Neurotrophin Levels Research Articles

Different serum protein factor levels in first-episode drug-naive patients with schizophrenia characterized by positive and negative symptoms.

The clinical features of schizophrenia can be mainly divided into two symptom domains: positive and negative. Patients in each symptom domain respond differently to treatments, and their prognoses vary accordingly. Serum protein factors, such as nerve growth factor (NGF), neurotrophin-3 (NT-3), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and the calcium-binding protein, S100β, have been reported to be involved in the pathogenesis of schizophrenia. However, their roles in the positive and negative symptom domains have not been determined. In this study, we investigated whether the serum levels of these five protein factors differed among first-episode drug-naive schizophrenia patients in each symptom domain and in healthy controls. Double-antibody sandwich ELISA were used to quantify the amounts of the five protein factors in serum. Compared with the levels in the controls (n = 60), increased serum levels of IL-6, IL-1β, and S100β and decreased serum levels of NGF and NT-3 were observed in first-episode drug-naive schizophrenia patients. Additionally, the serum levels of IL-6 and IL-1β were significantly higher in schizophrenia patients characterized by negative symptoms (negative group, n = 37) than in those characterized by positive symptoms (positive group, n = 46). Based on multivariate regression analyses, serum levels of IL-1β were positively associated with the Negative Symptom subscore of the Positive and Negative Syndrome Scale in the negative group and in all patients with schizophrenia. The two subtypes of schizophrenia may have different pathological mechanisms. Patients characterized by negative symptoms probably have more serious disturbances in neuroimmunology.

Preventive Effects of Different Aerobic Exercise Intensities on the Decline of Cognitive Function in High-Fat Diet-Induced Obese Growing Mice.

Background and Objectives: The purpose of this study was to elucidate the effects of different exercise intensities in preventing the decline of cognitive function and lipolysis associated with a high-fat diet-induced obesity in growing mice. Material and Methods: Forty male C57BL/6 mice, aged 4 weeks, were divided into the normal diet (CO, n = 10) and high-fat diet (HF, n = 30) groups to induce obesity for 8 weeks. Subsequently, the HF group was subdivided equally into the HF, HF + low-intensity training (HFLT), and HF + high-intensity training (HFHT) groups, and mice were subjected to treadmill training for 8 weeks. Results: Following the 8-week training intervention, body weight and fat mass were significantly lower in the training groups than in the HF group (p < 0.05). Adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoglyceride lipase levels were significantly higher in the training groups than in the HF group (p < 0.05), and the ATGL and HSL levels were significantly higher in the HFHT group than in the HFLT group (p < 0.05). The Y-maze test showed that the training groups had a higher number of total entries and percent alternation than the HF group (p < 0.05). Hippocampal nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 levels were significantly higher in the training group than in the HF group (p < 0.05). However, there was no significant difference according to the exercise intensity among the groups. Conclusions: The results of this study suggested that low-intensity exercise is as effective as a high-intensity exercise in preventing the decline of cognitive function and lipolysis, and far more effective in terms of an expected efficiency of workload and prevention of side effects.

Transcranial direct current stimulation (tDCS) affects neuroinflammation parameters and behavioral seizure activity in pentylenetetrazole-induced kindling in rats

Despite the introduction of new antiepileptic drugs, about 30 % of patients with epilepsy are refractory to drug therapy. Thus, the search for non-pharmacological interventions such as transcranial direct current stimulation (tDCS) may be an alternative, either alone or in combination with low doses of anticonvulsants. This study evaluated the effect of anodal (a-tDCS) and cathodal tDCS (c-tDCS) on seizure behavior and neuroinflammation parameters. Rats were submitted to the kindling model induced by pentylenetetrazole (PTZ) using diazepam (DZP) as anticonvulsant standard. tDCS groups were submitted to 10 sessions of a-tDCS or c-tDCS or SHAM-tDCS. Every 3 days they received saline (SAL), low dose of DZP (alone or in combination with tDCS) or effective dose of DZP 30 min before administration of PTZ, totaling 16 days of protocol. Neither a-tDCS nor c-tDCS reduced the occurrence of clonic forelimb seizures (convulsive motor seizures – stage 3 by the adapted Racine scale we based on). Associated with DZP, c-tDCS (c-tDCS/DZP0.15) increased the latency to first clonic forelimb seizure on the 10th and 16th days. Hippocampal IL-1β levels were reduced by c-tDCS and c-tDCS/DZP0.15. In contrast, these treatments induced an increase in cortical IL-1β levels. Hippocampal TNF-α levels were not altered by c-tDCS or a-tDCS, but c-tDCS and c-tDCS/DZP0.15 increased those levels in cerebral cortex. Cortical NGF levels were increased by c-tDCS and c-tDCS/DZP0.15. a-tDCS/DZP0.15 reduced hippocampal BDNF levels and c-tDCS/DZP0.15 increased these levels in cerebral cortex. In conclusion, c-tDCS alone or in combination with a low dose of DZP showed to affect neuroinflammation, improving central neurotrophin levels and decreasing hippocampal IL-1β levels after PTZ-induced kindling without statistically significant effect on seizure behavior.

M14. BDNF IS CORRELATE TO LOW EMOTION RECOGNITION IN UHR WOMEN: RESULTS FROM THE SSAPP POPULATIONAL UHR COHORT

BackgroundSchizophrenia is a disorder with prevalence rates of 1% in the general population. Science turned its efforts towards researching prodromal states, named “Ultra-high Risk” (UHR), in the hopes of impeding conversion to psychosis. Cognitive impairments are recognized among core features of schizophrenia and it is noted that they are already present at early stages of psychosis, such as ultra-high risk for psychosis (UHR). Schizophrenia in women has a more favorable outcome than in men with the disease in part mediated by cognitive performance. Neurotrophins, such as brain-derived neurotrophic factor (BDNF), play crucial roles in the expression of synaptic plasticity underpinning cognitive function, particularly expression of learning and memory. Previous studies showed conflicting results regarding neurotrophin levels in patients with psychosis. We hypothesized that UHR individuals would also show altered BDNF and cognitive performance levels.MethodsA sample of over 2500 individuals aged between 18 and 30 years old, from the city of São Paulo, Brazil, was drawn and screened with the Prodromal Questionnaire (PQ). 236 subjects with high scores (18+ points in the positive PQ subscale) where selected for psychiatric assessment with the SIPS (Structured Interview for Psychosis-Risk Syndromes), and 98 individuals were classified as UHR. Whole blood sample was collected and BDNF levels were analyzed with ELISA kits (Thermo-Fisher). Cognitive performance was measured by the emotion recognition task available via the UPenn Computerized neuropsychological testing (). Data was available for 93 UHR individuals (95%) and for 62 (46%) controls. IBM SPSS Statistics v23 for Mac was used to analyze data.ResultsBDNF levels and performance on emotion recognition task did not differ between control and UHR individuals. Differences were also not found if sample was analyzed according to sex. However, in UHR women (63% of UHR sample), worse performance was significantly associated with a higher BDNF level (Pearson correlation coefficient=-0.288, p=0.031).DiscussionIn our study, we found a correlation of worse emotion recognition task and higher BDNF levels in UHR women. This might be due a compensatory mechanism in which patients more severely impaired at baseline show higher BDNF levels. Estrogen might play a role in this difference as it induces BDNF expression. Several studies with psychotic patients shows higher BDNF levels in affected individuals as well as one study with UHR individual show higher BDNF levels within this group, but none showed differences between sexes. One study showed that treatment with selective estrogen receptor raloxifene increased activation in the right hippocampus and left inferior frontal gyrus areas, which are involved in facial recognition.Overall, literature suggests that women outperform men regarding overall cognitive function, including emotion recognition. Our findings might be related to a before homeostasis state has been reached in which baseline measures for emotion recognition in UHR women could be worse than in men but along time ameliorated via estrogen-induced BDNF expression.

Antioxidant properties of plant polyphenols in the counteraction of alcohol-abuse induced damage: Impact on the Mediterranean diet

Polyphenols are antioxidants contained in plants as olive and grape. As part of the Mediterranean diet, they may decrease the risk of cancer, of chronic and neurodegenerative diseases. Alcohol consumption plays a detrimental effect on health, causing tissue damage and disrupting the metabolism of Neurotrophins (NTs). NTs are crucial proteins for the life cycle of neuronal and non-neuronal cells. Alcohol abuse elicits changes in NTs levels in the brain and in other target organs, however, it was observed minor damage in animals early exposed to red wine, probably due to the antioxidant effects of polyphenols. Indeed, data show that resveratrol or other polyphenols extracted from the olive can effectively counteract serum free radicals’ formation caused by chronic alcohol intake, contrasting also alcohol-induced NTs liver elevation. The aim of the present review is to update pieces of evidences about the antioxidant properties of polyphenols and their role in counteracting alcohol-induced damage.

Autonomic and Cognitive Function Response to Normobaric Hyperoxia Exposure in Healthy Subjects. Preliminary Study.

Background and objective: This is the first study to investigate the effect of high-flow oxygen therapy, using a normobaric chamber on cognitive, biochemical (oxidative stress parameters and the level of neurotrophins), cardiovascular and autonomic functioning. Materials and methods: 17 healthy volunteers, eight males and nine females, with a mean age of 37.5 years, were examined. The experimental study involved ten two-hour exposures in a normobaric chamber with a total pressure of 1500 hPa, in air adjusted to 37% oxygen, 1.079% carbon dioxide and 0.44% hydrogen. Cognitive function was assessed by using Trail Making Test parts A, B and difference in results of these tests (TMT A, TMT B and TMT B-A); California Verbal Learning Test (CVLT); Digit symbol substitution test (DSST); and Digit Span (DS). Fatigue (Fatigue Severity Scale (FSS)), cardiovascular, autonomic and baroreceptor functioning (Task Force Monitor) and biochemical parameters were measured before and after intervention. Results: After 10 sessions in the normobaric chamber, significant decreases in weight, caused mainly by body fat % decrease (24.86 vs. 23.93%, p = 0.04 were observed. TMT part A and B results improved (p = 0.0007 and p = 0.001, respectively). In contrast, there was no statistically significant influence on TMT B-A. Moreover, decrease in the number of symbols left after a one-minute test in DSST was noted (p = 0.0001). The mean number of words correctly recalled in the CVLT Long Delay Free Recall test improved (p = 0.002), and a reduction in fatigue was observed (p = 0.001). Biochemical tests showed a reduction in levels of malondialdehyde (p < 0.001), with increased levels of Cu Zn superoxide dismutase (p < 0.001), Neurotrophin 4 (p = 0.0001) and brain-derived neurotrophic factor (p = 0.001). A significant increase in nitric oxide synthase 2 (Z = 2.29, p = 0.02) and Club cell secretory protein (p = 0.015) was also noted. Baroreceptor function was significantly improved after normobaric exposures (p = 0.003). Significant effect of normobaric exposures and BDNF in CVLT Long Delay Free Recall was noted. Conclusions: This study demonstrates that 10 exposures in a normobaric chamber have a positive impact on visual information and set-shifting processing speed and increase auditory-verbal short-term memory, neurotrophic levels and baroreceptor function. A response of the respiratory tract to oxidative stress was also noted. There is a need to rigorously examine the safety of normobaric therapy. Further studies should be carried out with physician examination, both pre and post treatment.

Transcranial direct current stimulation and sport performance: Brain Derived Neurotrophic Factor and neurotrophins as potential biomarkers of abuse

BackgroundTranscranial direct current stimulation (tDCS) is an emerging, non‐invasive brain stimulation technique that delivers an electrical stimulus to a specific brain region. It may be used to improve cognitive performance and resistance to fatigue. These effects are similar to those of some brain‐boosting drugs banned by the World Anti‐Doping Agency (WADA). It was recently reported that tDCS causes changes in the serum levels of some neurotransmitters and neurotrophins, such as brain‐derived neurotrophic factor (BDNF). We plan to evaluate whether the abuse of tDCS in sport can be detected by monitoring markers of effect, i.e. by targeting specific neurotrophins in serum. We are here reporting our preliminary data on the reference levels of the selected neurotrophins in elite athletes.MethodsSerum samples from elite athletes selected for doping control and resulted negative for all substances/methods were assayed by ELISA kit from for Aviscera Bioscience and R&amp;D systems Luminex “multiassay”. Genotyping of the samples for the presence of significant BDNF and pro‐BDNF related polymorphisms were performed by using Taqman probes and real‐time PCR methods and instrumentation (Thermo Fisher Scientific). Database includes both male and female subjects, age range 17–45 years. Serum samples from non‐athletes healthy individuals were also analyzed to assess baseline levels of the analytes in a time‐range of 24 hours and 1 months. All samples were analyzed after anonymization, and all participants subscribed an informed consent form.ResultsSerum levels of BDNF resulted always higher than proBDNF. BDNF resulted in a symmetric distribution, unlike proBDNF data that were strongly asymmetric, with a great difference between mean and median values. A weak negative correlation was observed between proBDNF and BDNF. No significant differences were observed for proBDNF and BDNF related to gender, age and sport discipline. Differences were instead detected between subjects tested “in competition” (IN) vs. “out of competition” (OUT): IN samples showed significantly higher levels, supporting previous literature data reporting that serum BDNF may increase as a consequence of physical exercise. Moreover, BDNF values in elite athletes were generally higher than those in non‐athletes. Longitudinal analysis of both proBDNF and BDNF revealed that the intra‐individual variability is considerably narrower than the inter‐individual variability. A common SNP polymorphism (rs6265, A&gt;G) seems to impact only on proBDNF: individuals carrying the GG genotype showed lower basal level or proBDNF than normal or heterozygous subjects. Serum levels of other neurotrophins (NGF, NT‐3, NT‐4) were very low, with no statistical correlation to the other analytes.ConclusionsData we collected in this pilot suggest the possible selection of BDNF, proBDNF and their ratio as putative biomarkers to detect the abuse of tDCS in sport doping. An approach based on the longitudinal monitoring of the values rather the development of populational normality ranges seems to be the most appropriate strategy of detection.Support or Funding InformationFederazione Medico Sportiva Italiana

Muscle Progenitors Derived from Extraocular Muscles Express Higher Levels of Neurotrophins and their Receptors than other Cranial and Limb Muscles.

Extraocular muscles (EOMs) show resistance to muscle dystrophies and sarcopenia. It has been recently demonstrated that they are endowed with different types of myogenic cells, all of which present an outstanding regenerative potential. Neurotrophins are important modulators of myogenic regeneration and act promoting myoblast proliferation, enhancing myogenic fusion rates and protecting myotubes from inflammatory stimuli. Here, we adapted the pre-plate cell isolation technique to obtain myogenic progenitors from the rat EOMs, and quantified their in vitro expression of neurotrophins and their receptors by RT–qPCR and immunohistochemistry, respectively. The results were compared with the expression on progenitors isolated from buccinator, tongue and limb muscles. Our quantitative analysis of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and neurotrophin-3 (NT-3) transcripts showed, for the first time, that EOMs-derived cells express more of these factors and that they expressed TrkA, but not TrkB and TrkC receptors. On the contrary, the immunofluorescence analysis demonstrated high expression of p75NTR on all myogenic progenitors, with the EOMs-derived cells showing higher expression. Taken together, these results suggest that the intrinsic trophic differences between EOMs-derived myogenic progenitors and their counterparts from other muscles could explain why those cells show higher proliferative and fusion rates, as well as better regenerative properties.

Plasma BDNF and TrkB mRNA in PBMCs Are Correlated With Anti-depressive Effects of 12-Weeks Supervised Exercise During Protracted Methamphetamine Abstinence.

Purpose: The aim of this study was to evaluate the potential neurotrophic factors and expression of neurotrophin receptors in peripheral blood mononuclear cells linked with the antidepressant action of exercise intervention during protracted methamphetamine (METH) abstinence.Materials and Methods: A total of 72 male METH addicts, including 47 individuals with depression and 25 individuals without depression, were recruited in this study. Individuals with depression were divided into the depression control group and the depression exercised group. Consequently, 12 weeks of supervised exercise intervention was applied. Depression and anxiety were analyzed; plasma brain-derived neurotrophic factor (BDNF), neuronal growth factor (NGF), neurotrophin-3 (NT-3), NT-4, and proBDNF levels were tested using enzyme-linked immunosorbent assay; the mRNA expressions of TrkA, TrkB-FL, TrkB-T1, TrkCB, and P75NTR in peripheral blood mononuclear cells were detected by quantitative real-time polymerase chain reaction (qRT-PCR).Results: NT-4 plasma levels were correlated with depression (r = −0.330, p = 0.005), which remained significant after Bonferroni correction. In addition, the BDNF and NT-3 levels in the plasma were significantly correlated with depression (r = −0.268, p = 0.023; r = −0.259, p = 0.028), but did not reach significance after Bonferroni correction. The BDNF, NT-3, and NT-4 plasma levels were significantly different between the depressive control group and the depressive exercise group using pre-exercise values as the covariate. The fold changes in TrkB-FL and TrkB-T1 mRNA in peripheral blood mononuclear cells between the post-exercise and pre-exercise demonstrated a remarkable decrease (fold change = −11.056 and −39.055).Conclusions: Exercise intervention can alleviate depression and anxiety during protracted METH abstinence. Decrease in BDNF and the expression of TrkB in peripheral blood mononuclear cells occur following the exercise intervention.

Dysfunctional neuroplasticity in newly arrived Middle Eastern refugees in the U.S.: Association with environmental exposures and mental health symptoms.

Psychological war trauma among displaced refugees is an established risk factor for mental health disorders, especially post-traumatic stress disorder (PTSD). Persons with trauma-induced disorders have heightened neuroplastic restructuring of limbic brain circuits (e.g., amygdala and hippocampus), which are critical factors in the pathophysiology of PTSD. Civilians in war are exposed to both psychological trauma and environmental hazards, such as metals. Little is known about the possible mental health impact from such environmental exposures, alone or in combination with trauma. It is of special interest to determine whether war exposures contribute to dysfunctional neuroplasticity; that is, an adverse outcome from sustained stress contributing to mental health disorders. The current study examined Middle Eastern refugees in the United States to determine the relationships among pre-displacement trauma and environmental exposures, brain derived neurotrophic growth factor (BDNF) and nerve growth factor (NGF)-two neurotrophins reported to mediate neuroplasticity responses to stress-related exposures-and mental health. Middle Eastern refugees (n = 64; 33 men, 31 women) from Syria (n = 40) or Iraq (n = 24) were assessed 1 month after arrival to Michigan, US. Participants were interviewed in Arabic using a semi-structured survey to assess pre-displacement trauma and environmental exposure, PTSD, depression, anxiety, and self-rated mental health. Whole blood was collected, and concentrations of six heavy metals as well as BDNF and NGF levels were determined. Because these two neurotrophins have similar functions in neuroplasticity, we combined them to create a neuroplasticity index. Linear regression tested whether psychosocial trauma, environmental exposures and biomarkers were associated with mental health symptoms. The neuroplasticity index was associated with PTSD (standardized beta, β = 0.25, p < 0.05), depression (0.26, < 0.05) and anxiety (0.32, < 0.01) after controlling for pre-displacement trauma exposures. In addition, pre-displacement environmental exposure was associated with PTSD (0.28, < 0.05) and anxiety (0.32, < 0.05). Syrian refugees and female gender were associated with higher scores on depression (0.25, < 0.05; 0.30, < 0.05) and anxiety scales (0.35, < 0.01; 0.27, < 0.05), and worse on self-rated mental health (0.32, < 0.05; 0.34, < 0.05). In bivariate analysis, the neuroplasticity index was related to blood lead levels (r = 0.40; p < 0.01). The current study confirms the adverse effects of war trauma on mental health. Higher levels of biomarkers of neuroplasticity correlated with worse mental health and higher blood lead levels. Higher neurotrophin levels in refugees might indicate dysfunctional neuroplasticity with increased consolidation of adverse war memories in the limbic system. Such a process may contribute to psychiatric symptoms. Further research is needed to clarify the pathobiological mechanisms linking war trauma and environmental exposures to adverse mental health.

Early life neuroimmune challenge protects the brain after sepsis in adult rats

Evidences has suggested that in the early life the innate immune system presents plasticity and the time and dose-adequate stimuli in this phase may program long-lasting immunological responses that persist until adulthood. We aimed to evaluate whether LPS challenge in early childhood period may modulate brain alterations after sepsis in adult life. Experiments were performed to evaluate the LPS challenge in early childhood or adult period on acute and long-term brain alterations after model of sepsis by cecal ligation and perforation (CLP) in adult life. Wistar rats were divided in saline+sham, LPS+sham, saline+CLP and LPS+CLP groups to determine cytokine levels and nitrite/nitrate concentration in cerebrospinal fluid (CSF); oxidative damage, activity of antioxidant enzymes (superoxide dismutase-SOD and catalase-CAT); blood brain barrier (BBB) permeability; myeloperoxidase (MPO) and epigenetic enzymes activities in the hippocampus and prefrontal cortex (at 24 h after CLP) and cognitive function, survival and brain-derived neurotrophic factor (BDNF) level (at ten days after CLP). LPS-preconditioning in early life could lead to decreased levels of TNF-α and IL-6 and oxidative damage parameters in the brain after CLP in adult rats. In addition, LPS-preconditioning in early life increase CAT activity, attenuates the BBB permeability and epigenetic enzymes alterations and in long term, improves the memory, BDNF levels and survival. In conclusion, rats submitted to CLP in adulthood displayed acute neuroinflammation, neurochemical and epigenetic alteration improvement accompanied in long term by an increase in survival, neurotrophin level and memory performance when preconditioned with LPS in the early life.

Human dental pulp stem cells exhibit enhanced properties in comparison to human bone marrow stem cells on neurites outgrowth.

Mesenchymal stem cells (MSCs) have the capacity to self-renew and differentiate into specific cell types and are, therefore, key players during tissue repair and regeneration. The use of MSCs for the regeneration of tissues in vivo is increasingly being explored and already constitutes a promising alternative to existing clinical treatments. MSCs also exert paracrine and trophic functions, including the promotion of innervation that plays fundamental roles in regeneration and in restoration of the function of organs. Human bone marrow stem cells (hBMSCs) and human dental pulp stem cells (hDPSCs) have been used in studies that aimed at the repair and/or regeneration of bone or other tissues of the craniofacial complex. However, the capabilities of hBMSCs and hDPSCs to elicit the growth of specific axons in order to reestablish functional innervation of the healing tissues are not known. Here, we compared the neurotrophic effects of hDPSCs and hBMSCs on trigeminal and dorsal root ganglia neurons using microfluidic organs-on-chips devices. We found that hDPSCs express significantly higher levels of neurotrophins than hBMSCs and consequently neurons cocultured with hDPSCs develop longer axons in the microfluidic co-culture system when compared to neurons cocultured with hBMSCs. Moreover, hDPSCs elicited the formation of extensive axonal networks and established close contacts with neurons, a phenomenon not observed in presence of hBMSCs. Taken together, these findings indicate that hDPSCs constitute a superior option for restoring the functionality of damaged craniofacial tissues, as they are able to support and promote extensive trigeminal innervation.

TLR4 Stimulation Promotes Human AVIC Fibrogenic Activity through Upregulation of Neurotrophin 3 Production.

Background: Calcific aortic valve disease (CAVD) is a chronic inflammatory disease that manifests as progressive valvular fibrosis and calcification. An inflammatory milieu in valvular tissue promotes fibrosis and calcification. Aortic valve interstitial cell (AVIC) proliferation and the over-production of the extracellular matrix (ECM) proteins contribute to valvular thickening. However, the mechanism underlying elevated AVIC fibrogenic activity remains unclear. Recently, we observed that AVICs from diseased aortic valves express higher levels of neurotrophin 3 (NT3) and that NT3 exerts pro-osteogenic and pro-fibrogenic effects on human AVICs. Hypothesis: Pro-inflammatory stimuli upregulate NT3 production in AVICs to promote fibrogenic activity in human aortic valves. Methods and Results: AVICs were isolated from normal human aortic valves and were treated with lipopolysaccharide (LPS, 0.20 µg/mL). LPS induced TLR4-dependent NT3 production. This effect of LPS was abolished by inhibition of the Akt and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) pathways. The stimulation of TLR4 in human AVICs with LPS resulted in a greater proliferation rate and an upregulated production of matrix metallopeptidases-9 (MMP-9) and collagen III, as well as augmented collagen deposition. Recombinant NT3 promoted AVIC proliferation in a tropomyosin receptor kinase (Trk)-dependent fashion. The neutralization of NT3 or the inhibition of Trk suppressed LPS-induced AVIC fibrogenic activity. Conclusions: The stimulation of TLR4 in human AVICs upregulates NT3 expression and promotes cell proliferation and collagen deposition. The NT3-Trk cascade plays a critical role in the TLR4-mediated elevation of fibrogenic activity in human AVICs. Upregulated NT3 production by endogenous TLR4 activators may contribute to aortic valve fibrosis associated with CAVD progression.

Exploring the association between depression, suicidality and serum neurotrophin levels in adolescents

Objective: The aim of this study was to identify potential differences in serum brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF) and neurotrophin-3 (NTF3) levels in adolescents with major depressive disorder (MDD) compared to healthy controls. The possible relationship between serum neurotrophin levels and suicidality in adolescents with MDD was also addressed.Methods: A total of 70 treatment-free adolescents with MDD and 40 healthy controls aged 11 to 19 years were enrolled. The severity of suicidality was determined using the Columbia-Suicide Severity Rating Scale, and the severity of depression and anxiety symptoms were evaluated by self-report inventories. Serum levels of neurotrophins were measured using an enzyme-linked immunosorbent assay.Results: The mean serum BDNF levels were significantly higher in adolescents with MDD than in control subjects; no significant difference was found between the groups for serum GDNF, NGF and NTF3 levels. No correlations were found between the levels of serum neurotrophins and the severity of depression or suicidality.Conclusions: The study results suggest that elevated serum BDNF levels may be related to MDD in adolescents. However, our findings did not support a role for neurotrophins in suicidality.Key pointsSerum BDNF levels were higher in adolescents with MDD than in controls.No significant alterations of serum levels of GDNF, NGF and NTF3 were evident in adolescents with MDD.Neurotrophin levels were not associated with suicidal ideation and behaviours.

Nerve growth factor in the psychiatric brain.

The nerve growth factor (NGF) belongs to a family of proteins named neurotrophins, consisting of NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), NT-4/5 and NT-6. NGF regulates a large number of physiological mechanisms that result in neurotrophic, metabotrophic and/or immunotrophic effects. Neurodegenerative diseases, including Alzheimer disease, psychiatric disorders (e.g. depression and schizophrenia) and brain parasitic infection have in common the effect of changing the brain levels of neurotrophins, in particular NGF. The contribution of both NGF and its receptor TrkA in such events and the recent promising results of NGF based therapies are here presented and discussed.

The opposing contribution of neurotrophin-3 and nerve growth factor to orofacial heat hyperalgesia in rats.

It has been proposed that neurotrophin-3 acts in a manner that is opposed to nerve growth factor, especially in the modulation of heat hyperalgesia. Injury to the constriction of the infraorbital nerve (CION) is a well-established model of trigeminal neuropathic pain that leads to robust heat, cold, and mechanical hyperalgesia. Here, we assessed the effect of local neurotrophin-3 treatment on CION-induced hyperalgesia, and we examined some mechanisms related to the effect of neurotrophin-3. Neurotrophin-3 (1 µg/50 µl) injected into the upper lip of CION rats caused a significant and long-lasting reduction of CION-induced heat hyperalgesia, but failed to affect cold and mechanical hyperalgesia. Increased levels of neurotrophin-3 were detected in the injured nerve at the time point that represents the peak of heat hyperalgesia. The anti-hyperalgesic effect of neurotrophin-3 was markedly reduced in the presence of an antagonist of TrkA receptors (K-252a, 1 μg/50 μl). Moreover, association of lower doses of neurotrophin-3 with an antibody anti-nerve growth factor resulted in a synergistic anti-hyperalgesic effect in CION rats. Local injection of nerve growth factor (3 µg/50 µl) or the TRPV1 agonist capsaicin (1 μg/50 μl), but not neurotrophin-3 injection (1 µg/50 µl), resulted in long-lasting facial heat hyperalgesia, which was both significantly reduced by previous neurotrophin-3 local treatment. In conclusion, we suggest that neurotrophin-3 is a potent modulator of facial heat hyperalgesia, which may exert an inhibitory influence on the trkA pathway. Neurotrophin-3 treatment may represent a promising approach, especially in pain conditions associated with increased levels of nerve growth factor.

Vigorous cool room treadmill training to improve walking ability in people with multiple sclerosis who use ambulatory assistive devices: a feasibility study

BackgroundAerobic training has the potential to restore function, stimulate brain repair, and reduce inflammation in people with Multiple Sclerosis (MS). However, disability, fatigue, and heat sensitivity are major barriers to exercise for people with MS. We aimed to determine the feasibility of conducting vigorous harness-supported treadmill training in a room cooled to 16 °C (10 weeks; 3times/week) and examine the longer-term effects on markers of function, brain repair, and inflammation among those using ambulatory aids.MethodsTen participants (9 females) aged 29 to 74 years with an Expanded Disability Status Scale ranging from 6 to 7 underwent training (40 to 65% heart rate reserve) starting at 80% self-selected walking speed. Feasibility of conducting vigorous training was assessed using a checklist, which included attendance rates, number of missed appointments, reasons for not attending, adverse events, safety hazards during training, reasons for dropout, tolerance to training load, subjective reporting of symptom worsening during and after exercise, and physiological responses to exercise. Functional outcomes were assessed before, after, and 3 months after training. Walking ability was measured using Timed 25 Foot Walk test and on an instrumented walkway at both fast and self-selected speeds. Fatigue was measured using fatigue/energy/vitality sub-scale of 36-Item Short-Form (SF-36) Health Survey, Fatigue Severity Scale, modified Fatigue Impact Scale. Aerobic fitness (maximal oxygen consumption) was measured using maximal graded exercise test (GXT). Quality-of-life was measured using SF-36 Health Survey. Serum levels of neurotrophin (brain-derived neurotrophic factor) and cytokine (interleukin-6) were assessed before and after GXT.ResultsEight of the ten participants completed training (attendance rates ≥ 80%). No adverse events were observed. Fast walking speed (cm/s), gait quality (double-support (%)) while walking at self-selected speed, fatigue (modified Fatigue Impact Scale), fitness (maximal workload achieved during GXT), and quality-of-life (physical functioning sub-scale of SF-36) improved significantly after training, and improvements were sustained after 3-months. Improvements in fitness (maximal respiratory exchange ratio and maximal oxygen consumption during GXT) were associated with increased brain-derived neurotrophic factor and decreased interleukin-6.ConclusionVigorous cool room training is feasible and can potentially improve walking, fatigue, fitness, and quality-of-life among people with moderate to severe MS-related disability.Trial registrationThe study was approved by the Newfoundland and Labrador Health Research Ethics Board (reference number: 2018.088) on 11/07/2018 prior to the enrollment of first participant (retrospectively registered at ClinicalTrials.gov: NCT04066972. Registered on 26 August 2019.

Serum Brain-Derived Neurotrophic Factor, Glial-Derived Neurotrophic Factor, Nerve Growth Factor and Neurotrophin-3 Levels in Preschool Children with Language Disorder.

Accumulating studies demonstrate that neurotrophins may play a crucial role in a variety of neurodevelopmental disorders. However, little data are available regarding the potential role of neurotrophins in language disorder (LD). This study aimed to investigate serum brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF) and neurotrophin-3 (NTF3) levels in preschool children with LD. A total of 43 cases with LD and 43 healthy controls aged 18 to 60 months were enrolled in the study. The development levels and psychiatric symptoms of the children were determined by the Ankara Developmental Screening Inventory and Child Behavior Checklist 1.5-5, respectively. Serum neurotrophin levels were assessed by enzyme-linked immunosorbent assay kits. Serum GDNF and NGF levels were significantly higher, serum BDNF and NTF3 levels were significantly lower in the LD group than in the control group. However, with logistic regression analyses, only negative relationship of BDNF and NTF3 levels with the presence of LD remained significant after accounting for the confounders including development level and coexisting psychiatric symptoms. These results suggest that low BDNF and NTF3 levels have independent negative relationships with LD, which could be contribute to etiopathogenesis of the disorder.

Maternal Deprivation and Sex Alter Central Levels of Neurotrophins and Inflammatory Cytokines in Rats Exposed to Palatable Food in Adolescence

Maternal deprivation (MD) in rodents is used to simulate human-infant early life stress, which leads to neural, hormonal, and behavioral alterations. Palatable food (PF) can reduce the stress response, and individuals use it as a self-applied stress relief method. Thus, the present study aimed to evaluate the effect of the association between MD in the early life (P1–P10) and PF consumption (condensed milk, P21–P44) in the central neuroplasticity (BDNF/NGF levels) and central neuroinflammatory parameters (TNF-α, IL-6, and IL-10 levels) in male and female Wistar rats in the adolescence. In addition, weight-related parameters (weight gain, Lee Index, and relative adipose tissue weight) were evaluated. PF exposure increased relative adipose tissue weight; however, it did not lead to a change in animals’ body weight. MD reduced hypothalamic BDNF and NGF levels, and hippocampal TNF-α levels in male and female rats. Animals of both sexes that received PF, exhibited reduced hypothalamic NGF levels. Neuroinflammatory marker evaluations showed that male rats were more susceptible to the interventions than female rats, since MD reduced their cortical IL-10 levels and PF increased their IL-6 levels. Differences in the Lee index, central BDNF, TNF-α, and IL-6levels were observed between sexes. Male animals per se presented greater Lee index. Female rats had higher BDNF and IL-6 levels in the hippocampus and hypothalamus and higher hypothalamic TNF-α levels than those observed in males. In conclusion, there were more noticeable effects of MD than PF on the variables measured in this study. Sex effect was identified as an important factor and influenced most of the neurochemical measures in this study. In this way, we suggest including both female and male animals in researches to improve the quality of translational studies.

Is There any Possible Role of Neurotrophin 3 in the Pathogenesis of Antrochoanal Polyp?

Objective:Antrochoanal polyp (ACP) is a benign soft tissue lesion arising from the inner wall of the maxillary sinus that extends into the nasal cavity and choana. Although it was first explained by Killian in 1906, the underlying pathogenesis has not been yet fully understood. Neurotrophins have been demonstrated to have a possible role in the pathogenesis of allergic rhinitis, idiopathic rhinitis and nasal polyps. To date any study has not investigated the function of neuronal inflammation and neurotrophins in the development of ACP. The objective of this study was to investigate the possible effect of neurotrophin-3 (NT-3) in ACP pathogenesis.Method:Twenty adult patients with ACP who underwent endoscopic sinus surgery in our department were included in the study group. The control group included 15 patients with concha bullosa of middle concha who underwent lateral excisional surgery. Nasal tissue NT-3 staining scores were evaluated using immunohistochemical methods. Blood NT-3 levels of both groups were evaluated by enzyme-linked immunosorbent assay (ELISA).Results:There were no statistically significant differences between these two groups regarding tissue NT-3 staining scores (p=0.843) and blood NT-3 levels (p=0.463). In addition, no statistically significant correlation has been observed between tissue NT-3 staining scores and blood NT-3 levels in both ACP (p=0.578) and control (p=0.359) group patients.Conclusion:NT-3-related neuronal inflammation does not seem to have any role in ACP pathogenesis.