Glial-derived Neurotrophic Factor Levels Research Articles

Sepsis sensitizes behavioural amphetamine responses while inducing inflammatory and neurotrophic vulnerability in the cecal ligation and puncture model.

The present study aimed to evaluate if sepsis sensitizes behavioural and biochemical responses induced by m-amphetamine. For this, Wistar rats were submitted to the cecal ligation and puncture. After 30 days of cecal ligation and puncture procedure, the animals were submitted to a single intraperitoneal injection of saline or m-amphetamine (.25, .50, or 1.0 mg/kg). Locomotor behaviour was assessed 2 h after the administration. Interleukin (IL)-1β, IL-6, IL-10, tumour necrosis factor-α, dopamine-cAMP-regulated phosphoprotein of 32,000 kDa (DARPP-32) and neuronal calcium sensor (NCS-1) levels were evaluated in the frontal cortex, hippocampus and striatum. Also, brain-derived neurotrophic factor (BDNF), neuronal growth factor and glial-derived neurotrophic factor levels were assessed in the hippocampus. M-amphetamine alone (.25 and 1.0 mg/kg) increased rats' locomotion and exploratory behaviour compared with the Sham + Sal. Animals from the cecal ligation and puncture + m-amphetamine (.5 and/or 1.0 mg/kg) group showed an increase in locomotion, exploratory and risk-like behaviour when compared with the Sham + Saline group and with its respective Sham groups. Cecal ligation and puncture increased interleukin levels compared with the Sham + Sal. However, cecal ligation and puncture animals that received m-amphetamine (1 mg/kg) increased even more, these inflammatory parameters compared with the Sham + Sal and the cecal ligation and puncture + saline group. M-amphetamine at lower doses increased neurotrophic factors, but higher doses decreased these parameters in the brain of cecal ligation and puncture rats. M-amphetamine dose-dependently increased DARPP-32 and NCS-1 levels in cecal ligation and puncture rats in some structures. In conclusion, these results demonstrate that sepsis sensitizes behavioural amphetamine responses while inducing inflammatory and neurotrophic vulnerability in the cecal ligation and puncture model.

Low Levels of Adenosine and GDNF Are Potential Risk Factors for Parkinson's Disease with Sleep Disorders.

Sleep disturbances are the most prevalent non-motor symptoms in the preclinical stage of Parkinson's disease (PD). Adenosine, glial-derived neurotrophic factor (GDNF), and associated neurotransmitters are crucial in the control of sleep arousal. This study aimed to detect the serum levels of adenosine, GDNF, and associated neurotransmitters and explored their correlations with PD with sleep disorders. Demographic characteristics and clinical information of PD patients and healthy participants were assessed. Serum concentrations of adenosine, GDNF, and related neurotransmitters were detected by ELISA and LC-MS. The correlation between serum levels of adenosine, GDNF, and associated neurotransmitters and sleep disorders was explored using logistic regression. PD patients with sleep disorders had higher scores of HAMA, HAMD, ESS, UPDRS-III, and H-Y stage. Lower levels of adenosine, GDNF, and γ-GABA were observed in PD patients who had sleep problems. Logistic regression analysis showed adenosine and GDNF were protective factors for preventing sleep disorders. Adenosine combined with GDNF had a higher diagnostic efficiency in predicting PD with sleep disorders by ROC analysis. This study revealed low adenosine and GDNF levels may be risk factors for sleep disorders in PD. The decrease of serum adenosine and GDNF levels may contribute to the diagnosis of PD with sleep disturbances.

Нейротрофические факторы у пациентов с первичной открытоугольной глаукомой и возрастной катарактой. Сообщение 3. Глиальный нейротрофический фактор

Purpose. To evaluate content of glial-derived neurotrophic factor (GDNF) in the aqueous humor (AH), lacrimal fluid (LF), and blood serum (BS) in patients with primary open-angle glaucoma (POAG) and agerelated cataract. Material and methods. A comprehensive examination of a group of patients with POAG in combination with age-related cataract was carried out. As a comparison group, previously examined patients with age-related cataract were taken. The content of GDNF in the LF, AH and BS was studied in all patients. Collection of stimulated LF was performed with a pipette dispenser on the day preceding surgery; the AH and BS were sampled during the phacoemulsification of a cataract. The concentration of GDNF was measured using an enzyme immunoassay. Results. At the early stages of POAG (stages 1–2 according to classification by Mills et al, 2006) there was a significant decrease in the level of GDNF in all studied biological fluids, especially pronounced in the AH and LF – about 2 times (P <0.001); the decrease of GDNF in the BS was less than 20% (P <0.05). In stages 3-4, the GDNF levels consistently increased; the levels of GDNF in the LF and AH remained significantly reduced in comparison with patients without glaucoma. An inverse correlation with the perimetric index VFI was found for the content of GDNF in LF and BS; a direct correlation was found between the GDNF levels in BS and AH. Conclusion. In patients with POAG, a significant decrease of GDNF content in the LF, AH and BS was revealed, especially in the early stages of the disease. In subsequent stages, reduction of GDNF levels in the AH and LF was consistently less significant. With the disease progression, there is a gradual increase in the concentration of GDNF in the AH and LF; nevertheless, the level of GDNF in these fluids remains significantly reduced compared to patients without glaucoma. An inverse correlation with the perimetric index VFI was found for the content of GDNF in LF and BS, as well as a direct correlation of GDNF levels in the BS and AH. Key words: glial-derived neurotrophic factor, primary open-angle glaucoma, age-related cataract, lacrimal fluid, aqueous humor, blood serum.

Lower GDNF Serum Level Is a Possible Risk Factor for Constipation in Patients With Parkinson Disease: A Case-Control Study.

Background: Constipation is a significant symptom of Parkinson's disease (PD). Glial-derived neurotrophic factor (GDNF) is important for the morphogenesis of the enteric nervous system and plays a critical role in the preservation of mucosal integrity under enteric glia surveillance. The aim of this work was to evaluate the serum levels of GDNF in patients with PD with and without constipation.Methods: This work included 128 patients with PD. The patients were classified into three groups: those with PD but no constipation (nCons-PD) (n = 49), those with prodromal stage constipation (Cons-Pro-PD) (n = 48), and those with clinical stage constipation (Cons-Clinic-PD) (n = 31). The association between serum GDNF concentration and constipation was explored using logical regression.Results: The nCons-PD group's mean GDNF levels were 528.44 pg/ml, which was higher than the Cons-Pro-PD group's 360.72 pg/ml and the Cons-Clinic-PD group's 331.36 pg/ml. The results of binary logistic regression indicated that GDNF was a protective factor in the prevention of constipation. Cons-Clinic-PD group had a higher score of MDS-UPDRS-II, MDS-UPDRS-III, MDS-UPDRS-IV, and a higher H-Y staging as compared with nCons-PD group. Relative to the nCons-PD group, Cons-Clinic-PD had higher NMSS scores, lower MoCA and PDSS scores, and were more likely to have RBD.Conclusions: GDNF serum levels are lower in patients with PD who are constipated. A low GDNF level is a potential risk factor for constipation in patients with PD.

Serum Levels of Brain Derived Neurotrophic Factor, Nerve Growth Factor, Neurotrophin 3, and Glial Derived Neurotrophic Factor in Children with Specific Learning Disorder

Specific learning disorder (SLD) is a neurodevelopmental disorder that involves complex interactions of genetic, neurobiological and environmental factors, but the definite mechanisms remain mostly unknown. The possible role of neurotrophins has been implicated in the pathophysiology of various neurodevelopmental disorders. This study aimed to investigate whether serum levels of brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3) in children with SLD deviate from those of neurotypical brains. Forty-four patients with SLD and 44 healthy controls aged 7--12 years were included. SLD diagnosis and severity was determined using DSM-5-based interviews and SLD clinical observation battery. Serum neurotrophins were measured using enzyme-linked immunosorbent assay. BDNF (p=0.032), NGF (p=0.029), and NT-3 (p=0.025) serum levels were significantly higher in the SLD group compared to the control group; however, serum levels of GDNF did not show any significant difference between groups. On the other hand, GDNF serum levels were significantly different between mild and severe SLD groups (p=0.007) and were lower in severe SLD subjects than in mild cases. There was also a significant correlation between patients' reading speeds and serum levels of GDNF (p=0.025), and GDNF serum levels were lower in patients with slower reading speeds. These findings suggest that neurotrophins might play a role in the pathophysiology of SLD. Increased serum levels of BDNF, NGF, and NT-3 might reflect compensatory attempts at neuroprotection against neurodevelopmental impairment.

Klotho, BDNF, NGF, GDNF Levels and Related Factors in Withdrawal Period in Chronic Cannabinoid Users.

Klotho and neurotropic factors have recently been shown to be related to some psychiatric disorders and neurocognitive disorders, but there is no study on this issue within substance users. In this study, brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), glial derived neurotrophic factor (GDNF) and klotho serum levels of a patient group consisting of 27 chronic cannabis users according to the DSM-V and 27 healthy volunteers were compared, and their relationships with other the clinical features of other patients were evaluated. Clinical scales, the Buss-Perry Aggression Scale, and the Substance Craving Scale were repeated on the first day of hospitalisation and on the seventh day of withdrawal. BDNF, GDNF, NGF and klotho levels were analysed using the ELISA method. There was no differences between the cannabinoid use disorder group and the control group regarding their klotho and other neurotrophic levels, but initiation age of cannabis use was negatively correlated with these levels. In addition, there was a relationship between verbal aggression scores and BDNF and NGF levels. There was a positive correlation between klotho and neurotrophic factors in all groups (patient group Day 1, patient group Day 7, control group) (p < 0.01). When comparing the difference between the correlations using the cocor (a comprehensive solution for the statistical comparison of correlations), the klotho-GDNF and klotho-NGF correlations for the first day of the patient group and the control group were different. In this study, rather than a difference in klotho levels and neurotropic factors, a significant relationship between these markers and each other and clinical parameters was demonstrated; further studies are needed to understand the exact mechanism.

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.

Correlation analysis between executive dysfunction and serum glial-derived neurotrophic factor level in children with attention deficit/hyperactivity disorder

Objective To explore the correlation between executive dysfunction and serum glial-derived neurotrophic factor (GDNF) levels in children with attention deficit hyperactivity disorder (ADHD). Methods 32 drug-free ADHD patients and 34 normal children matched in gender, age and IQ were included.The executive function was assessed using Digital Span Back Test (DSB-T), Trail Making Test (TMT), Semantic Fluency Test (SFT) and Stroop Color Word Test (SCW-T), and peripheral GDNF levels were measured by the enzyme linked immunosorbent assay (ELISA). The executive functional test scores and serum GDNF levels were compared between groups, and then the correlation between executive dysfunction and GDNF was analyzed by Spearman or pearson correlation analysis. Results (1) In the ADHD group, the DSB-T and SFT scores were lower than those in the normal control group(DSB-T4: (2) vs 5(1); SFT(13.66±2.34) vs (15.21±2.13)(Z=3.16, t=2.82, both P<0.05) and the TMT-A and TMT-B time-consuming were higher than those in the normal control group(TMT-A(61.12±19.03)s vs (48.76±21.06)s; TMT-B(158.66±63.78)s vs (123.62±45.24)s, t=2.50, 2.59, both P<0.05). The Word color consumption, word interference and word color errors of SCW-T in ADHD group were higher than those in the normal control group(Word color consumption(56.41±21.65)s vs (45.97±13.42)s; word interference 27(25)s vs 20(15)s; word color errors 4(3) vs 2(1)), and the differences were statistically significant(t=2.37, Z=2.31, 2.11, all P<0.05). (2) Serum levels of GDNF in the ADHD group were lower than that in the normal control group((481.59±68.74)pg/ml vs (552.47±110.13)pg/ml) , and the difference was statistically significant (t=3.11, P<0.05). (3) In the ADHD group, serum GDNF levels were negatively correlated with TMT-A, TMT-B and SCW-T word interference performance (r=-0.512, r=-0.578, r=-0.432, all P<0.05), and positively correlated with DSB-T performance(r=0.381, P<0.05). Conclusion Executive function is extensively damaged in ADHD patients, and GDNF may be involved in the pathophysiology of executive impairment. Key words: Attention deficit hyperactivity disorder; Glial-derived neurotrophic factor; Executive function; Children

Диагностическая значимость определения нейроспецифических белков в крови у больных с менингиомами

The purpose was to study the diagnostic value of the content of brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF) in patients with meningiomas before and after surgery. Material and methods. The study involved 70 patients with meningiomas and 62 healthy people. The examination of the patients included clinical and neurological examination, determination of BDNF and GDNF (R&amp;D Systems, USA) content in blood plasma using enzyme immunoassay performed before the surgery and 5–6 days after meningioma surgery. The totality of meningioma removal was determined intraoperatively, which was then confirmed by control neuroimaging a day after the operation. Results. BDNF level less than 2038,6 PG/ml allows diagnosing the characteristic of meningiomas changes with a sensitivity of 88% and a specificity of 44%. GDNF level more than 3.1 PG/ml allows diagnosing the meningioma-related changes in the brain with sensitivity of 84% and specificity of 51%. The plasma level of BDNF in patients after subtotal removal of meningioma on 5–6 days after surgery significantly increased, compared with the preoperative value, p = 0,01. The plasma concentration of GDNF in patients with meningiomas after radical removal of the tumor significantly decreased compared to its preoperative lever, p = 0,01. Conclusion. To summarize, our data show that none of the investigated markers is suitable to substitute histological diagnosis. However, measurement of circulating BDNF and GDNF before and after surgery may be a support to diagnose the totality of meningioma removal.

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.

The Association of Decreased Serum Gdnf Level with Hyperglycemia and Depression in Type 2 Diabetes Mellitus

Objective: Comorbidity of diabetes and depression is a critical problem. Decreased glial-derived neurotrophic factor (GDNF) has been demonstrated in depression, but no evidence of a relationship between GDNF and diabetes has been shown. The present studies were designed to investigate the relationship between GDNF and metabolism. Methods: In Study 1, we performed a case-control study in which subjects with type 2 diabetes mellitus (T2DM), prediabetes (p-DM), and normal glucose tolerance (NGT) were included. In Study 2, we performed a cross-sectional study in 296 patients having pre-existing diabetes in whom the levels of serum GDNF, blood glucose, blood lipids, blood pressure, body mass index, scores from the Patient Health Questionnaire (PHQ-9), the EuroQol-5 scale, and the diabetes distress scale were measured, as well as single-nucleotide polymorphisms of GDNF including rs884344, rs3812047, and rs2075680. Results: In Study 1, serum GDNF concentration was significantly lower in the T2DM group than in the NGT group (NGT: 11.706 ± 3.918 pg/mL; p-DM: 10.736 ± 3.722 pg/mL; type 2 diabetes mellitus [T2DM group]: 9.884 ± 2.804 pg/mL, P = .008). In Study 2, significantly decreased serum GDNF levels were observed in subjects with poor glycemic control or depression (glycated hemoglobin [HbA1c] <7.0% without depression: 11.524 ± 2.903 pg/mL; HbA1c ≥7.0% without depression: 10.625 ± 2.577 pg/mL; HbA1c <7.0% with depression: 10.355 ± 2.432 pg/mL; HbA1c ≥7.0% with depression: 8.824 ± 2.102 pg/mL, P = .008). Double-factor variance analysis showed that glycemic control and depression were independent factors for the GDNF level. Moreover, the serum GDNF level was significantly inversely associated with the fasting plasma glucose, 2 hours postprandial plasma glucose, HbA1c, and PHQ-9 score. Conclusion: Glycemic dysregulation was an independent factor for the GDNF level. These findings suggest that GDNF level might be involved in the pathophysiology of T2DM and depression through various pathways. Abbreviations: BP = blood pressure; CHO = cholesterol; DDS = diabetes distress scale; DM = diabetes mellitus; EQ-5D = the health-related dimensions of the EuroQol-5 scale; FPG = fasting plasma glucose; GDNF = glial-derived neurotrophic factor; HbA1c = glycated hemoglobin; HDL = high-density lipoprotein; LDL = low-density lipoprotein; NGT = normal glucose tolerance; PHQ-9 = Patient Health Questionnaire; p-DM = prediabetes; PPG = postprandial plasma glucose; SNP = single-nucleotide polymorphism; T2DM = type 2 diabetes mellitus; TG = triglyceride.

Study on the level of peripheral serum glial-derived neurotrophic factor in children with attention deficit hyperactivity disorder

Objective To explore the changes of peripheral serum glial-derived neurotrophic factor(GDNF) levels in children with attention deficit hyperactivity disorder(ADHD), and to provide a new marker for early identification of ADHD in clinical practice. Methods Totally 42 drug-naive children with ADHD(ADHD group) and 45 healthy children(HC group) were included. General demographic information, scale scores, and fasting peripheral serum GDNF levels were compared between the two groups. Meanwhile, the correlation between GDNF level and symptom severity score of children with ADHD was analyzed. Results There were significant differences in FSIQ, attention deficit, and hyperactivity/impulsivity scores between ADHD group and HC group(FSIQ(105.26±13.82) vs (114.73±9.93); attention deficit(23.60±5.06) vs (20.04±2.85); hyperactivity/impulsivity(19.43±3.47) vs (15.93±2.42), all P<0.05). Serum level of GDNF in the ADHD patients was significant lower than that in the HC group ((442.52±70.01)pg/ml vs (554.02±101.37)pg/ml, P<0.01). In addition, GDNF levels were negatively correlated with attention deficit scores in children with ADHD (radj=-0.447, P<0.01). More importantly, ROC curve results show that GDNF had good diagnostic value (AUC=0.81). Conclusion GDNF levels decreased child with ADHD.Decreased serum GDNF levels have certain promising value in the diagnosis of ADHD. Key words: Attention deficit hyperactivity disorder; Glial-derived neurotrophic factor; Children

Altered serum levels of vascular endothelial growth factor and glial-derived neurotrophic factor but not fibroblast growth factor-2 in treatment-naive children with attention deficit/hyperactivity disorder

Background and aim: Recent evidence suggests that growth factors might be involved in the pathophysiology of attention deficit hyperactivity disorder (ADHD). The aim of this study was to determine whether serum levels of brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3), nerve growth factor (NGF), fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor (VEGF) were altered in children with ADHD.Methods: Serum levels of BDNF, GDNF, NT-3, NGF, VEGF and FGF-2 were analyzed in 49 treatment- naive children with ADHD and age, gender matched 36 healthy controls using enzyme-linked immunosorbent assay. ADHD symptoms were scored by Du Paul ADHD Rating Scale and Strengths and Difficulties Questionnaire.Results: We found that serum VEGF levels were significantly lower (p < 0.001) and GDNF levels were significantly higher in ADHD group compared to control group (p = 0.003). However, we found no correlations between ADHD symptoms and serum VEGF or GDNF levels. Furthermore, we observed no significant alterations in serum BDNF, NT-3, NGF, FGF-2 levels in children with ADHD.Conclusion: To our knowledge, the present study is the first to examine serum VEGF and FGF-2 levels in children with ADHD. Our results indicate that VEGF and GDNF might be involved in the etiology of ADHD. Further studies are required to determine the role of growth factors in the etiology and consequently in the treatment of ADHD.

The role of neurotrophic factors in manic-, anxious- and depressive-like behaviors induced by amphetamine sensitization: Implications to the animal model of bipolar disorder

BackgroundBipolar disorder (BD) and substance use disorders share common symptoms, such as behavioral sensitization. Amphetamine-induced behavioral sensitization can serve as an animal model of BD. Neurotrophic factors have an important role in BD pathophysiology. This study evaluated the effects of amphetamine sensitization on behavior and neurotrophic factor levels in the brains of rats. MethodsWistar rats received daily intraperitoneal (i.p) injections of dextroamphetamine (d-AMPH) 2 mg/kg or saline for 14 days. After seven days of withdrawal, the animals were challenged with d-AMPH (0.5 mg/kg, i.p) and locomotor behavior was assessed. In a second protocol, rats were similarly treated with d-AMPH (2 mg/kg, i.p) for 14 days. After withdrawal, without d-AMPH challenge, depressive- and anxiety-like behaviors were evaluated through forced swimming test and elevated plus maze. Levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin 3 (NT-3), neurotrophin 4/5 (NT-4/5) and glial-derived neurotrophic factor (GDNF) were evaluated in the frontal cortex, hippocampus, and striatum. ResultsD-AMPH for 14 days augmented locomotor sensitization to a lower dose of d-AMPH (0.5 mg/kg) after the withdrawal. d-AMPH withdrawal induced depressive- and anxious-like behaviors. BDNF, NGF, and GDNF levels were decreased, while NT-3 and NT-4 levels were increased in brains after d-AMPH sensitization. LimitationsAlthough d-AMPH induces manic-like behavior, the mechanisms underlying these effects can also be related to phenotypes of drug abuse. ConclusionsTogether, vulnerability to mania-like behavior following d-AMPH challenge and extensive neurotrophic alterations, suggest amphetamine-induced behavioral sensitization is a good model of BD pathophysiology.

Nesting Environment Provides Sex-Specific Neuroprotection in a Rat Model of Neonatal Hypoxic-Ischemic Injury.

Hypoxic-ischemic (HI) encephalopathy is a devastating injury that occurs when the fetal brain is deprived of oxygen and blood to a degree that may lead to neurological damage, seizing and cerebral palsy. In rodents, early environmental enrichment that promotes maternal care-taking behavior (mCTB) can improve neurobehavioral outcomes and protect against neurological decline. We hypothesized that an enhanced nesting environment would improve mCTB as measured by pup weight gain, and support greater HI recovery in developing rats. Pregnant dams (E15-16) were introduced to either control Standard Facility (SF) housing or closed nestbox (CN) conditions and maintained in larger cages through pup weaning. On postnatal day (PND) 7, male and female Long-Evans rat pups (N = 73) were randomly sorted into one of two surgical conditions: control and HI. HI pups received isoflurane anesthesia and right carotid artery ligation, a 2-h rest followed by 90 min exposure to a moist hypoxic (92% N, 8% O2) chamber. Pups (PND 8) were weighed daily, and tested on the Morris Water Maze (MWM) task (PND 35-50). Results demonstrate significant differences afforded to male and female pups based on weight measure, where CN-rearing modifies pre-weaning adolescent weights in females and increases post-weaning weights in males and females by an average of 10 g. Following successful MWM training and acquisition (PND 35-37), both male and female CN-raised animals demonstrated faster latency to find the hidden platform (HP) during HP trials (PND 38-42) and appeared to freely explore the MWM pool during an additional probe trial (PND 43). Moreover, after sacrifice (PND 60), CN rearing created sex-specific alterations in brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF) immunopositive cell staining of the dorsomedial striatum and CA1 of the hippocampus. CN-rearing afforded HI males higher BDNF levels in the striatum and produced greater GDNF levels in the hippocampus of HI-injured females. These results suggest that early life environmental enrichment positively modifies nesting environment, increases weight gain, as well as spatial learning and memory in a sex-specific directionality. Our findings also implicate correlative changes in corticolimbic neurotrophin protein levels in the CN-reared animals that may contribute to these benefits.

Changing muscle function with sustained glial derived neurotrophic factor treatment of rabbit extraocular muscle

Recent microarray and RNAseq experiments provided evidence that glial derived neurotrophic factor (GDNF) levels were decreased in extraocular muscles from human strabismic subjects compared to age-matched controls. We assessed the effect of sustained GDNF treatment of the superior rectus muscles of rabbits on their physiological and morphological characteristics, and these were compared to naïve control muscles. Superior rectus muscles of rabbits were implanted with a sustained release pellet of GDNF to deliver 2μg/day, with the contralateral side receiving a placebo pellet. After one month, the muscles were assessed using in vitro physiological methods. The muscles were examined histologically for alteration in fiber size, myosin expression patterns, neuromuscular junction size, and stem cell numbers and compared to age-matched naïve control muscles. GDNF resulted in decreased force generation, which was also seen on the untreated contralateral superior rectus muscles. Muscle relaxation times were increased in the GDNF treated muscles. Myofiber mean cross-sectional areas were increased after the GDNF treatment, but there was a compensatory increase in expression of developmental, neonatal, and slow tonic myosin heavy chain isoforms. In addition, in the GDNF treated muscles there was a large increase in Pitx2-positive myogenic precursor cells. One month of GDNF resulted in significant extraocular muscle adaptation. These changes are interesting relative to the decreased levels of GDNF in the muscles from subjects with strabismus and preliminary data in infant non-human primates where sustained GDNF treatment produced a strabismus. These data support the view that GDNF has the potential for improving eye alignment in subjects with strabismus.

Neurotrophins and cholinergic enzyme regulated by calpain-2: New insights into neuronal apoptosis induced by polybrominated diphenyl ether-153

Polybrominated diphenyl ether-153 (BDE-153) has been demonstrated to induce neuronal apoptosis in rat cerebral cortex and primary neurons. Neurotrophins and cholinergic enzymes play critical roles in the neuronal survival, maintenance, synaptic plasticity and learning memory, however, their roles in neuronal apoptosis following the BDE-153 treatment remain unclear. In this study, we firstly explored the possible predominant pathway underlying the neuronal apoptotic induced by the BDE-153 treatment in rat cerebral cortex, by measuring expression levels (mRNA and protein) of p53, caspase-3, 8, 9, calpain-1, and calpain-2, detected the levels (protein contents and mRNA) of neurotrophins including brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), and measured acetylcholinesterase (AchE) and choline acetyltransferase (ChaT) activities in rat cerebral cortex and primary neurons following BDE-153 treatment with or without pretreatment with inhibitors. Results showed that the neuronal apoptosis induced by BDE-153 was dependent on p53, and dependent on more calpain-2 than caspase-3 in the cerebral cortex of rats. Following the BDE-153 treatment, the protein contents and mRNA levels of BDNF, GDNF, NGF, NT-3, and NT-4, as well as the AchE and ChaT activities were significantly decreased in the cerebral cortex and primary neurons when compared to the untreated group. When pretreated primary neurons with calpain inhibitor PD150606 or cyclin-dependent kinase (cdk5, the downstream complex of calpain) inhibitor Roscovitine, the neurotrophins contents and activities of ChaT and AchE were reverted, along with the improvement of neuron survival compared with BDE-153 treatment alone. We conclude that neurotrophins and cholinergic enzymes were regulated by the calpain-2 activation and its downstream cdk5 pathway, and which was involved in the neuronal apoptosis induced by the BDE-153 treatment.

Sporadic amyotrophic lateral sclerosis (SALS) - skeletal muscle response to cerebrospinal fluid from SALS patients in a rat model.

ABSTRACTSkeletal muscle atrophy is the most prominent feature of amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease of motor neurons. However, the contribution of skeletal muscle to disease progression remains elusive. Our previous studies have shown that intrathecal injection of cerebrospinal fluid from sporadic ALS patients (ALS-CSF) induces several degenerative changes in motor neurons and glia of neonatal rats. Here, we describe various pathologic events in the rat extensor digitorum longus muscle following intrathecal injection of ALS-CSF. Adenosine triphosphatase staining and electron microscopic (EM) analysis revealed significant atrophy and grouping of type 2 fibres in ALS-CSF-injected rats. Profound neuromuscular junction (NMJ) damage, such as fragmentation accompanied by denervation, were revealed by α-bungarotoxin immunostaining. Altered expression of key NMJ proteins, rapsyn and calpain, was also observed by immunoblotting. In addition, EM analysis showed sarcolemmal folding, Z-line streaming, structural alterations of mitochondria and dilated sarcoplasmic reticulum. The expression of trophic factors was affected, with significant downregulation of vascular endothelial growth factor (VEGF), marginal reduction in insulin-like growth factor-1 (IGF-1), and upregulation of brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF). However, motor neurons might be unable to harness the enhanced levels of BDNF and GDNF, owing to impaired NMJs. We propose that ALS-CSF triggers motor neuronal degeneration, resulting in pathological changes in the skeletal muscle. Muscle damage further aggravates the motor neuronal pathology, because of the interdependency between them. This sets in a vicious cycle, leading to rapid and progressive loss of motor neurons, which could explain the relentless course of ALS.This article has an associated First Person interview with the first author of the paper.

Neuroprotection of Transplanting Human Umbilical Cord Mesenchymal Stem Cells in a Microbead Induced Ocular Hypertension Rat Model

ABSTRACTPurpose: The purpose of this study is to investigate the potential therapeutic benefits of intravitreally transplanted human umbilical cord mesenchymal stem cells (UC-MSCs) in an animal model of microbead-injection-induced ocular hypertension (OHT).Methods: UC-MSCs were isolated from human umbilical cords and then cultured. The OHT model was induced via intracameral injection of polystyrene microbeads in Sprague–Dawley adult rat eyes. Fifty-four healthy adult rats were randomly divided into three groups: normal control, OHT model treated with intravitreal transplantation of UC-MSCs, or phosphate-buffered saline (PBS). Two days after OHT was induced, either 5 µl 105 UC-MSCs suspension or PBS was injected into the vitreous cavity of rats. UC-MSCs localization and integration were examined via immunohistochemistry. Neuroprotection was quantified by counting retinal ganglion cells (RGCs) and axons 2 weeks following transplantation. The expression levels of glial-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), and glial fibrillary acidic protein (GFAP) were assessed via immunohistochemistry and Western blot. Functional recovery was assessed 2 weeks after transplantation via scotopic threshold response (STR) electroretinography.Results: Elevated IOP levels were sustained at least 3 weeks after intracameral microbead injection and the number of β-III-tubulin+ RGCs significantly declined compared to PBS-injected eyes. UC-MSCs survived for at least 2 weeks after intravitreal transplantation and predominantly located in the vitreous cavity. A fraction of cells migrated into the ganglion cell layer of host retina, but without differentiation. Intravitreal UC-MSC transplantation resulted in increased number of RGCs, axons, and increased expression of GDNF and BDNF but decreased expression of GFAP. Intravitreal delivery of UC-MSCs significantly improved the recovery of the positive STR.Conclusions: Intravitreal transplantation of UC-MSCs revealed the neuroprotection in the microbead-injection induced OHT. The effects could be related to the secretion of tropic factors (BDNF and GDNF) and the modulation of glial cell activation.

Serum nerve growth factor beta, brain- and glial-derived neurotrophic factor levels and psychopathology in unmedicated patients with schizophrenia

BackgroundThere is accumulating evidence that neurotrophic factors may be involved in the pathophysiology of patients with schizophrenia. This study aimed to explore the relationship between serum nerve growth factor beta (NGF-beta), brain-derived neurotrophic factor (BDNF), and glial-derived neurotrophic factor (GDNF) levels and psychopathology in unmedicated patients with schizophrenia. MethodsSerum NGF-beta, BDNF, and GDNF levels were determined using enzyme-linked-immunosorbent assay (ELISA) in the serum of 30 unmedicated patients with schizophrenia. Symptomatology was assessed with the expanded version of the 24-items brief psychiatric rating scale (BPRS-E), which was divided into four conceptual domains: manic excitement/disorganization, depression/anxiety, negative symptoms, and positive symptoms. Kolmogorov–Smirnov one sample test was performed to test non-parametric variables. Spearman's correlation was performed to examine the correlations between the cytokines of interest and psychopathology. Benjamini-Hochberg procedure was applied for multiple corrections. ResultsSerum GDNF levels correlated negatively with the BPRS-total (r = −0.533, corrected p = 0.002) and BPRS-manic (r = −0.456, corrected p = 0.011) subtests. BDNF levels showed a positive correlation with BPRS-total (r = 0.480, corrected p = 0.007). In addition, NGF-beta did not associate with psychopathology measured by BPRS scores. ConclusionNeurotrophic factors play a vital role in the regulation of neuroplasticity and neurogenesis in humans. This study suggests that BDNF and GDNF may be contributing to the pathological mechanisms involved in unmedicated patients with schizophrenia.