation of oxidative stress, COX-2, and diminution of AChE, BDNF and NGF levels in cerebral cortex and hippocampus. The BDNF-COX-2 AChE signalling pathway may be involved in the neurotoxicity of Ni and Al.

Brain-derived neurotrophic factor levels and macular ganglion cell-inner plexiform layer thickness in macular telangiectasia type 2.

To determine brain-derived neurotrophic factor (BDNF) levels in the serum and aqueous humor (AH) and assess the relationship between BDNF levels and the thickness of the macular ganglion cell-inner plexiform layer (GCIPL) in macular telangiectasia type 2 (MacTel). This study included 25 patients with MacTel (MacTel group) and 25 control subjects (control group). The levels of BDNF in the serum and AH were tested using an enzyme-binding immunosorbent assay. GCIPL thickness was measured by segmentation analysis using optical coherence tomography (OCT). There was no significant difference in the mean serum BDNF levels between the MacTel and control groups (p = 0.145). The average BDNF level in the AH was significantly lower than that in the control group (p = 0.026). OCT segmentation analyses revealed that the minimum GCIPL thickness was significantly lower in the MacTel group than in the control group (p = 0.039). In the correlation analysis of BDNF levels with GCIPL thickness, significant correlations existed between the BDNF level of the AH and minimum GCIPL thickness in the MacTel group. The concentration of BDNF in the AH was decreased in the MacTel group, and this reduction was related to the minimum GCIPL thickness. The low BDNF levels detected in the MacTel group may have resulted in thinning of the GCIPL due to the loss of retinal ganglion cells.

Gene- and Gender-Related Decrease in Serum BDNF Levels in Alzheimer’s Disease

Brain-derived neurotrophic factor (BDNF) has a protective role in Alzheimer's disease (AD). Oxidative stress and inflammatory cytokines are potentially implicated in AD risk. In this study, BDNF was detected in serum of AD and mild cognitive impairment (MCI) patients and investigated in association with gene polymorphisms of BDNF (Val66Met and C270T), of some oxidative stress-related genes (FOXO3A, SIRT3, GLO1, and SOD2), and of interleukin-1 family genes (IL-1α, IL-1β, and IL-38). The APOE status and mini-mental state examination (MMSE) score were also evaluated. Serum BDNF was significantly lower in AD (p = 0.029), especially when comparing the female subsets (p = 0.005). Patients with BDNFVal/Val homozygous also had significantly lower circulating BDNF compared with controls (p = 0.010). Moreover, lower BDNF was associated with the presence of the T mutant allele of IL-1α(rs1800587) in AD (p = 0.040). These results were even more significant in the female subsets (BDNFVal/Val, p = 0.001; IL-1α, p = 0.013; males: ns). In conclusion, reduced serum levels of BDNF were found in AD; polymorphisms of the IL-1α and BDNF genes appear to be involved in changes in serum BDNF, particularly in female patients, while no effects of other gene variants affecting oxidative stress have been found. These findings add another step in identifying gender-related susceptibility to AD.

Dietary insulin index and insulin load in relation to hypertriglyceridemic waist phenotype and low brain derived neurotrophic factor in adults.

BackgroundThe evidence about the relation of the insulinemic potential of food with visceral obesity and brain-derived neurotrophic factor (BDNF) was limited. We aimed to investigate the relation of dietary insulin index (DII) and dietary insulin load (DIL) with hypertriglyceridemic waist phenotype (HTGW) and serum BDNF in Iranian adults.MethodsThis cross-sectional study included 528 middle-aged adults (45.6% women), using a multistage cluster random-sampling method. Dietary intakes were assessed using a validated semi-quantitative 168-item food frequency questionnaire. Blood samples were collected after 12 h of fasting for assessing the serum BDNF and triglyceride concentrations. HTGW was defined as triacylglycerol ≥ 150 mg/dL plus enlarged waist circumference. The values less than the first decile of serum BDNF were considered as the low level.ResultsIndividuals in the top tertile of DIL, in comparison to those in the bottom tertile, had higher odds of HTGW in both crude (OR = 1.96, 95% CI: 1.14–3.37) and fully adjusted model (OR = 6.10, 95% CI: 1.58–23.53). However, the relation between DII and odds of HTGW was statistically insignificant in crude (OR = 1.30, 95% CI: 0.78–2.16) and maximally adjusted model (OR = 1.25, 95% CI: 0.65–2.40). After considering confounders, participants in the top tertile of DIL had marginally higher odds of having low BDNF values (OR = 2.00, 95% CI: 0.95–4.21). Nevertheless, the association between DII and odds of low BDNF values was statistically insignificant.ConclusionThis population-based study demonstrated that adults with higher DIL had significantly higher chance of HTGW phenotype and slightly higher chance for low BDNF level. DII was not associated with HTGW phenotype or BDNF values.

Intra-mPFC injection of sodium butyrate promotes BDNF expression and ameliorates extinction recall impairment in an experimental paradigm of post-traumatic stress disorder.

Objective(s):Therapeutic strategies that facilitate extinction are promising in the treatment of post-traumatic stress disorder (PTSD). Brain-derived neurotrophic factor (BDNF) has a crucial role in neural plasticity, a process needed for the retention of fear extinction. In this study, we investigated the effects of local administration of a histone deacetylase (HDAC) inhibitor, sodium butyrate (NaBu), on BDNF transcription and behavioral markers of extinction in the single prolonged stress (SPS) model of PTSD. Materials and Methods:NaBu was infused into the infralimbic (IL) subregion of the medial prefrontal cortex (mPFC) of male rats. The freezing response was recorded as the criterion to assess fear strength on the day of extinction as well as 24 hr later in the retention test. Other behavioral tests were also measured to evaluate the anxiety level, locomotor activity, and working memory on the retention day. HDAC activity and BDNF mRNA expression were evaluated after the behavioral experiments. Results: NaBu facilitated the recall of fear extinction in SPS rats (P<0.0001). SPS rats had higher HDAC activity (P<0.0001) and lower BDNF expression (P<0.05) than non-SPS animals. Also, anxiety was higher in the SPS group (P<0.0001), but locomotor activity (P=0.61) and working memory (P=0.36) were not different between SPS and Non-SPS groups.Conclusion:Our findings provide evidence that the mechanism of action of NaBu in the improvement of extinction recall is mediated, in part, by enhancing histone acetylation and reviving BDNF expression in IL.

Brain-Derived Neurotrophic Factor Expression in Patients with Acute Pulmonary Embolism Compared to the General Population: Diagnostic and Prognostic Implications.

(1) Background: Pulmonary embolism (PE) is a severe condition, representing the third most important cardiovascular cause of death after myocardial infarction and stroke. Despite the use of clinical pre-test probability scores, D-dimer measuring, and computer tomography pulmonary angiography (CTPA), PE diagnosis remains a challenge. Brain-derived neurotrophic factor (BDNF) is the most important member of the neurotrophin family, which has also been shown to be involved in the physiopathology of cardiovascular conditions such as heart failure and myocardial infarction. In this study, we aimed to assess the BDNF expression in patients with acute PE compared to the general population, and to also investigate its diagnostic and prognostic role. (2) Methods: We conducted a single center prospective study, which included 90 patients with PE and 55 healthy volunteers. Clinical and paraclinical parameters, together with plasma levels of BDNF, were evaluated in all patients after admission. (3) Results: The plasma levels of BDNF were significantly lower in the PE patients compared with the control group (403 vs. 644 pg/mL, p < 0.001). ROC analysis revealed an AUC of 0.806 (95% CI 0.738–0.876, p < 0.001) and a cut-off value of 564 pg/mL, which associated a sensitivity of 74.4% and a specificity of 78.2% for PE. Low BDNF levels also correlated with prognostic markers of PE, such as PESI score (p = 0.023), NT-proBNP (p < 0.01), right ventricular diameter (p = 0.029), and tricuspid annular plane systolic elevation (p = 0.016). Moreover, we identified a decreased BDNF expression in patients with high-risk PE (p < 0.01), thrombolytic treatment (p = 0.01), and patients who died within 30 days (p = 0.05). (4) Conclusions: Our study revealed that plasma BNDF is significantly lower in patients with PE when compared with the general population, and may be considered as a promising biomarker in complementing the current diagnostic tools for PE. Furthermore, low levels of BDNF might also be used to predict a poor outcome of this condition.

Serum brain-derived neurotrophic factor and glial cell-derived neurotrophic factor in patients with first-episode depression at different ages

Objectives We investigated the differences in serum brain-derived neurotrophic factor (BDNF) and glial cell line–derived neurotrophic factor (GDNF) levels and clinical symptoms with first-episode depression at different ages. Methods Ninety patients (15–60 years old) diagnosed with first-episode depression were enrolled as the study group, and they were divided into early-onset, adult and late-onset groups. The age-matched control groups were healthy volunteers. Serum BDNF and GDNF concentrations were determined by enzyme-linked immunosorbent assay (ELISA). GraphPad Prism 9 was used for t tests, one-way ANOVAs, chi-square tests, and correlation analyses. p < 0.05 indicated significant differences. Results Serum BDNF and GDNF levels were lower in the whole study group and the three subgroups than in the healthy groups. Illness severity, anxiety and education were higher in the early-onset than late-onset patients. Serum BDNF levels were lower in the adult than late-onset patients. Serum BDNF levels were negatively correlated with patient CGI-SI scores. After the LSD test for multiple comparisons, the results were also significant. Conclusions Low serum BDNF and GDNF levels may be involved in the pathophysiology of first-episode depression, and there were differences in serum BDNF levels at different ages, verifying that serum BDNF and GDNF could serve as potential biomarkers of depression. KEY POINTS Depression is often conceptualised as a systemic illness with different biological mechanisms, but satisfactory explanations have not been provided thus far. The aim of our study was to investigate differences in serum BDNF and GDNF levels and their relationships with clinical symptoms in patients with first-episode depression at different ages. The potential of the neurotrophic factor hypothesis to advance the diagnosis and treatment of depression will be a very exciting new strategy for future research.

Growth factors in anorexia nervosa: a systematic review and meta-analysis of cross-sectional and longitudinal data

Objectives Growth factors are signalling molecules that play roles in the survival, proliferation, migration, and differentiation of cells. Studies have found alterations in specific growth factors in anorexia nervosa (AN). Methods This systematic review and meta-analysis examined articles from three databases, measuring growth factors in AN cross-sectionally and longitudinally, and in recovered AN (rec-AN) cross-sectionally. Random-effects meta-analyses were conducted for brain-derived neurotrophic factor (BDNF) and insulin growth factor-I (IGF-1) for cross-sectional and longitudinal studies. Results A total of 82 studies were included: 56 cross-sectional (BDNF: n = 15; IGF-1: n = 41) and 24 longitudinal (BDNF: n = 5; IGF-1: n = 19) were meta-analysed and 20 studies were narratively synthesised. In cross-sectional analyses, BDNF and IGF-1 were lower in AN compared to controls, and BDNF was marginally greater in rec-AN compared to controls. In longitudinal meta-analyses, BDNF and IGF-1 increased from baseline to follow-up. Cross-sectional subgroup analyses revealed no differences in BDNF between controls and AN binge-eating/purging subtypes. Conclusions It is likely that the low BDNF and IGF-1 levels found in AN are consequences of starvation, which are reversible with weight restoration. The increase in BDNF and IGF-1 during therapeutic weight restoration might improve neuroplasticity, which is the basis of learning, and thus psychotherapeutic success.

Influence of Effort-based Reward Training on Neuroadaptive Cognitive Responses: Implications for Preclinical Behavioral Approaches for Depressive Symptoms

Despite the presence of multiple pharmacotherapeutic options, incidence rates for depressive disorders continue to rise. Nonpharmacological approaches (e.g., cognitive and behavioral therapies) exhibit encouraging efficacy rates; however, a lack of preclinical models has prevented progress in the identification of relevant neurobiological mechanisms of these approaches. Accordingly, the effort-based reward (EBR) preclinical model exposes rats to response-outcome (R-O) contingencies and provides an opportunity to investigate behavioral clinical approaches. In the current study, male and female rats were assigned to either an EBR contingent- or noncontingent-trained group and exposed to 7 weeks of training. Neuroadaptive cognitive responses were assessed in a cognitive uncertainty task (UT) and an object pattern separation task (OPST). Although no significant effects of EBR were observed in the UT, EBR contingent-trained rats approached the novel panel in the most difficult trial of the OPST faster than the noncontingent-trained group. Additionally, female EBR contingent-trained rats exhibited increased engagement with the novel stimulus panel across all trials. Examination of brain-derived neurotrophic factor (BDNF) in the lateral habenula (LHb), a putative neurobiological target for depressive symptoms, revealed lower BDNF immunoreactivity in EBR contingent-trained rats. Females in both training groups exhibited higher dehydroepiandrosterone/cortisol (DHEA/CORT) ratios, suggesting, along with the increased engagement with novel stimulus panels, that female rats may be more responsive to EBR contingency training than males. Together, these results suggest that EBR contingency training offers promise as a preclinical rat model for behavioral therapeutic interventions for depressive symptoms leading to a clearer understanding of putative neurobiological mechanisms.

The serum concentration of brain‑derived neurotrophic factor is lower in ambulatory and clinically stable patients with more advanced systolic heart failure.

Brain‑derived neurotrophic factor (BDNF) is decreased in heart failure (HF), but whether serum BDNF concentration is related to the severity of HF with reduced left ventricular (LV) ejection fraction (LVEF) below 50% is uncertain. We aimed to compare cardiac structure and function in ambulatory and clinically stable patients with HF and LVEF below 50% for lower and higher BDNF serum concentrations. A total of 361 ambulatory patients with a compensated HF and LVEF below 50% underwent cardiac evaluation and measurement of serum BDNF and N‑terminal pro-B‑type natriuretic peptide (NT‑proBNP). Patients from the lower (below median) and higher (equal to or above median) BDNF serum concentration groups were compared by analysis of covariance (ANCOVA) adjusted for age, sex, body mass index, resting heart rate, and systolic blood pressure. The patients were at a median age of 63.8 (interquartile range [IQR], 57.7-71.5) years and had a median LVEF of 31.0% (IQR, 23.0-37.4). Individuals with lower BDNF (<23.5 ng/ml) had significantly (P ≤0.05) more dilated right and left atria both before and after emptying, larger right ventricular end-diastolic diameter, LV end-systolic diameter, lower tricuspid annulus plane systolic excursion, shorter pulmonary acceleration time, higher mitral E to A waves ratio and mitral E wave to tissue Doppler e' wave ratio, and higher concentration of NT‑proBNP. HF patients with LVEF below 50% and lower serum BDNF concentration present more advanced cardiac remodeling and dysfunction than individuals with higher BDNF. Potential mechanisms and clinical consequences of these findings require further investigation.