Elevated Brain-derived Neurotrophic Factor Levels Research Articles

BDNF augmentation reverses cranial radiation therapy-induced cognitive decline and neurodegenerative consequences.

Cranial radiation therapy (RT) for brain cancers is often associated with the development of radiation-induced cognitive dysfunction (RICD). RICD significantly impacts the quality of life for cancer survivors, highlighting an unmet medical need. Previous human studies revealed a marked reduction in plasma brain-derived neurotrophic factor (BDNF) post-chronic chemotherapy, linking this decline to a substantial cognitive dysfunction among cancer survivors. Moreover, riluzole (RZ)-mediated increased BDNF in vivo in the chemotherapy-exposed mice reversed cognitive decline. RZ is an FDA-approved medication for ALS known to increase BDNF in vivo . In an effort to mitigate the detrimental effects of RT-induced BDNF decline in RICD, we tested the efficacy of RZ in a cranially irradiated (9 Gy) adult mouse model. Notably, RT-exposed mice exhibited significantly reduced hippocampal BDNF, accompanied by increased neuroinflammation, loss of neuronal plasticity-related immediate early gene product, cFos, and synaptic density. Spatial transcriptomic profiling comparing the RT+Veh with the RT+RZ group showed gene expression signatures of neuroprotection of hippocampal excitatory neurons post-RZ. RT-exposed mice performed poorly on learning and memory, and memory consolidation tasks. However, irradiated mice receiving RZ (13 mg/kg, drinking water) for 6-7 weeks showed a significant improvement in cognitive function compared to RT-exposed mice receiving vehicle. Dual-immunofluorescence staining, spatial transcriptomics, and biochemical assessment of RZ-treated irradiated brains demonstrated preservation of synaptic integrity and neuronal plasticity but not neurogenesis and reduced neuroinflammation concurrent with elevated BDNF levels and transcripts compared to vehicle-treated irradiated brains. In summary, oral administration of RZ represents a viable and translationally feasible neuroprotective approach against RICD.

Exploring the impact of acetylsalicylic acid and conditioned medium obtained from mesenchymal cells, individually and in combination, on cognitive function, histological changes, and oxidant-antioxidant balance in male rats with hippocampal injury.

The hippocampus is susceptible to damage, leading to negative impacts on cognition. Conditioned medium (CM) obtained from adipose tissue-derived mesenchymal stem cells (MSCs) and acetylsalicylic acid (ASA) have shown neuroprotective effects independently. This study explored the synergistic potential of ASA and CM from adipose-derived MSCs against hippocampal injury. Adult male Wistar rats received bilateral hippocampal ethidium bromide (EB) injections to induce hippocampal damage. Rats were treated with ASA and/or CM derived from adipose tissue MSCs every 48h for 16 days. Behavioral tests (open field test, Morris water maze, novel object recognition, and passive avoidance), oxidative stress, Western blot analysis of brain-derived neurotrophic factor (BDNF) and cerebral dopamine neurotrophic factor (CDNF) expression, and hippocampal histological investigation were conducted. Administration of EB caused impairments in spatial, recognition, and passive avoidance memory, as well as heightened oxidative stress, reduced BDNF/CDNF expression, and pyramidal cell loss in the hippocampal CA1 region. Administration of ASA, CM, or a combination of both mitigated these hippocampal damages and cognitive deficits, elevated BDNF and CDNF levels, and alleviated the CA1 necrosis caused by EB. Moreover, co-administering ASA and CM resulted in greater improvements in spatial memory compared to administering ASA alone, suggesting possible synergistic interactions. The ability of ASA, CM obtained from adipose tissue-derived MSCs, and their combination therapy to alleviate hippocampal injuries highlights their promising therapeutic potential as a neuroprotection strategy against brain damage. Our findings provide preliminary evidence of the potential synergistic effects of ASA and CM, which warrants further investigations.

Vagus Nerve Stimulation (VNS) Modulates Synaptic Plasticity in the Infralimbic Cortex via Trk-B Receptor Activation to Reduce Drug-Seeking in Male Rats.

Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drug-seeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces relapse. Vagus nerve stimulation (VNS) has previously been shown to enhance extinction learning and reduce drug-seeking. Here we determined the effects of VNS-mediated release of brain-derived neurotrophic factor (BDNF) on extinction and cue-induced reinstatement in male rats trained to self-administer cocaine. Pairing 10 d of extinction training with VNS facilitated extinction and reduced drug-seeking behavior during reinstatement. Rats that received a single extinction session with VNS showed elevated BDNF levels in the medial PFC as determined via an enzyme-linked immunosorbent assay. Systemic blockade of tropomyosin receptor kinase B (TrkB) receptors during extinction, via the TrkB antagonist ANA-12, decreased the effects of VNS on extinction and reinstatement. Whole-cell recordings in brain slices showed that cocaine self-administration induced alterations in the ratio of AMPA and NMDA receptor-mediated currents in Layer 5 pyramidal neurons of the infralimbic cortex (IL). Pairing extinction with VNS reversed cocaine-induced changes in glutamatergic transmission by enhancing AMPAR currents, and this effect was blocked by ANA-12. Our study suggests that VNS consolidates the extinction of drug-seeking behavior by reversing drug-induced changes in synaptic AMPA receptors in the IL, and this effect is abolished by blocking TrkB receptors during extinction, highlighting a potential mechanism for the therapeutic effects of VNS in addiction.

Assessment of Ameliorative Potential of Co-enzyme Q10 (Co_Q10) Supplementation in Brain Derived Neurotrophic Factor (BDNF) and Serum Acetylcholinesterase (AChE) Altered Rat Models

Neurodegenerative diseases affect millions of people worldwide. And the levels of some biomolecules like brain-derived neurotrophic factor (BDNF) and acetylcholinesterase (AChE) are known to play significant roles in different neurodegenerative diseases. The present study therefore assessed the ameliorative potential of Co-enzyme Q10 (CoQ10 or Co_Q10) supplementation in altered levels of BDNF and AChE in thioacetamide (TAA) induced hepatic encephalopathy (HE) in male Wistar rat models. Male Wistar rats weighing 250±30 g were used for the study and were randomly separated into six different groups of twenty rats each. The groups included Group 1-control and received 1ml of normal saline (intraperitoneally―ip), Group 2 received only 200 mg/kg TAA (ip) twice weekly, Group 3 received 5mg/kg Co_Q10, daily per oral (po), Group 4 received 10mg/kg Co_Q10 daily (po), Group 5 received 200 mg/kg TAA (ip) twice weekly and 5mg/kg Co_Q10 (po) daily and Group 6 received 200 mg/kg TAA (ip) twice weekly and 10mg/kg Co_Q10 (po) daily. At the end of weeks 3, 6, 9 and 12 of treatment, blood samples were immediately transferred into appropriately labeled blood sample bottles containing anticoagulant. Numerical data obtained from the study were subjected to statistical analyses using analyses of variance and Post Hoc tools of the statistical package for social sciences 21.0V software. The result indicated significantly (P<0.05) depressed level of BDNF and significantly (P<0.05) raised level of AChE in the TAA only treated Group 2 when compared to Group 1 and the rest groups. It was observed that, both of Co_Q10 only treated and Co_Q10 + TAA treated groups had marked (P<0.05) elevated and depressed levels of BDNF and AChE respectively in the study models. Supplementations with different doses of Co_Q10 (5 and 10mg/kg) indicated significant improvement in TAA altered levels of BDNF and AChE in a mammalian model.

Immunosuppressive role of BDNF in therapy-induced neuroendocrine prostate cancer.

Prostate stromal cells play a crucial role in the promotion of tumor growth and immune evasion in the tumor microenvironment (TME) through intricate molecular alterations in their interaction with prostate cancer (PCa) cells. While the impact of these cells on establishing an immunosuppressive response and influencing PCa aggressiveness remains incompletely understood. Our study shows that the activation of the leukemia inhibitory factor (LIF)/LIF receptor (LIFR) pathway in both prostate tumor and stromal cells, following androgen deprivation therapy (ADT), leads to the development of an immunosuppressive TME. Activation of LIF/LIFR signaling in PCa cells induces neuroendocrine differentiation (NED) and upregulates immune checkpoint expression. Inhibition of LIF/LIFR attenuates these effects, underscoring the crucial role of LIF/LIFR in linking NED to immunosuppression. Prostate stromal cells expressing LIFR contribute to NED and immunosuppressive marker abundance in PCa cells, while LIFR knockdown in prostate stromal cells reverses these effects. ADT-driven LIF/LIFR signaling induces brain-derived neurotrophic factor (BDNF) expression, which, in turn, promotes NED, aggressiveness, and immune evasion in PCa cells. Clinical analyses demonstrate elevated BDNF levels in metastatic castration-resistant PCa (CRPC) and a positive correlation with programmed death-ligand 1 (PDL1) and immunosuppressive signatures. This study shows that the crosstalk between PCa cells and prostate stromal cells enhances LIF/LIFR signaling, contributing to an immunosuppressive TME and NED in PCa cells through the upregulation of BDNF.

High-Serum Brain-Derived Neurotrophic Factor Levels Are Associated With Decreased Risk of Poststroke Cognitive Impairment.

BDNF (brain-derived neurotrophic factor) is widely implicated in the pathophysiological process of stroke, but the effect of BDNF on poststroke cognitive impairment (PSCI) remains unclear. We aimed to investigate the association between baseline serum BDNF and the risk of PSCI at 3 months in a multicenter study based on a preplanned ancillary study of the CATIS trial (China Antihypertensive Trial in Acute Ischemic Stroke). We examined serum BDNF levels at baseline and used the Mini-Mental State Examination and Montreal Cognitive Assessment to evaluate cognitive function at 3-month follow-up after ischemic stroke. PSCI was defined as Mini-Mental State Examination score <27 or Montreal Cognitive Assessment score <25. Logistic regression analyses were performed to evaluate the association between serum BDNF and the risk of 3-month PSCI. In this ancillary study, a total of 660 patients with ischemic stroke with hypertension were included, and 593 patients (mean age, 59.90±10.44 years; 410 males and 183 females) were finally included in this analysis. According to mini-mental state examination score, after adjustment for age, sex, education, baseline National Institutes of Health Stroke Scale score, APOE ɛ4 carriers, and other potential confounders, the odds ratio of PSCI for the highest tertile of BDNF was 0.60 ([95% CI, 0.39-0.94]; P=0.024) compared with the lowest tertile. Multiple-adjusted spline regression model showed a linear association of serum BDNF levels with PSCI at 3 months (P value for linearity=0.010). Adding serum BDNF to conventional prognostic factors slightly improved the risk reclassification of PSCI (net reclassification improvement: 27.46%, P=0.001; integrated discrimination index: 1.02%, P=0.015). Similar significant findings were observed when PSCI was defined by the Montreal Cognitive Assessment score. Elevated serum BDNF levels were associated with a decreased risk of PSCI at 3 months, suggesting that serum BDNF might be a potential predictive biomarker for PSCI among patients with ischemic stroke with hypertension.

The Role of the Brain-Derived Neurotrophic Factor in Chronic Pain: Links to Central Sensitization and Neuroinflammation.

Chronic pain is sustained, in part, through the intricate process of central sensitization (CS), marked by maladaptive neuroplasticity and neuronal hyperexcitability within central pain pathways. Accumulating evidence suggests that CS is also driven by neuroinflammation in the peripheral and central nervous system. In any chronic disease, the search for perpetuating factors is crucial in identifying therapeutic targets and developing primary preventive strategies. The brain-derived neurotrophic factor (BDNF) emerges as a critical regulator of synaptic plasticity, serving as both a neurotransmitter and neuromodulator. Mounting evidence supports BDNF's pro-nociceptive role, spanning from its pain-sensitizing capacity across multiple levels of nociceptive pathways to its intricate involvement in CS and neuroinflammation. Moreover, consistently elevated BDNF levels are observed in various chronic pain disorders. To comprehensively understand the profound impact of BDNF in chronic pain, we delve into its key characteristics, focusing on its role in underlying molecular mechanisms contributing to chronic pain. Additionally, we also explore the potential utility of BDNF as an objective biomarker for chronic pain. This discussion encompasses emerging therapeutic approaches aimed at modulating BDNF expression, offering insights into addressing the intricate complexities of chronic pain.

Elevated Brain-Derived Neurotrophic Factor Levels During Depressive Mixed States.

Neurotrophin-like brain-derived neurotrophic factor (BDNF) and pro-inflammatory cytokines may modulate the pathophysiology of mood disorders. Although several studies show alterations in these biomarkers during the depressive, manic, and euthymic states of mood disorders, evidence is lacking for those in a mixed state. Therefore, this study aimed to investigate the relationship between the depressive mixed state (DMX) and peripheral neurobiological factors. We enrolled 136 patients with major depressive episodes. Depressive symptoms were assessed using the Quick Inventory of Depressive Symptomatology Self-Report Japanese version (QIDS-SR-J). The severity of DMX was assessed using the self-administered 12-item questionnaire (DMX-12). Categorical screening as DMX-positive (n=54) was determined by a cutoff score of 13 or more in the specific eight symptoms from the DMX-12; the remaining were DMX-negative (n=82). Serum BDNF, tumor necrosis factor-α, highsensitivity C-reactive protein, and interleukin-6 levels were measured. When comparing biomarkers between the DMX-positive and DMX-negative groups, higher serum BDNF concentration in the DMX-positive group than in the DMX-negative group was the only significant finding (p=0.009). A positive correlation existed between the total score of the eight specific symptoms of DMX-12 and the BDNF concentration (r=0.190, p=0.027). After adjustment for confounders, logistic regression analysis revealed that BDNF (odds ratio [OR]=1.07, 95% confidence interval [CI]=1.00-1.14, p=0.045), bipolar diagnosis (OR=3.43, 95% CI=1.36-8.66, p=0.009), and total QIDS-SR-J score (OR=1.29, 95% CI=1.15-1.43, p<0.001) were significantly associated with DMX positivity. BDNF was positively associated with DMX severity, suggesting that higher BDNF concentrations may be involved in the pathophysiology of DMX.

SIRT1/PARP-1/NLRP3 cascade as a potential target for niacin neuroprotective effect in lipopolysaccharide-induced depressive-like behavior in mice

Depression is a serious mood disorder characterized by monoamines deficiency, oxidative stress, neuroinflammation, and cell death. Niacin (vitamin B3 or nicotinic acid, NA), a chief mediator of neuronal development and survival in the central nervous system, exerts neuroprotective effects in several experimental models. AimsThis study aimed to investigate the effect of NA in lipopolysaccharide (LPS) mouse model of depression exploring its ability to regulate sirtuin1/poly (ADP-ribose) polymerase-1 (PARP-1)/nod-likereceptor protein 3 (NLRP3) signaling. Main methodsMice were injected with LPS (500 µg/kg, i.p) every other day alone or concurrently with oral doses of either NA (40 mg/kg/day) or escitalopram (10 mg/kg/day) for 14 days. Key findingsAdministration of NA resulted in significant attenuation of animals' despair reflected by decreased immobility time in forced swimming test. Moreover, NA induced monoamines upsurge in addition to sirtuin1 activation with subsequent down regulation of PARP-1 in the hippocampus. Further, it diminished nuclear factor-κB (NF-κB) levels and inhibited NLRP3 inflammasome with consequent reduction of caspase-1, interleukin-1β and tumor necrosis factor-α levels, thus mitigating LPS-induced neuroinflammation. NA also reduced tumor suppressor protein (p53) while elevating brain-derived neurotrophic factor levels. LPS-induced decline in neuronal survival was reversed by NA administration with an obvious increase in the number of intact cells recorded in the histopathological micrographs. SignificanceAccordingly, NA is deemed as a prosperous candidate for depression management via targeting SIRT1/PARP-1 pathway.

Relationship between Brain-Derived Neurotrophic Factor and Cognitive Decline in Patients with Mild Cognitive Impairment and Dementia.

In the last decade, increasing evidence has emerged linking alterations in the brain-derived neurotrophic factor (BDNF) expression with the development of Alzheimer's disease (AD). Because of the important role of BDNF in cognition and its association with AD pathogenesis, the aim of this study was to evaluate the potential difference in plasma BDNF concentrations between subjects with mild cognitive impairment (MCI; N = 209) and AD patients (N = 295) and to determine the possible association between BDNF plasma levels and the degree of cognitive decline in these individuals. The results showed a significantly higher (p < 0.001) concentration of plasma BDNF in subjects with AD (1.16; 0.13-21.34) compared with individuals with MCI (0.68; 0.02-19.14). The results of the present study additionally indicated a negative correlation between cognitive functions and BDNF plasma concentrations, suggesting higher BDNF levels in subjects with more pronounced cognitive decline. The correlation analysis revealed a significant negative correlation between BDNF plasma levels and both Mini-Mental State Examination (p < 0.001) and Clock Drawing test (p < 0.001) scores. In conclusion, the results of our study point towards elevated plasma BDNF levels in AD patients compared with MCI subjects, which may be due to the body's attempt to counteract the early and middle stages of neurodegeneration.

Diet Control and Swimming Exercise Ameliorate HFD-Induced Cognitive Impairment Related to the SIRT1-NF-κB/PGC-1α Pathways in ApoE-/- Mice.

High-fat diet- (HFD-) induced neuroinflammation may ultimately lead to an increased risk of cognitive impairment. Here, we evaluate the effects of diet control and swimming or both on the prevention of cognitive impairment by enhancing SIRT1 activity. Twenty-week-old ApoE-/- mice were fed a HFD for 8 weeks and then were treated with diet control and/or swimming for 8 weeks. Cognitive function was assessed using the novel object recognition test (NORT) and Y-maze test. The expression of sirtuin-1 (SIRT1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), brain-derived neurotrophic factor (BDNF), nuclear factor kappa B p65 (NF-κB p65), interleukin-1β (IL-1β), and tumour necrosis factor-α (TNF-α) in the hippocampus was measured by western blotting. The levels of fractional anisotropy (FA), N-acetylaspartate (NAA)/creatine (Cr) ratio, choline (Cho)/Cr ratio, and myo-inositol (MI)/Cr ratio in the hippocampus were evaluated by diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) using 7.0-T magnetic resonance imaging (MRI). Our results showed that cognitive dysfunction and hippocampal neuroinflammation appeared to be remarkably observed in apolipoprotein E (ApoE)-/- mice fed with HFD. Diet control plus swimming significantly reversed HFD-induced cognitive decline, reduced the time spent exploring the novel object, and ameliorated spontaneous alternation in the Y-maze test. Compared with the HFD group, ApoE-/- mice fed diet control and/or subjected to swimming had an increase in FA, NAA/Cr, and Cho/Cr; a drop in MI/Cr; elevated expression levels of SIRT1, PGC-1α, and BDNF; and inhibited production of proinflammatory cytokines, including NF-κB p65, IL-1β, and TNF-α. SIRT1, an NAD+-dependent class III histone enzyme, deacetylases and regulates the activity of PGC-1α and NF-κB. These data indicated that diet control and/or swimming ameliorate cognitive deficits through the inhibitory effect of neuroinflammation via SIRT1-mediated pathways, strongly suggesting that swimming and/or diet control could be potentially effective nonpharmacological treatments for cognitive impairment.

Fast and Sustained Axonal Growth by BDNF Released from Chitosan Microspheres.

Brain-derived neurotrophic factor (BDNF) regulates dendritic branching and dendritic spine morphology, as well as synaptic plasticity and long-term potentiation. Consequently, BDNF deficiency has been associated with some neurological disorders such as Alzheimer's, Parkinson's or Huntington's diseases. In contrast, elevated BDNF levels correlate with recovery after traumatic central nervous system (CNS) injuries. The utility of BDNF as a therapeutic agent is limited by its short half-life in a pathological microenvironment and its low efficacy caused by unwanted consumption of non-neuronal cells or inappropriate dosing. Here, we tested the activity of chitosan microsphere-encapsulated BDNF to prevent clearance and prolong the efficacy of this neurotrophin. Neuritic growth activity of BDNF release from chitosan microspheres was observed in the PC12 rat pheochromocytoma cell line, which is dependent on neurotrophins to differentiate via the neurotrophin receptor (NTR). We obtained a rapid and sustained increase in neuritic out-growth of cells treated with BDNF-loaded chitosan microspheres over control cells (p < 0.001). The average of neuritic out-growth velocity was three times higher in the BDNF-loaded chitosan microspheres than in the free BDNF. We conclude that the slow release of BDNF from chitosan microspheres enhances signaling through NTR and promotes axonal growth in neurons, which could constitute an important therapeutic agent in neurodegenerative diseases and CNS lesions.

Acute effects of ambient nitrogen dioxide exposure on serum biomarkers of nervous system damage in healthy older adults

Ambient nitrogen dioxide (NO2)-induced adverse health effects have been studied, but documented evidence on neural systems is limited. This study aimed to determine the acute effect of NO2 exposure on nervous system damage biomarker levels in healthy older adults. Five rounds of follow-up among 34 healthy retired people were scheduled from December 2018 to April 2019 in Xinxiang, China. The real-time NO2 concentrations were measured using a fixed site monitor. Serum samples were acquired during each round to measure nervous system damage biomarker levels: brain-derived neurotrophic factor (BDNF), neurofilament light chain (NfL), neuron-specific enolase (NSE), protein gene product 9.5 (PGP9.5), and S100 calcium-binding protein B (S100B). A linear mixed-effect model was incorporated to analyze the association between short-term NO2 exposure and serum concentrations of the above-mentioned biomarkers. Stratification analysis based on sex, educational attainment, glutathione S-transferase theta 1 gene (GSTT1) polymorphism, and physical activity intensity was conducted to explore their potential modification effect. The NO2 concentration ranged from 34.7 to 59.0 µg/m3 during the study period. Acute exposure to ambient NO2 was significantly associated with elevated serum levels of NfL, PGP9.5, and BDNF. In response to a 10 µg/m3 increase in NO2 concentration, NfL and PGP9.5 levels increased by 76 % (95 % confidence interval [CI]: 12–140 %) and 54 % (95 % CI: 1–107 %) on the lag0 day, respectively, while BDNF levels increased by 49 % (95 % CI: 2–96 %) at lag4 day. The estimated effect of NO2 on NSE levels in GSTT1-sufficient participants was significantly higher than that in GSTT1-null participants. Intriguingly, the estimation of NO2 on PGP9.5 levels in females was significantly higher than that in males. Most two-pollutant models showed robust results, except for O3, which might have had confounding effects on NO2-induced BDNF stimulation. In summary, acute exposure to NO2 was associated with increased levels of serum nervous system damage biomarker levels including NFL, PGP9.5, and BDNF. The present study provided insights into NO2 exposure-induced adverse neural effects.

Melatonin treatment improves cognitive deficits by altering inflammatory and neurotrophic factors in the hippocampus of obese mice

Overweight and obesity are associated with an increased risk of developing dementia and cognitive deficits. Neuroinflammation is one of the most important mechanisms behind cognitive impairment in obese patients. In recent years, the neuroendocrine hormone melatonin has been suggested to have therapeutic effects for memory decline in several neuropsychiatric and neurological conditions. However, the effects of melatonin on cognitive function under obesity conditions still need to be clarified. The purpose of this study was to determine whether melatonin treatment can improve cognitive impairment in obese mice. To this end, male C57BL6 mice were treated with a high-fat diet (HFD) for 20 weeks to induce obesity. The animal received melatonin for 8 weeks. Cognitive functions were evaluated using the Y maze, object recognition test, and the Morris water maze. We measured inflammatory cytokines including tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-17A, and brain-derived neurotrophic factor (BDNF) in the hippocampus of obese mice. Our results show that HFD-induced obesity significantly impaired working, spatial and recognition memory by increasing IFN-γ and IL-17A and decreasing BDNF levels in the hippocampus of mice. On the other hand, melatonin treatment effectively improved all cognitive impairments and reduced TNF-α, IFN-γ, and IL-17A and elevated BDNF levels in the hippocampus of obese mice. Taken together, this study suggests that melatonin treatment could have a beneficial role in the treatment of cognitive impairment in obesity.

Antidepressant-like effect of sodium orthovanadate in a mouse model of chronic unpredictable mild stress

Depression is a psychiatric disorder characterized by low-esteem, anhedonia, social deficit, and lack of interest. Decreased brain-derived neurotrophic factor (BDNF) and impaired tropomyosin kinase B receptor (TrkB receptor) signaling are associated with depression. In our study, depressive-like behavior was induced in mice by chronic unpredictable mild stress (CUMS) model. Various behavioral tests like tail suspension test (TST), open field test (OFT), sucrose preference test (SPT); biochemical analyses for corticosterone, reduced glutathione (GSH), lipid peroxidation (LPO), superoxide dismutase (SOD), nitric oxide (NO) and enzyme-linked immunosorbent assay (ELISA) for BDNF were performed. Body weight was measured every week. CUMS induced depressive-like behavior was found to be associated with increased oxidative stress in the brain and serum corticisterone with subsequent reduction of BDNF. Sodium orthovanadate (SOV), a protein tyrosine phosphatase inhibitor already reported to elevate BDNF levels, was used as the test drug. Sodium orthovanadate (5 mg/kg, 10 mg/kg) and fluoxetine (FLX-10 mg/kg) was given to mice orally for 21days before 30 min of stress induction. The behavioral tests reflected depressive-like behavior in CUMS, which was attenuated by both SOV and fluoxetine. SOV at 10 mg/kg demonstrated significant results in the present study characterized by decreased malondialdehyde levels (MDA/LPO), NO levels, and increased GSH level and SOD activity in both the cortex and hippocampus. Besides, ELISA has revealed the significant elevation of BDNF levels in the treatment groups (SOV-5 mg/kg, 10 mg/kg and FLX-10 mg/kg) as compared to the disease group (CUMS). Therefore, the treatment with SOV appeared to reverse both oxidative and nitrosative stress. Decreased serum corticosterone levels observed with SOV (5 & 10 mg/kg), FLX-10 mg/kg, FLX (10 mg/kg) + SOV (5 mg/kg); and SOV-10 mg/kg per-se treatment and elevated BDNF level with SOV (5 & 10 mg/kg), FLX-10 mg/kg were associated with attenuation of depressive-like behavior. The findings of this preliminary study indicate that SOV has the potential to restore antidepressant-like effects or prevent stress-induced anhedonia and so further molecular mechanisms are warranted for clinical translation.

Identification of traditional Japanese Kampo medicines and crude drugs that upregulate brain‑derived neurotrophic factor in human peripheral cells

The neurotrophic hypothesis of depression, which suggests that decreased hippocampal brain‑derived neurotrophic factor (BDNF) levels cause depression, has become increasingly popular. BDNF, a member of the neurotrophin family, promotes neuronal differentiation and survival. BDNF is synthesized in various peripheral tissues, as well as in the brain. Considering that peripheral BDNF can be transported into the brain across the blood‑brain barrier, substances with the ability to upregulate BDNF activity in peripheral tissues may be useful in the management of depression. Previously, we demonstrated that the human kidney adenocarcinoma cell line ACHN produces BDNF; hence, this cell line was employed for screening upregulators of peripheral BDNF. Here, we aimed to identify Kampo (traditional Japanese) medicines and their crude drug components that upregulate BDNF levels using ACHN cells. Chotosan, Hochuekkito, Kososan, and Ninjinyoeito, Kampo medicines used in treating psychiatric disorders, increased BDNF levels in the culture media of ACHN cells. Furthermore, Chinpi (Citrus unshiu peel), a crude drug contained in these four Kampo medicines, as well as Onji (Polygala tenuifolia root), and Saiko (Bupleurum falcatum root) elevated BDNF levels in ACHN cells. Chinpi, showing strong BDNF elevating effect, increased BDNF mRNA expression. Inhibitors of protein kinase B, mitogen‑activated protein kinase kinase, and cAMP‑dependent protein kinase, involved in the transcription of BDNF, attenuated Chinpi‑induced BDNF elevation. Our results suggest that Chinpi and Kampo medicines containing Chinpi can promote the production of BDNF in peripheral tissues, potentially alleviating depression symptoms.

Changes in serum brain derived neurotrophic factor following high intensity interval training among obese undergraduates

The study examined changes in Serum Brain Derived Neurotrophic Factor (BDNF) following High Intensity Interval Training (HIIT) programme among obese undergraduates. The pretest-posttest randomized experimental design was employed for the study. The population of the study comprised one hundred and twenty (120) obese undergraduates, out of which a total of twenty-four (24) obese undergraduates made up the sample for the study. Simple random sampling technique was employed to select the participants. The anthropometric profiles of the participants were descriptively analyzed using mean and standard deviation, while independent sample t-test was used to test the hypothesis. Statistical significance was accepted at p value of &lt;0.05. The results obtained indicated an increase in Serum BDNF (1.05 1.4 vs 1.42 2.2) among HIIT group, with no statistical significant difference. It was therefore concluded that the HIIT protocol-initiated alterations in the serum BDNF concentration of the obese undergraduates. HIIT may represent an effective intervention for elevating BDNF levels, as well as potentially promoting brain health. It was recommended that further research with prolonged exercise duration and larger sample size is required to elicit statistical significance, as well as to confirm the finding that increased serum BDNF levels are associated with HIIT intervention among obese undergraduate population.

Interaction between Zinc, GPR39, BDNF and Neuropeptides in Depression.

As one of the most important elements in our body, zinc plays a part in both the pathophysiology of depression and the antidepressant response. Patients suffering from major depression show significantly reduced zinc levels, which are normalized following successful antidepressant treatment. Recent studies have shown the interaction between zinc, GPR39 and neuropeptides, including galanin and neuropeptide Y (NPY). The zinc-sensing receptor GPR39 forms heterotrimers with 5-HT1A and the galanin receptor GalR1 upon their co-expression in mammalian cells. The oligomerization of these heterotrimers is regulated by the zinc concentration, and this may have an influence on depressive-like behavior. The antidepressant-like effect of zinc is linked to elevated levels of brain-derived neurotrophic factor (BDNF) in brain structures associated with emotion, such as the hippocampus and the amygdala. BDNF regulates neuropeptides, including NPY, cholecystokinin (CCK), and substance P or galanin, which are also implicated in mood disorders. This review focuses for the first time on the interaction between zinc, the GPR39 zinc receptor, BDNF and selected neuropeptides in terms of depression in order to determine its possible role in the neuropharmacology of that illness.

Effect of 5-HT6 Receptor Ligands Combined with Haloperidol or Risperidone on Antidepressant-/Anxiolytic-Like Behavior and BDNF Regulation in Hippocampus and Prefrontal Cortex of Rats.

BackgroundThe presence of depressive and anxiety symptoms in patients with schizophrenia may have an important impact on treatment and compliance. Hence, interventions addressing such comorbidity in schizophrenia should be explored. One target may be a serotonergic 5-HT6 receptor (5-HT6R) since its ligands displayed antidepressant- and anxiolytic-like activities in preclinical experiments.MethodsAcute and chronic (21 days) administration of haloperidol or risperidone in combination with a selective 5-HT6R agonist (WAY-181187) or antagonist (SB-742457) to rats was performed for detecting antidepressant- and anxiolytic-like behaviors. In addition, the level of brain-derived neurotrophic factor (BDNF) protein and its gene expression in hippocampus and prefrontal cortex were determined.ResultsBoth single and chronic administration of WAY-181187 with haloperidol produced antidepressant- and anxiolytic-like activities. SB-742457 did not provide full benefits in terms of improvement of haloperidol-induced adverse mood effects. However, the administration of SB-742457 with risperidone triggered its anxiolytic-like activity. Both 5-HT6R ligands evoked no changes in haloperidol-induced effects on BDNF level. WAY-181187 induced repression of the BDNF gene while SB-742457 increased its expression in both structures. 5-HT6R ligands, when combined with risperidone, did not change BDNF protein level and increased gene expression in the hippocampus, while they elevated BDNF level and potentiated gene expression in the prefrontal cortex.ConclusionThe combined administration of WAY-181187 and haloperidol provided the greatest benefits, which were manifested by antidepressant-like effects and suppression of the anxiogenic-like properties. The combined administration of risperidone with both agonist and antagonist resulted only in an anxiolytic-like effect. It seems that the anxiolytic-like effects induced by haloperidol or risperidone with the addition of 5-HT6R ligands are task-specific. The data on BDNF protein and gene expression did not fully correspond with the behavioral outcomes, and thus it appears that other factors/mechanisms are involved in the observed antidepressant- and/or anxiolytic-like effects.

Plasma brain-derived neurotrophic factor (BDNF) in Egyptian children with attention deficit hyperactivity disorder

BackgroundTo date, researchers do not fully understand what the aetiology of attention deficit hyperactivity disorder (ADHD) is. As a neurotrophin, the brain-derived neurotrophic factor (BDNF) contributes to the growth of neurons as well as to the efficiency and plasticity of the neuronal synapse, which suggests that it may be a contributing aetiological factor in ADHD. Therefore, we sought to investigate the relationship between ADHD and plasma BDNF, including whether there is an association between BDNF and the degree of severity of ADHD and with ADHD subtypes.ResultsWe found significantly elevated plasma BDNF in ADHD subjects in comparison with healthy subjects, but differences among the three subtypes of ADHD did not reach statistical significance.ConclusionCompared with the control group, elevated plasma BDNF levels were found in the ADHD group, which suggests it may contribute to the aetiology of ADHD.