Decrease In Brain-derived Neurotrophic Factor Research Articles

Repetitive transcranial magnetic stimulation and fluoxetine attenuate astroglial activation and benefit behaviours in a chronic unpredictable mild stress mouse model of depression

Objectives: Repetitive transcranial magnetic stimulation (rTMS) has been considered as an effective antidepressant treatment; however, the mechanism of its antidepressant effect is still unclear. Fluoxetine, a selective serotonin reuptake inhibitor antidepressant, may be neuroprotective. The objective of the present study was to evaluate the effect and underlying possible neuroprotective mechanism of rTMS and fluoxetine on abnormal behaviours in a depressive mouse model induced by chronic unpredictable mild stress (CUMS).Methods: After 28 days of CUMS exposure, mice were chronically treated with rTMS (10 Hz for 5 s per train, total 20 trains per day) and (or) fluoxetine (5 mg/kg/day, intraperitoneally) for 28 days targeting on the frontal cortex. After the behavioural tests, the protein expressions of glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) were measured by immunohistochemistry and (or) Western Blot.Results: The results showed rTMS and (or) fluoxetine attenuated the locomotion decrease, anxiety and depressive like behaviours in the CUMS-exposed mice.Conclusion: Our results suggest that both rTMS and fluoxetine could benefit the CUMS-induced abnormal behaviours including depressive-like behaviours, and the beneficial effects of rTMS as well as fluoxetine on depression might be partly related to their neuroprotective effect on attenuating astroglial activation and BDNF decrease

Aerobic exercise alters DNA hydroxymethylation levels in an experimental rodent model of temporal lobe epilepsy

The therapeutic potential of aerobic exercise in mitigating seizures and cognitive issues in temporal lobe epilepsy (TLE) is recognized, yet the underlying mechanisms are not well understood. Using a rodent TLE model induced by Kainic acid (KA), we investigated the impact of a single bout of exercise (i.e., acute) or 4 weeks of aerobic exercise (i.e., chronic). Blood was processed for epilepsy-associated serum markers, and DNA methylation (DNAme), and hippocampal area CA3 was assessed for gene expression levels for DNAme-associated enzymes. While acute aerobic exercise did not alter serum Brain-Derived Neurotrophic Factor (BDNF) or Interleukin-6 (IL-6), chronic exercise resulted in an exercise-specific decrease in serum BDNF and an increase in serum IL-6 levels in epileptic rats. Additionally, whole blood DNAme levels, specifically 5-hydroxymethylcytosine (5-hmC), decreased in epileptic animals following chronic exercise. Hippocampal CA3 5-hmC levels and ten-eleven translocation protein (TET1) expression mirrored these changes. Furthermore, immunohistochemistry analysis revealed that most 5-hmC changes in response to chronic exercise were neuron-specific within area CA3 of the hippocampus. Together, these findings suggest that DNAme mechanisms in the rodent model of TLE are responsive to chronic aerobic exercise, with emphasis on neuronal 5-hmC DNAme in the epileptic hippocampus.

Behavioral stress and antidepressant treatments altered hippocampal expression of Nogo signal-related proteins in rats

Some immune molecules including neurite outgrowth inhibitor (Nogo) ligands and their receptor（Nogo receptor-1: NgR1）are expressed at the neuronal synaptic sites. Paired immunoglobulin-like receptor B (PirB) is another Nogo receptor that also binds to major histocompatibility complex I and β-amyloid and suppresses dendritic immune cell functions and neuronal plasticity in the central nervous system. Augmenting structural and functional neural plasticity by manipulating the Nogo signaling pathway is a novel promising strategy for treating brain ischemia and degenerative processes such as Alzheimer's disease. In recent decades psychiatric research using experimental animals has focused on the attenuation of neural plasticity by stress loadings and on the enhanced resilience by psychopharmacological treatments. In the present study, we examined possible expressional alterations in Nogo signal-related proteins in the rat hippocampus after behavioral stress loadings and antidepressant treatments. To validate the effectiveness of the procedures, previously reported increase in brain-derived neurotrophic factor (BDNF) by ECS or ketamine administration and decrease of BDNF by stress loadings are also shown in the present study. Significant increases in hippocampal NgR1 and PirB expression were observed following chronic variable stress, and a significant increase in NgR1 expression was observed under a single prolonged stress paradigm. These results indicate a possible contribution of enhanced Nogo signaling to the attenuation of neural plasticity in response to stressful experiences. Additionally, the suppression of hippocampal NgR1 expression using electroconvulsive seizure treatment and administration of subanesthetic dose of ketamine supported the increased neural plasticity induced by the antidepressant treatments.

Cognitive impairment is associated with BDNF-TrkB signaling mediating synaptic damage and reduction of amino acid neurotransmitters in heart failure.

Heart failure (HF) is often accompanied by cognitive impairment (CI). Brain-derived neurotrophic factor (BDNF) deficiency is closely associated with CI. However, the role and mechanism of BDNF in HF with CI is still not fully understood. Here, the case-control study was designed including 25 HF without CI patients (HF-NCI) and 50 HF with CI patients (HF-CI) to investigate the predictive value of BDNF in HF-CI while animal and cell experiments were used for mechanism research. Results found that BDNF levels in serum neuronal-derived exosomes were downregulated in HF-CI patients. There was no significant difference in serum BDNF levels among the two groups. HF rats showed obvious impairment in learning and memory; also, they had reduced thickness and length of postsynaptic density (PSD) and increased synaptic cleft width. Expression of BDNF, TrkB, PSD95, and VGLUT1 was significantly decreased in HF rats brain. In addition, compared with sham rats, amino acids were significantly reduced with no changes in the acetylcholine and monoamine neurotransmitters. Further examination showed that the number of synaptic bifurcations and the expression of BDNF, TrkB, PSD95, and VGLUT1 were all decreased in the neurons that interfered with BDNF-siRNA compared with those in the negative control neurons. Together, our results demonstrated that neuronal-derived exosomal BDNF act as effective biomarkers for prediction of HF-CI. The decrease of BDNF in the brain triggers synaptic structural damage and a decline in amino acid neurotransmitters via the BDNF-TrkB-PSD95/VGLUT1 pathway. This discovery unveils a novel pathological mechanism underlying cognitive impairment following heart failure.

β-glucan, a specific immuno-stimulant, produces rapid antidepressant effects by stimulating ERK1/2-dependent synthesis of BDNF in the hippocampus

A decline in microglia in the dentate gyrus of the hippocampus has recently been described as an important mechanism for the progression of depression. Reversal of this decline by innate immune system stimulants may represent a novel strategy to ameliorate the depressive phenotype in chronically stressed animals. β-glucan is a polysaccharide from Saccharomyces cerevisiae. It can efficiently stimulate microglia without inducing the production of pro-inflammatory cytokines. Therefore, β-glucan could be an ideal drug to ameliorate depressive phenotypes. In the present study, we found that a single injection of β-glucan reversed depression-like behaviors in mice induced by chronic unpredictable stress (CUS) in a dose-dependent manner, which was accompanied by a reversal of the CUS-induced decrease in brain-derived neurotrophic factor (BDNF) protein levels in the dentate gyrus. The crucial role of BDNF signaling in the antidepressant effect of β-glucan was demonstrated by experiments showing that infusion of an anti-BDNF antibody into dentate gyrus, construction of BDNF-Val68Met allele knock-in mice, or treatment with the BDNF receptor antagonist K252a abolished the antidepressant effect of β-glucan. The increased BDNF signaling induced by β-glucan was mediated by extracellular signal-regulated kinase1/2 (ERK1/2)-mediated BDNF synthesis, and inhibition of ERK1/2 by SL327 was able to abolish the antidepressant effect of β-glucan. Moreover, inhibition or depletion of microglia by minocycline or PLX3397 abolished the reversal effect of β-glucan on CUS-induced depression-like behaviors and CUS-induced impairment of ERK1/2-BDNF signaling. These results suggest that β-glucan exhibits antidepressant effects by stimulating microglia-mediated activation of ERK1/2 and synthesis of BDNF in the hippocampus.

Amisulpride attenuates 5-fluorouracil-induced cognitive deficits via modulating hippocampal Wnt/GSK-3β/β-catenin signaling in Wistar rats

Chemotherapy-induced cognitive impairment (CICI) is a general term describing cognitive dysfunction during/after treatment with chemotherapeutic agents. CICI represents a significant medical problem due to its increasing prevalence with the lack of robust therapeutic approaches. This study aimed at investigating the effects of chronic treatment with amisulpride (5 mg/kg/day) in the management of 5-fluorouracil (5-FU)-induced cognitive deficits in Wistar rats. Rats received 5 intraperitoneal injections of 5-FU (25 mg/kg every 3 days). 5-FU treatment induced impairments in spatial learning (reduction in object location discrimination ratio) and non-spatial learning (reduction in novel object recognition discrimination ratio). Moreover, 5-FU induced a decrease in the activity of the Wnt/GSK-3β/β-catenin pathway with a decrease in brain-derived neurotrophic factor (BDNF) level in the hippocampus. These changes were associated with an increase in the expression of the pro-inflammatory cytokines; tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), in hippocampal tissue sections accompanied by a decrease in the number of Ki-67 positive cells (indicating a decrease in proliferative capacity), a decrease in the Nissl’s granules optical density (denoting neurodegeneration), a decrease in the number of viable intact neurons with an increase in the expression of β-amyloid and caspase-3. Amisulpride enhanced Wnt/GSK-3β/β-catenin signaling, increased BDNF levels, and abrogated 5-FU-induced neuroinflammation, apoptosis, β-amyloid accumulation, and neurodegenerative changes with an improvement of cognitive performance. This study draws attention to the pro-cognitive effects of amisulpride in 5-FU-exposed rats that could be attributed to enhancing hippocampal Wnt/GSK-3β/β-catenin signaling pathway, and this could offer a promising therapeutic option for subjects with CICI.

Alterations of Plasmatic Biomarkers of Neurodegeneration in Mucopolysaccharidosis Type II Patients Under Enzyme Replacement Therapy.

Mucopolysaccharidosis type II (MPS II) is a disorder caused by a deficient activity of iduronate-2-sulfatase, a lysosomal enzyme responsible for degrading glycosaminoglycans (GAGs). The abnormal storage of GAGs within lysosomes disrupts cellular homeostasis and leads to a severe symptomatology. Patients present neuropsychiatric impairment characterized by mental retardation and impaired cognition. The aim of this study was to quantify four neurodegeneration biomarkers in plasma: brain-derived neurotrophic factor (BDNF), platelet-derived growth factor (PDGF-AA), neural cell adhesion molecule (NCAM) and cathepsin-D, as well as to identify possible correlations with urinary GAGs in seven patients undergoing treatment with ERT (Elaprase® 0.5 mg/kg of body weight). Patients with both severe and attenuated forms of MPS II showed signs of neurodegeneration in neuroimaging exams. Patients have a decrease in BDNF and PDGF-AA concentrations, and an increase in NCAM level compared to controls. No alterations in cathepsin-D concentration were seen. GAGs levels were higher in patients than in controls, but no significant correlations between GAGs and biomarkers were observed. These results evidence that patients have neurodegeneration and that monitoring these biomarkers might be useful for assessing this process. To this date, this is the first work to analyze these plasmatic markers of neurodegeneration in patients.

18β-glycyrrhetinic acid ameliorates MPTP-induced neurotoxicity in mice through activation of microglial anti-inflammatory phenotype.

18β-glycyrrhetinic acid (18β-GA) has been reported to have anti-inflammatory and neuroprotective effects. However, the therapeutic effect of 18β-GA in Parkinson's disease (PD) has not been defined. The current study aimed to evaluate the potential therapeutic effects of 18β-GA in treating PD by mitigating 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. The study showed that 18β-GA has anti-inflammatory effects by upregulating TREM2 expression in BV2 cells, which correlates with the presence of NF-E2-related factor-2 (Nrf2). 18β-GA reduced inflammation in BV2 cells treated with 1-methyl-4- phenylpyridinium (MPP+) by enhancing TREM2 expression, which promotes an anti-inflammatory microglial phenotype. Repeated administration of 18β-GA in MPTP-treated mice led to therapeutic effects by enhancing TREM2 expression, resulting in the activation of anti-inflammatory microglia. Moreover, 18β-GA attenuated the decrease in brain-derived neurotrophic factor (BDNF) levels in both MPP+-induced BV2 cells and MPTP-intoxicated mice, indicating the involvement of BDNF in the beneficial effects of 18β-GA. It is probable that activating microglial anti-inflammatory response through TREM2 expression might serve as a novel therapeutic strategy for PD. Additionally, 18β-GA seems to hold potential as a new therapeutic agent for PD.

Analysis of Protein Markers in Plasma of Patients with Drug Dependence Syndrome: Observational Clinical Study

Background. In drug addiction treatment, the diagnostic process is based on the chemical toxicological determination of the intoxication substrate or its metabolite. Laboratory monitoring and prediction issues that could form the basis of secondary prevention remain unresolved. Specific nervous tissue proteins are considered to be the most promising laboratory markers of drug pathology.Objective — to determine some potential biomarkers of protein-chemical nature in the plasma of patients with drug dependence syndrome.Methods. The study was conducted according to the design of an observational clinical trial at the Narcological Dispensary of Krasnodar Krai in the period from 07.2021 to 07.2022. The main group (group 2) included 31 patients diagnosed with substance dependence syndrome. The control group (group 1, n = 15) consisted of healthy subjects submitted to occupational medical examinations. During the detoxification-stabilization therapy and rehabilitation, 5 proteins were determined in the plasma: brainand glial-derived neurotrophic factors, neuron-specific enolase, alpha-synuclein and calcium-binding protein S100B. Statistical analysis of the data involved the Mann-Whitney test for comparing the values of the control and experimental groups and the Wilcoxon test for comparing the values of one group obtained at different stages of observation. The calculations were carried out using StatPlus version 7 (AnalystSoft Inc., USA).Results. A total of 31 patients were included in the main group, 18 of them were followed up with a diagnosis of opioid dependence syndrome (n = 11) or psychostimulant dependence syndrome (n = 7). Patients dropped out of the study due to their refusal to participate in the study or undergo rehabilitation, or due to relapse of the disease. When admitted to the hospital, patients indicated a 45% decrease in brain-derived neurotrophic factor in the plasma ( p < 0.001), and a 3.9-fold decrease after rehabilitation course ( p < 0.001). Glial-derived neurotrophic factor in the plasma exceeded the controls 1.9 times ( p < 0.001) upon admission to hospital, but rapidly returned to normal values thereafter. Level of neuron-specific enolase in the plasma was also poor, 36% lower than the controls ( p <0.001), but approached the control values by the end of rehabilitation.Conclusion. The study obtained data indicating the changes in neurotrophic factors in the blood plasma of patients with opioid or psychostimulant dependence. The rehabilitation period was marked by a relatively rapid improving level of neurotrophins; however, brain-derived neurotrophic factor remained reduced despite the successful treatment, which may indicate the irreversible changes.

Perceived Stress and Cfognition Function Quantification in a Scary Video Game: An Electroencephalogram Features and Biochemical Measures.

Video games affect the stress system and cognitive abilities in different ways. Here, we evaluated electrophysiological and biochemical indicators of stress and assessed their effects on cognition and behavioral indexes after playing a scary video game. Thirty volunteers were recruited into two groups as control and experimental. The saliva and blood samples were collected before and after intervention (watching/playing the scary game for control and experimental groups respectively). To measure cortisol and salivary alpha-amylase (sAA) levels, oxytocin (OT), and brain-derived neurotrophic factor (BDNF) plasma levels, dedicated ELISA kits were used. Electroencephalography recording was done before and after interventions for electroencephalogram (EEG)-based emotion and stress recognition. Then, the feature extraction (for mental stress, arousal, and valence) was done. Matrix laboratory (MATLAB) software, version 7.0.1 was used for processing EEG-acquired data. The repeated measures were applied to determine the intragroup significance level of difference. Scary gameplay increases mental stress (P<0.001) and arousal (P<0.001) features and decreases the valence (P<0.001) one. The salivary cortisol and alpha-amylase levels were significantly higher after the gameplay (P<0.001 for both). OT and BDNF plasma levels decreased after playing the scary game (P<0.05 for both). We conclude that perceived stress considerably elevates among players of scary video games, which adversely affects the emotional and cognitive capabilities, possibly via the strength of synaptic connections, and dendritic thorn construction of the brain neurons among players. The mental stress level increases in players of scary video games.The salivary cortisol and alpha-amylase levels are significantly higher after the scary gameplay.Plasma levels of oxytocin and brain-derived neurotrophic factor decrease after the scary gameplay.The arousal and valence features increase in players of scary video game.Cognitive capabilities are adversely affected by the scary gameplay. Nowadays, video games have become an important part of human life at different ages. Therefore, assessing their effects (improving and/or damaging) on cognition and behavior is important for understanding how they affect the nervous system. The results of such studies can be used to design a variety of games in the future in a way that minimizes the harmful side effects of video games on human cognitive functions and maximizes their beneficial effects.

Nöbetli Çalışan Erkeklerde Beyin Kökenli Nörotrofik Faktör, Glial Hücre Dizisinden Kaynaklanan Nörotrofik Faktör ve Nörotrofin-3 Düzeylerinin ve Beyin Hacimlerinin İncelenmesi: Klinik Araştırma

Objective: This study aims to examine the levels of brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and neurotrophin-3 (NT-3) and brain volumes in shift-working men. Material and Methods: Forty-nine men who have been working in shifts for at least 1 year were included in the study. Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality, Montreal Cognitive Assessment (MoCA) test and trail making test (TMT) were used to assess cognitive performance, and Beck Anxiety Inventory (BAI) was used to assess anxiety level. Afterwards, plasma BDNF, GDNF and NT-3 levels were examined. Brain volume measurement was performed. Results: Since the PSQI results of shift-working men were above 5, it was determined that they had 'poor sleep quality'. According to the BAI results, 85% of them had anxiety. Primary-secondary school graduate shift-working men had lower MoCA value and TMT-A and TMT-B test scores were higher (p <0.05).Working in shifts for 6 years or more caused a significant decrease in BDNF and NT-3 levels (p<0.05). According to the correlation analysis results, it was observed that the prefrontal cortex, dorsolateral prefrontal cortex and cerebral cortex in the left lobe of the brain were smaller in elderly shift workers (p<0.05). Conclusion: There is a decrease in BDNF and NT-3 levels in shift workers of 6 years or more. Some brain regions associated with learning and memory have been found to be in smaller volumes in older shift workers.

Potential value of serum brain-derived neurotrophic factor, vascular endothelial growth factor, and S100B for identifying major depressive disorder in knee osteoarthritis patients.

The chronic pain and functional limitations in osteoarthritis (OA) patients can increase risk of psychiatric disorders, e.g., major depression disorder (MDD), which may further aggravate the clinical symptoms of OA. Early detection of MDD is essential in the clinical practice of OA. Two hundred and fifteen participants with knee OA were recruited, including 134 MDD patients (i.e., MDD group) and 81 ones without MDD (i.e., control group). Among them, 81 OA participants in the control group received a 3-year follow-up and were divided into trans-MDD group (who transforming into MDD; N = 39) and non-MDD group (who keeping non-MDD; N = 42) at the end of the follow-up. The 17-item Hamilton Depression Scale (HAMD-17), Self-Rating Depression Scale (SDS), and Visual Analogue Scale (VAS) were performed. Furthermore, serum levels of brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), S100B, and IGF-1 were detected. (1) Compared with OA participants without MDD, there were significant decrease in serum BDNF and significant increase in serum VEGF and S100B and VAS scores in OA participants with MDD. (2) A mediation of the association was found between the VAS scores and the HAMD-17 scores through the BDNF as mediator in OA participants with MDD. (3) Significantly lower baseline BDNF levels and higher baseline S100B levels were detected in OA participants who transforming to MDD after a 3-year follow-up when compared with those who keeping non-MDD. (4) In the trans-MDD group, significant associations of the change of serum BDNF levels with rate of change of HAMD-17 scores were found, and baseline serum S100B levels positively correlated with the HAMD-17 scores at the end of the follow-up. (5) In OA participants, the composite indicator of BDNF, VEGF, and S100B differentiated MDD patients from controls with the area under the curve (AUC) value of 0.806, and the combined indicator of baseline BDNF and S100B distinguished trans-MDD participants from non-MDD ones with an AUC value of 0.806. Serum BDNF, VEGF, and S100B may be potential biomarkers to identify MDD in OA patients. Meanwhile, serum BDNF and S100B shows great potential to predict the risk of MDD for OA.

Metrnl regulates cognitive dysfunction and hippocampal BDNF levels in D-galactose-induced aging mice.

Aging is one of the main risk factors for cognitive dysfunction. During aging process, the decrease of brain-derived neurotrophic factor (BDNF) and the impairment of astrocyte function contribute to the cognitive impairment. Metrnl, a neurotrophic factor, promotes neural growth, migration and survival, and supports neural function. In this study, we investigated the role of Metrnl in cognitive functions. D-galactose (D-gal)-induced aging model was used to simulate the process of aging. Cognitive impairment was assessed by the Morris water maze test. We showed that Metrnl expression levels were significantly increased in the hippocampus of D-gal-induced aging mice. Metrnl knockout did not affect the cognitive functions in the baseline state, but aggravated the cognitive impairment in the D-gal-induced aging mice. Furthermore, Metrnl knockout significantly reduced hippocampal BDNF, TrkB, and glial fibrillary acidic protein (GFAP) levels in the D-gal-induced aging mice. In the D-gal-induced aging cell model in vitro, Metrnl levels in the hippocampal astrocytes were significantly increased, and Metrnl knockdown and overexpression regulated the BDNF levels in primary hippocampal astrocytes rather than in neurons. We conclude that Metrnl regulates cognitive functions and hippocampal BDNF levels during aging process. As a neurotrophic factor and an endogenous protein, Metrnl is expected to become a new candidate for the treatment or alleviation of aging-related cognitive dysfunction.

Boswellic acids ameliorate neurodegeneration induced by AlCl3: the implication of Wnt/β-catenin pathway

Alzheimer’s disease (AD) is a neurodegenerative disease (ND) that represents the principal cause of dementia. Effective treatment is still lacking. Without prevention, Alzheimer’s disease (AD) incidence is expected to triple within 30 years. The risk increases in highly polluted areas and is positively linked to chronic aluminum (Al) exposure. Canonical Wingless-Int (Wnt)/β-catenin pathway has been found to play a considerable role in ND pathogenesis. Resins of Boswellia serrata (frankincense) have been used traditionally for their psychoactive activity, in addition to their memory-boosting effects. Boswellic acids (BA) are pentacyclic triterpenes. They have antioxidant, anti-inflammatory, antinociceptive, and immunomodulatory activities. This study aimed to elucidate the role of the Wnt/β-catenin pathway in BA protective activity against aluminum-induced Alzheimer’s disease. For 6 weeks, rats were treated daily with AlCl3 (100 mg/kg/i.p.) either alone or with BA (125 or 250 mg/kg PO). Results indicated that BA significantly improved learning and memory impairments induced by AlCl3 treatment. Moreover, BA treatment significantly decreased acetylcholinesterase levels and reduced amyloid-beta (Aβ) expression. In addition, BA ameliorated the increased expression of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), inhibited lipid peroxidation, and increased total antioxidants in the brain. Indeed, BA significantly suppressed AlCl3-induced decrease of brain-derived neurotrophic factor, pGSK-3β (Ser 9), and β-catenin. BA (250 mg/kg) showed a significant protective effect compared to a lower dose. The results conclude that BA administration modulated the expression of Wnt/β-catenin pathway-related parameters, contributing to BA’s role against Al-induced Alzheimer’s disease.Graphical abstractEffect of Boswellic acids on AlCl3-induced neurodegenerative changes. ChE cholinesterase, Ach acetylcholine, BDNF brain-derived neurotrophic factor, IL-1β interleukin-1β, TNF-α tumor necrosis factor-α

Brain-Derived Neurotropic Factor in Neurodegenerative Disorders.

Globally, neurodegenerative diseases cause a significant degree of disability and distress. Brain-derived neurotrophic factor (BDNF), primarily found in the brain, has a substantial role in the development and maintenance of various nerve roles and is associated with the family of neurotrophins, including neuronal growth factor (NGF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5). BDNF has affinity with tropomyosin receptor kinase B (TrKB), which is found in the brain in large amounts and is expressed in several cells. Several studies have shown that decrease in BDNF causes an imbalance in neuronal functioning and survival. Moreover, BDNF has several important roles, such as improving synaptic plasticity and contributing to long-lasting memory formation. BDNF has been linked to the pathology of the most common neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease. This review aims to describe recent efforts to understand the connection between the level of BDNF and neurodegenerative diseases. Several studies have shown that a high level of BDNF is associated with a lower risk for developing a neurodegenerative disease.

Preventive putative mechanisms involved in the psychopathologies of mice passively coping with psychosocial defeat stress by quercetin

Derangements of neuroimmune, neurotrophic and neurochemical homeostasis have important implications in psychosocial stress-induced psychopathologies. Whether quercetin, a neuroactive compound, protects against psychosocial stress-induced psychiatric disturbances particularly via neurochemical mechanisms remain less well elucidated. Therefore, we further investigated the putative neurochemical as well as other cellular mechanisms of quercetin on social-defeat stress (SDS) model of psychosocial impairments. Saline (10 mL/kg,i.p.), quercetin (25, 50 and 100 mg/kg,i.p.) and ginseng (50 mg/kg,i.p.) were given to intruder mice for 14 days. From days 7–14, ten minutes of aggressive-resident-induced SDS (physical and psychological) were conducted thirty minutes after treatments. Subsequently, behavioral assessments: open-field, light/dark board, Y-maze, novel-object recognition, social-interaction and tail-suspension tests were conducted on day 14. Adrenal weight and glucose levels were measured. Monoamines, brain-derived neurotrophic factor (BDNF), corticosterone, inflammatory cytokines (TNF-α, IL-6) and executioner caspase-3 concentrations were determined in specific brain regions by ELISA. Oxidative/nitrergic stress and cholinergic markers were determined with UV-spectrophotometry. Psychosocial stress-induced anxiety, depression and cognitive defects were improved by quercetin. The decreased serotonin in the prefrontal-cortex and dopamine in the striatum, elevated levels of noradrenaline and acetylcholinesterase in the prefrontal-cortex and hippocampus with corresponding decrease in BDNF were reversed by quercetin. Quercetin reduced SDS-induced increased neuronal inflammation, caspase-3 activity, malondialdehyde, nitrite levels, but increased antioxidant activities in the three brain regions. Adrenal hypertrophy, increased serum glucose and corticosterone release were reduced by quercetin. Our findings showed that quercetin attenuates psychosocial stress-induced passive coping behavior via normalization of HPA-axis, modulation of neurochemical release, enhancement of BDNF, and inhibition of brain oxidative/nitrergic stress, neuroinflammation and apoptotic pathway.

The Neuroprotective Effect of α-Lipoic Acid and/or Metformin against the Behavioral and Neurochemical Changes Induced by Hypothyroidism in Rat.

The present study evaluates the neuroprotective effect of α-lipoic acid (ALA) and/or metformin (MET) on the behavioral and neurochemical changes induced by hypothyroidism. Rats were divided into control, rat model of hypothyroidism induced by propylthiouracil, and rat model of hypothyroidism treated with ALA, MET, or their combination. Behaviorally, hypothyroid rats revealed impaired memory and reduced motor activity as indicated from the novel object recognition test and open-field test, respectively. Hypothyroidism induced a significant increase in lipid peroxidation (malondialdehyde [MDA]) and a significant decrease in reduced glutathione (GSH) and nitric oxide (NO) in the cortex and hippocampus. These were associated with a significant increase in tumor necrosis factor-α (TNF-α) and a significant decrease in brain-derived neurotrophic factor (BDNF). Hypothyroidism decreased significantly the levels of serotonin (5-HT), norepinephrine (NE), and dopamine (DA) and reduced the activities of acetylcholinesterase (AchE) and Na+, K+-ATPase in the cortex and hippocampus. Treatment of hypothyroid rats with ALA and/or MET showed an improvement in memory function and motor activity. Moreover, ALA and/or MET prevented the increase in MDA and TNF-α, and the decline in GSH, NO, BDNF, 5-HT, NE, and DA. It also restored AchE and Na+, K+-ATPase activities in the studied brain regions. ALA and/or MET has a potential neuroprotective effect against the adverse behavioral and neurochemical changes induced by hypothyroidism in rats.

Protective effects of melatonin in cisplatin-induced cardiac toxicity: possible role of BDNF-TNF-α signaling pathway.

ABSTRACTPurpose:The present study explored the role of melatonin in cisplatin-induced cardiac injury along with the possible role of brain-derived neurotrophic factor (BDNF) in melatonin-mediated effects.Methods:Wistar rats were administered cisplatin (10 mg/kg), and cardiac injury was assessed by measuring the levels of cardiac troponin (cTnT) and lactate dehydrogenase (LDH-1).The extent of apoptosis was measured by measuring caspase-3 (pro-apoptotic) and Bcl-2 (anti-apoptotic) in hearts. The levels of BDNF, tumour necrosis factor α (TNF-α) and reduced glutathione were measured in heart. Melatonin (5 and 10 mg/kg) was administered for 15 days, and the role of BDNF was identified by co-administering BDNF inhibitor, ANA-12 (0.25 and 0.5 mg/kg).Results:Melatonin attenuated cTnT and LDH-1 levels along with reduction in caspase-3 and increase in Bcl-2. It also increased cisplatin-induced decrease in BDNF, increase in TNF-α and decrease in reduced glutathione levels. Moreover, ANA-12 abolished the cardioprotective effects, anti-inflammatory and antioxidant effects of melatonin suggesting the role of BDNF in melatonin-mediated effects in cisplatin-induced cardiac injury.Conclusions:Melatonin is useful in cisplatin-induced cardiac injury, which may be due to an increase in BDNF, decrease in inflammation and increase in antioxidant activities.

BDNF-ОПОСРЕДОВАННЫЙ МЕХАНИЗМ АНТИСТРЕССОРНОГО ДЕЙСТВИЯ МЕЛАНОКОРТИНОВ

In recent years studies devoted to the study of the mechanisms of regulation of physiological and pathophysiological processes are of particular interest in connection with the active development of molecular medicine. Stress caused by various biological, social and technogenic factors is an integral part of modern human life and is a non-specific reaction of the body to various extreme influences. Despite the formation of adaptive mechanisms under stress in the form of generalized activation of the body, focusing of attention and memory, stress-induced analgesia, under conditions of intense and prolonged influence of a negative factor, the central nervous system loses its ability to adapt and the processes of neurogenesis are often disturbed as a result of distress. This fact explains the development of stress-induced pathological processes in the central nervous system, which emphasizes the relevance of the search and study of the mechanisms of action of pharmacological agents exhibiting stress-protective and neurotropic properties. Melanocortins (N-terminal fragments of adrenocorticotropic hormone, fragments of proopiomelanocortin and their synthetic analogs) are characterized by pronounced neurometabolic, neuroregenerative and antistress activity. One of the possible mechanisms of action of melanocortins is the influence on the levels of expression in the central nervous system of neurotrophic factors that provide the main processes of regulation of homeostasis of the body. Brain Derived Neurotrophic Factor (BDNF) which is able to reduce the negative effects of hypoxic, toxic and stressful damage to brain cells, which is due to binding to tyrosine kinase B receptor and activation of the main metabolic cascades, is one of the effective regulatory proteins. Taking into account the fact that the question of the mechanisms of the stress-protective action of substances capable of protecting brain cells from the damaging effect of stress factors is relevant, the study of the effect of melanocortins on the level of neurotrophic factors is of scientific interest. The study was carried out on 70 male white rats of 6 months of age. Sensory contact in the absence of physical contact with the subsequent formation of aggressive and submissive types of behavior was used as an experimental model of «social» stress. Laboratory animals, taking into account the gradation by types of behavior, were divided into groups: a group of control / intact animals; a group of rats exposed to «social» stress for 20 days; a group of individuals who received Semax (ACTH(4-7)-Pro-Gly-Pro) at a dose of 100 μg / kg / day intraperitoneally from the 1st day of stress exposure for a course of 20 days; a group of animals that received ACTH(6-9)-Pro-Gly-Pro at a dose of 100 μg/kg/day intraperitoneally from day 1 of stress exposure for a course of 20 days. The BDNF level in the blood serum of white rats was assessed by the enzyme-linked immunosorbent assay using ELISA Kit for Brain Derived Neurotrophic Factor (BDNF) (USA). It was found that under conditions of «social» stress, a decrease in the level of BDNF was observed. The introduction of the studied melanocortins (ACTH(4-7)-Pro-Gly-Pro (Semax) and ACTH(6-9)-Pro-Gly-Pro) under conditions of induced «social» stress increases the concentration of BDNF in the blood serum of experimental animals. The study of the mechanisms of disturbances induced by experimental stress in various models showed that stress provokes the development of a depression-like state in rodents, which is accompanied by neuroplastic changes, including inhibition of neurogenesis in the hippocampus. Currently a large amount of experimental data has been accumulated, indicating that a pathological stress response contributes to a decrease in the level of BDNF. Deficiency of BDNF plays an important role in the pathophysiology of stress, inducing impairments of neurogenesis associated with impaired neuroplasticity, as well as dysfunction of the hypothalamic-pituitary-adrenal and neurotransmitter serotonergic systems. The effectiveness of therapy with stress protectors and antidepressants is due to their effect on neurogenesis and neuronal plasticity. Thus the fact of a decrease of BDNF under conditions of «social» stress established in the work and the positive effect of melanocortins (ACTH(4-7)-Pro-Gly-Pro (Semax) and ACTH(6-9)-Pro-Gly-Pro), contributing to the restoration of these parameters, indicates the effect of neuropeptides on the expression of BDNF and allows us to suggest a possible mechanism of the antistress effect. It should be noted that the serum level of brain neurotrophic factor can be considered as a biomarker of stress-induced disorders and affective disorders, as well as an indicator of the effectiveness of therapy with stress protectors. In addition, the level of BDNF in the blood serum can be considered as indicators of prognosis and evaluation of the effectiveness of therapy.

Neurotrophic factors in Alzheimer’s disease: pathogenesis and therapy

Alzheimer's disease (AD) is a common neurodegenerative disease with a prevalence estimated to reach 115 million by 2050. It is characterized by abnormal extracellular accumulation of amyloid‑beta (Aβ) peptide and intracellular neurofibrillary tangles (NFTs) that result in neuro‑inflammation, synaptic dysfunction, neurotransmitter imbalance, neuronal loss, and dendritic changes. A hypothesis of neurotrophic factor (NTF) involvement in neurodegenerative diseases and their potential as a therapeutic tool has emerged. There are wide information gaps on this topic. However, consistent with this hypothesis, AD may be caused by a deficiency in neurotrophin proteins or receptors expression. In AD brains, an increase in nerve growth factor and a decrease in brain-derived neurotrophic factor in the hippocampus and certain neocortical regions, and a decrease in TrkA in the cortex and nucleus basalis has been observed. Thus, comparative data relating to recent hypotheses addressing NTF content and receptors in experimental animals and human brains, along with their potential roles in the treat ment of AD, are discussed in this review.