Neurotrophic factor levels and executive functions in children of parents with bipolar disorder: A case controlled study.

BACKGROUND: In the current study, it was aimed to evaluate neurotrophic factor levels and their relationship with executive functions in high-risk children and adolescents (high-risk group) whose parents were diagnosed with bipolar disorder (BD) but not affected by any psychiatric disease,and in order to determine possible vulnerability factors related to the disease. METHODS: The study sample consisted of 32 high-risk group and 34 healthy controls. The Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version-Turkish Adaptation (KSADS-PL-T), Stroop Test, Serial Digit Learning Test (SDLT) and Cancellation Test to evaluate executive functions were administered to all participants by the clinician.Serum levels of neurotrophic factors were measured using commercial enzyme linked immunosorbent assay kits. RESULTS: Serum BDNF, NT-3, NT-4 levels and SDLT scores were significantly lower in the high-risk group for BD compared to the healthy control group. A moderate negative correlation was found between BDNF levels and the Cancellation Test scores in the high-risk group. In addition to these results, the odds ratios of age, NT-4, SDLT scores for being in the risky group in terms of BD diagnosis were 1.26, 0.99 and 0.86 respectively. LIMITATIONS: This was a cross-sectional study. Causality between study results is therefore difficult to establish. The relatively small sample size of the study is another limitation. CONCLUSION: The results of the present study suggest that BDNF, NT-3, NT-4 may play a role in the physiopathology of BD and may be associated with impaired executive function areas such as attention and response inhibition in the high-risk group.

Relationship Between Serum Brain-Derived Neurotrophic Factor and Neurotrophin-3 Levels and Hearing Thresholds in Patients With Age-Related Hearing Loss.

BACKGROUND: Age-related hearing loss (ARHL) is a general term used to describe the sensorineural type of hearing loss occurring in both ears in older adults. Neurotrophins are the most promising candidates for supporting the auditory nerve by increasing neuronal survival. This study aimed to help elucidate the pathophysiology of ARHL by determining whether any relationship exists between brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) levels in serum samples from patients diagnosed with ARHL. MATERIALS AND METHOD: Seventy-seven individuals, a study group of 41 patients diagnosed with ARHL, and a control group of 36 participants without hearing loss were evaluated. Serum samples were collected and used to measure serum BDNF and NT-3 levels with the new Nepenthe enzyme-linked immunosorbent assay method. RESULTS: Median pure-tone average results in the 2000, 4000, and 6000 Hz ranges were 52.5 (44.3-67.3) dB HL in the ARHL group and 13.5 (11.1-17.1) dB HL in the control group. The difference was statistically significant (p = .001). Although NT-3 and BDNF levels were both lower in ARHL patients than in participants without hearing loss, only the BDNF levels were significantly (p = .002) lower. Mean left and right ear word recognition scores were also lower in ARHL patients than in control groups. The ARHL group was further divided into two subgroups based on word recognition scores to evaluate significant differences in BDNF and NT-3 levels. No statistically significant difference was observed in BDNF and NT-3 levels between these subgroups. However, there was a significant difference in word recognition scores. CONCLUSIONS: Low BDNF levels in the ARHL group suggest that BDNF may play a role in the pathogenesis of ARHL. Patients with low (ARHL1) and high (ARHL2) word recognition scores were compared for the first time in the literature in terms of BDNF and NT-3 levels. However, the results were not statistically significant. This article is a preliminary study and was written to provide guidance for our next comprehensive project.

Serum Levels of Growth-Associated Protein-43 and Neurotrophin-3 in Childhood Epilepsy and Their Relation to Zinc Levels.

BACKGROUND: Epilepsy is one of the most common neurological disorders, and it places a significant economic strain on the healthcare system around the world. Although the exact mechanism of epilepsy has yet to be illustrated, various pathogenic cascades involving neurotransmitters and trace elements have been reported. We aimed to investigate the serum levels of growth-associated protein-43 (GAP-43) and neurotrophin-3 (NT-3) among cohort of Egyptian children with epilepsy and correlate these biomarkers with their zinc levels. METHODS: This case-control study included 50 pediatric patients with epilepsy who were comparable with 50 controls. Neurological assessment and electroencephalogram (EEG) were done to all included children. Biochemical measurements of serum GAP-43 and NT-3 using enzyme linked immunosorbent assays (ELISA), and total antioxidant capacity (TAC) and zinc using colorimetric assays, were performed to all participants. RESULTS: There was significantly frequent positive parental consanguinity among cases with significantly frequent generalized onset seizures (94%) than simple partial seizure (6%). There were significantly lower serum GAP-43 and zinc levels with significantly higher TAC among cases vs. the controls, p˂0.05 for all. There was no significant difference in the serum levels of NT-3 among epileptic children vs. the controls, p = 0.269. Serum Zn was positively correlated with GAP-43 level among epileptic children (r = 0.381, p = 0.006). Serum GAP-43 in diagnosing childhood epilepsy at cut-off point ≤ 0.6 ng/mL showed 78% sensitivity, 62% specificity, positive predictive value (PPV) = 50.6%, negative predictive value (NPP) = 84.9% with AUC = 0.574. CONCLUSION: GAP-43 can be considered a sensitive good negative biomarker in childhood epilepsy which correlated positively with the zinc status.

Effects of butylphthalide on the levels of serum C-reactive protein, Parkinson disease protein 7 and neurotrophin-3 and neurological function in patients with acute cerebral infarction.

To explore the effects of butylphthalide on the levels of serum CRP, PAPK7, NT-3 and neurological function in patients with acute cerebral infarction (ACI). 120 patients with ACI who were treated at Peking University First Hospital from September 2014 to June 2016 were selected as the research objects. The patients were randomly divided into a control group and an observation group, with 60 cases in each group. Conventional methods were adopted in the control group, and the observation group used butylphthalide for treatment. Two months later, the clinical efficacy, serum C-reactive protein (CRP), Parkinson's disease protein 7 (PAPK7), neurotrophic factor-3 (NT-3) levels, and the National Institutes of Health Stroke Scale (NIHSS) score before and after treatment were put into comparison and analysis. Before treatment, the NIHSS score showed no significant difference between the two groups (p>0.05); An observably higher NIHSS score of the observation group compared with the control group was seen after treatment (p=0.000). Butylphthalide has a significant therapeutic effect on patients with ACI. It can effectively restore the patients' neurological function, and remarkably improve the serum CRP, PAPK7 and NT-3 levels, which is worthy of clinical promotion.

Biochemical Assessments of Neurotrophin-3 and Zinc Involvement in the Pathophysiology of Pediatric Febrile Seizures : Biochemical Markers in Febrile Seizures.

Febrile seizures (FSs) are a common occurrence in young children and a serious concern in pediatric practice; nevertheless, the causes and mechanisms of FS are still unknown. We hypothesized a relation of neuropeptides such as neurotrophin-3 (NT-3) and growth-associated protein-43 (GAP-43) as well as zinc and the oxidant/antioxidant system with pediatric FS. The study included 100 infants categorized into 50 infants with FS and 50 febrile infants without seizures as controls. Clinical assessments, biochemical assays of NT-3 and GAP-43 using ELISA assay kits, and colorimetric measurements of TAC and Zn were performed to all participants. Overall, significant rises of the values of NT-3 and insignificant increases of GAP-43 were detected in children with FS. At the same time, zinc values and the total antioxidant capacity in serum samples were found to be decreased significantly. In addition, a negative correlation was estimated between NT-3 and zinc levels. Serum NT-3 in diagnosing febrile seizures at cutoff point > 49.62 ng/L showed 100% sensitivity, 46% specificity, positive predictive value (PPV) = 48.1%, and negative predictive value (NPP) = 100% with AUC = 0.678. Significant altered circulating NT-3 and zinc levels in FS may indicate their possible role in the pathogenesis of FS. This may open a way for further research and warrants enlightening of the pathophysiological details of FS.

Evaluation of neurotrophic factors and education level as predictors of cognitive decline in alcohol use disorder.

Cognitive reserve (CR) is the capability of an individual to cope with a brain pathology through compensatory mechanisms developed through cognitive stimulation by mental and physical activity. Recently, it has been suggested that CR has a protective role against the initiation of substance use, substance consumption patterns and cognitive decline and can improve responses to treatment. However, CR has never been linked to cognitive function and neurotrophic factors in the context of alcohol consumption. The present cross-sectional study aims to evaluate the association between CR (evaluated by educational level), cognitive impairment (assessed using a frontal and memory loss assessment battery) and circulating levels of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) in patients with alcohol use disorder (AUD). Our results indicated that lower educational levels were accompanied by earlier onset of alcohol consumption and earlier development of alcohol dependence, as well as impaired frontal cognitive function. They also suggest that CR, NT-3 and BDNF may act as compensatory mechanisms for cognitive decline in the early stages of AUD, but not in later phases. These parameters allow the identification of patients with AUD who are at risk of cognitive deterioration and the implementation of personalized interventions to preserve cognitive function.

Blood biomarkers associated to complete pathological response on NSCLC patients treated with neoadjuvant chemoimmunotherapy included in NADIM clinical trial.

BACKGROUND: Immunotherapy is being tested in early-stage non-small cell lung cancer (NSCLC), and achieving higher rates of complete pathological responses (CPR) as compared to standard of care. Early identification of CPR patients has vital clinical implications. In this study, we focused on basal peripheral immune cells and their treatment-related changes to find biomarkers associated to CPR. METHODS: Blood from 29 stage IIIA NSCLC patients participating in the NADIM trial (NCT03081689) was collected at diagnosis and post neoadjuvant treatment. More than 400 parameters of peripheral blood mononuclear cells (PBMCs) phenotype and plasma soluble factors were analyzed. RESULTS: Neoadjuvant chemoimmunotherapy altered more than 150 immune parameters. At diagnosis, 11 biomarkers associated to CPR were described, with an area under the ROC curve >0.70 and p-value <.05. CPR patients had significantly higher levels of CD4+ PD-1+ cells, NKG2D, and CD56 expression on T CD56 cells, intensity of CD25 expression on CD4+ CD25hi+ cells and CD69 expression on intermediate monocytes; but lower levels of CD3+ CD56- CTLA-4+ cells, CD14++ CD16+ CTLA-4+ cells, CTLA-4 expression on T CD56 cells and lower levels of b-NGF, NT-3, and VEGF-D in plasma compared to non-CPR. Post treatment, CPR patients had significantly higher levels of CD19 expression on B cells, BCMA, 4-1BB, MCSF, and PARC and lower levels of MPIF-1 and Flt-3L in plasma compared to non-CPR. CONCLUSIONS: Patients achieving CPR seem to have a distinctive peripheral blood immune status at diagnosis, even showing different immune response to treatment. These results reinforce the different biology behind CPR and non-CPR responses.

Peripheral blood neurotrophic factor levels in children with autism spectrum disorder: a meta-analysis.

Increasing evidence suggests that abnormal regulation of neurotrophic factors is involved in the etiology and pathogenesis of Autism Spectrum Disorder (ASD). However, clinical data on neurotrophic factor levels in children with ASD were inconsistent. Therefore, we performed a systematic review of peripheral blood neurotrophic factors levels in children with ASD, and quantitatively summarized the clinical data of peripheral blood neurotrophic factors in ASD children and healthy controls. A systematic search of PubMed and Web of Science identified 31 studies with 2627 ASD children and 4418 healthy controls to be included in the meta-analysis. The results of random effect meta-analysis showed that the peripheral blood levels of brain-derived neurotrophic factor (Hedges' g = 0.302; 95% CI = 0.014 to 0.591; P = 0.040) , nerve growth factor (Hedges' g = 0.395; 95% CI = 0.104 to 0.686; P = 0.008) and vascular endothelial growth factor (VEGF) (Hedges' g = 0.097; 95% CI = 0.018 to 0.175; P = 0.016) in children with ASD were significantly higher than that of healthy controls, whereas blood neurotrophin-3 (Hedges' g = - 0.795; 95% CI = - 1.723 to 0.134; P = 0.093) and neurotrophin-4 (Hedges' g = 0.182; 95% CI = - 0.285 to 0.650; P = 0.445) levels did not show significant differences between cases and controls. Taken together, these results clarified circulating neurotrophic factor profile in children with ASD, strengthening clinical evidence of neurotrophic factor aberrations in children with ASD.

Neurotrophins as a reliable biomarker for brain function, structure and cognition: A systematic review and meta-analysis.

Neurotrophins are signalling molecules involved in the formation and maintenance of synapses in the brain. They can cross the blood-brain barrier and be detected in peripheral blood, suggesting they may be a potential biomarker for brain health and function. In this review, the available literature was systematically searched for studies comparing peripheral neurotrophins levels with MRI and cognitive measures in healthy adults. Twenty-four studies were identified, six of which included a neuroimaging outcome. Fifteen studies measuring cognition were eligible for meta-analysis. The majority of studies measured levels of brain-derived neurotrophic factor (BDNF), with few assessing other neurotrophins. Results revealed BDNF is related to some neuroimaging outcomes, with some studies suggesting older age may be an important factor. A higher proportion of studies who had older samples observed significant effects between cognition and neurotrophin levels. When cognitive studies were pooled together in a meta-analysis, there was a weak non-significant effect between BDNF and cognitive outcomes. There was also a high level of heterogeneity between cognitive studies. Results indicated that gender was a notable source of the heterogeneity, but additional studies employing relevant covariates are necessary to better characterise the inter-relationship between circulating neurotrophins and cognition.

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

AIM: 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-1ß), and the calcium-binding protein, S100ß, 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. METHODS: Double-antibody sandwich ELISA were used to quantify the amounts of the five protein factors in serum. RESULTS: Compared with the levels in the controls (n = 60), increased serum levels of IL-6, IL-1ß, and S100ß 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-1ß 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-1ß 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. CONCLUSION: The two subtypes of schizophrenia may have different pathological mechanisms. Patients characterized by negative symptoms probably have more serious disturbances in neuroimmunology.

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.

Updated overview on interplay between physical exercise, neurotrophins, and cognitive function in humans.

The many important benefits of physical exercise also encompass maintenance or improvement of cognitive functions. Among the various mechanisms underlying the association between physical exercise and brain health, recent evidence attests that neurotrophin receptor signaling may have an important role, because the activation of this pathway leads to growth and differentiation of new neurons and synapses, supports axonal and dendritic growth, fosters synaptic plasticity, and preserves survival of existing neurons. In this review of published evidence, we highlight that a positive relationship exists between physical exercise and circulating brain-derived neurotrophic factor levels and that the postexercise variation of this molecule is associated with improvement of neurocognitive functioning. Less clear evidence has instead been published for other neurotrophins, such as nerve growth factor, neurotrophin-3, and neurotrophin-4. Overall, promotion of adequate volumes and intensities of physical exercise (i.e., approximately 3 months of moderate-intensity aerobic exercise, with 2-3 sessions/week lasting not less than 30 min) may hence be regarded as an inexpensive and safe strategy for boosting brain-derived neurotrophic factor release, thus preserving or restoring cognitive functions.

Effects of Vitamin D3 in Long-Term Ovariectomized Rats Subjected to Chronic Unpredictable Mild Stress: BDNF, NT-3, and NT-4 Implications.

The purpose of this study was to explore the antidepressant-like effects of vitamin D3 at different doses (1.0, 2.5, and 5.0 mg/kg sc) on a model of depression produced by chronic unpredictable mild stress (CUMS) for 28 days in long-term (3 months) ovariectomized (OVX) adult rats. Sucrose preference (SPT), forced swimming (FST) and open-field (OFT) tests were conducted to examine the depression-like state. Serum corticosterone/adrenocorticotrophic hormone (ACTH) levels and hippocampal brain-derived neurotrophic factor (BDNF) and neurotrophin (NT)-3/NT-4 expressions by ELISA kits and/or western blotting were determined to assess the possible mechanisms of the vitamin D3 effects on the depression-like profile in long-term OVX rats subjected to CUMS. The results showed that vitamin D3 (5.0 mg/kg), as well as fluoxetine treatment, considerably reversed the depression-like state in the SPT and FST, decreased serum corticosterone/ACTH levels, and increased BDNF and NT-3/NT-4 levels in the hippocampus of long-term OVX rats compared to OVX rats with CUMS (p < 0.05). Thus, a high dose of vitamin D3 (5.0 mg/kg sc) could improve the depression-like profile in long-term OVX adult female rats subjected to the CUMS procedure, which might be mediated by the regulation of BDNF and the NT-3/NT-4 signaling pathways in the hippocampus, as well as the corticosterone/ACTH levels of the blood serum.

Serum levels of neurotrophic factors in active toxoplasmic retinochoroiditis

Abstract Toxoplasmic retinochoroiditis (TR) is the most common identifiable cause of posterior uveitis in Brazil. Response to treatment and clinical presentation may vary significantly. We assessed serum levels of brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), neurotrophin (NT)-3, and NT-4/5 in patients with active TR, before and after TR treatment. Methods: Twenty patients with active lesion and 15 healthy controls were enrolled in the study. Serum concentration of neurotrophic factors was determined by enzyme-linked immunosorbent assay. Results: BDNF levels were significantly higher in patients before treatment when compared with controls (p = 0.0015). There was no significant difference in pro-BDNF, NGF, GDNF, NT-3, and NT-4/5 levels between TR patients and controls. Treatment did not affect the levels of these factors. Conclusion: BDNF may be released in the context of the active TR inflammatory response.

Serum brain-derived neurotrophic factor, glial-derived neurotrophic factor, nerve growth factor, and neurotrophin-3 levels in children with attention-deficit/hyperactivity disorder.

It has been suggested that neurotrophins are involved in the etiopathogenesis of attention-deficit/hyperactivity disorder (ADHD). This study aimed to investigate whether there are differences in serum brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and neurotrophin-3 (NTF3) levels between children with ADHD and healthy controls. A total of 110 treatment-naive children with the combined presentation of ADHD and 44 healthy controls aged 8-18 years were enrolled in this study. The severity of ADHD symptoms was determined by scores on the Conners' Parent Rating Scale-Revised Short and Conners' Teacher Rating Scale-Revised Short. The severity of depression and anxiety symptoms of the children were evaluated by the self-report inventories. Serum levels of neurotrophins were measured using commercial enzyme-linked immunosorbent assay kits. The multivariate analysis of covariance (MANCOVA) revealed a significant main effect of groups in the levels of serum neurotrophins, an effect that was independent of age, sex, and the severity of the depression and anxiety. The analysis of covariance (ANCOVA) indicated that the mean serum GDNF and NTF3 levels of ADHD patients were significantly higher than that of controls. However, serum BDNF and NGF levels did not show any significant differences between groups. No correlations between the levels of serum neurotrophins and the severity of ADHD were observed. These results suggest that elevated serum GDNF and NTF3 levels may be related to ADHD in children.

Serum levels of neurotrophic factors in active toxoplasmic retinochoroiditis.

Toxoplasmic retinochoroiditis (TR) is the most common identifiable cause of posterior uveitis in Brazil. Response to treatment and clinical presentation may vary significantly. We assessed serum levels of brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), neurotrophin (NT)-3, and NT-4/5 in patients with active TR, before and after TR treatment. METHODS: Twenty patients with active lesion and 15 healthy controls were enrolled in the study. Serum concentration of neurotrophic factors was determined by enzyme-linked immunosorbent assay. RESULTS: BDNF levels were significantly higher in patients before treatment when compared with controls (p=0.0015). There was no significant difference in pro-BDNF, NGF, GDNF, NT-3, and NT-4/5 levels between TR patients and controls. Treatment did not affect the levels of these factors. CONCLUSION: BDNF may be released in the context of the active TR inflammatory response.

Antenatal steroid exposure in the late preterm period is associated with reduced cord blood neurotrophin-3.

BACKGROUND: Neurotrophins are proteins critically involved in neural growth, survival and differentiation, and therefore important for fetal brain development. Reduced cord blood neurotrophins have been observed in very preterm infants (<32weeks gestation) who subsequently develop brain injury. Antenatal steroid exposure can alter neurotrophin concentrations, yet studies to date have not examined whether this occurs in the late preterm infant (33-36weeks gestation), despite increasing recognition of subtle neurodevelopmental deficits in this population. AIM: To assess the impact of antenatal steroids on cord blood neurotrophins in late preterm infants following antenatal steroid exposure. STUDY DESIGN: Retrospective analysis. SUBJECTS: Late preterm infants (33-36weeks; n=119) and term infants (37-41weeks; n=129) born at the Women's and Children's Hospital, Adelaide. OUTCOME MEASURES: Cord blood neurotrophin-3 (NT-3), NT-4, nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) concentrations measured by ELISA. RESULTS: Cord blood NT-4 and NGF were increased at term compared to the late preterm period (p<0.001), while BDNF and NT-3 were not different. In the late preterm period, cord blood NT-3 was reduced when antenatal steroids were administered >24h prior to delivery (p<0.01). CONCLUSION: This study identified an association between reduced cord blood NT-3 and antenatal steroid exposure in the late preterm period. The reduced NT-3 may be a consequence of steroids inducing neuronal apoptosis, thereby reducing endogenous neuronal NT3 production, or be an action of steroids on other maternal or fetal NT-3 producing cells, which may then affect neuronal growth, differentiation and survival. Regardless of the specific mechanism, a reduction in NT-3 may have long term implications for child neurodevelopment, and emphasizes the ongoing vulnerability of the fetal brain across the full preterm period.

Delayed intramuscular human neurotrophin-3 improves recovery in adult and elderly rats after stroke.

There is an urgent need for a therapy that reverses disability after stroke when initiated in a time frame suitable for the majority of new victims. We show here that intramuscular delivery of neurotrophin-3 (NT3, encoded by NTF3) can induce sensorimotor recovery when treatment is initiated 24 h after stroke. Specifically, in two randomized, blinded preclinical trials, we show improved sensory and locomotor function in adult (6 months) and elderly (18 months) rats treated 24 h following cortical ischaemic stroke with human NT3 delivered using a clinically approved serotype of adeno-associated viral vector (AAV1). Importantly, AAV1-hNT3 was given in a clinically-feasible timeframe using a straightforward, targeted route (injections into disabled forelimb muscles). Magnetic resonance imaging and histology showed that recovery was not due to neuroprotection, as expected given the delayed treatment. Rather, treatment caused corticospinal axons from the less affected hemisphere to sprout in the spinal cord. This treatment is the first gene therapy that reverses disability after stroke when administered intramuscularly in an elderly body. Importantly, phase I and II clinical trials by others show that repeated, peripherally administered high doses of recombinant NT3 are safe and well tolerated in humans with other conditions. This paves the way for NT3 as a therapy for stroke.

AAV1.NT-3 gene therapy attenuates spontaneous autoimmune peripheral polyneuropathy.

The spontaneous autoimmune peripheral polyneuropathy (SAPP) model in B7-2 knockout non-obese diabetic mice shares clinical and histological features with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Secondary axonal loss is prominent in the progressive phase of this neuropathy. Neurotrophin 3 (NT-3) is an important autocrine factor supporting Schwann cell survival and differentiation and stimulates neurite outgrowth and myelination. The anti-inflammatory and immunomodulatory effects of NT-3 raised considerations of potential efficacy in the SAPP model that could be applicable to CIDP. For this study, scAAV1.tMCK.NT-3 was delivered to the gastrocnemius muscle of 25-week-old SAPP mice. Measurable NT-3 levels were found in the serum at 7-week postgene delivery. The outcome measures included functional, electrophysiological and histological assessments. At week 32, NT-3-treated mice showed increased hind limb grip strength that correlated with improved compound muscle action potential amplitude. Myelinated fiber density was 1.9 times higher in the NT-3-treated group compared with controls and the number of demyelinated axons was significantly lower. The remyelinated nerve fiber population was significantly increased. These improved histopathological parameters from scAAV1.tMCK.NT-3 treatment occurred in the setting of reduced sciatic nerve inflammation. Collectively, these findings suggest a translational application to CIDP.

[Neurotrophins up-express in peripheral blood of allergic rhinitis patients and related to Th2 hypothesis].

OBJECTIVE: To detect the expression of NGF, BDNF, NT-3 mRNA in the peripheral blood of patients with allergic rhinitis (AR). And to analyze the correlation between NGF, BDNF, NT-3 mRNA expression and the epidsode of rhinitis through Th-2 Hypothesis. METHOD: This study was a group controlled trial. The expression of NGF, BDNF and NT-3 mRNA were tested by real-time quantitative RT-PCR and the concentrations of IL-4, IL-6, IL-10 and INF-alpha were tested by ELISA. RESULT: The expression of NGF, BDNF and NT-3 mRNA in AR patients were 2.44, 4.46 and 1.78 times the amount of those in the healthy adults, respectively. The increased expression of NT-3 correlated positively with the scores of visual analog scale of AR. The concentrations of IL-4, IL-6 and IL-10, which were 2198 +/- 472 pg/mL, 9407 +/- 703 pg/mL and 3917 +/- 323 pg/mL respectively, were higher than those in the healthy adults. The concentration of INF-alpha was 2198 +/- 472 pg/mL and less than the healthy adults. The increased expressions of NGF, NT-3 were positively related to the increase of IL-4, IL-6 and IL-10. CONCLUSION: The expressions of NGF, BDNF and NT-3 mRNA in AR patients are higher than those in the healthy adults. NGF, BDNF and NT-3 may contribute to the pathogenesis of AR. Moreover, NGF and NT-3 may induce the episode of rhinitis through Th-2 Hypothesis.