Glial Cell Line-derived Neurotrophic Factor Research Articles

Circulating inflammatory cytokines and colorectal cancer: New insights from Mendelian randomization.

Colorectal cancer (CRC) is one of the most common cancers worldwide and inflammation is believed to play an important role in CRC. In this study, we comprehensively analyzed the causal association between 91 circulating inflammatory cytokines and the risk of CRC using Mendelian randomization (MR). Based on genome-wide association study summary statistics, we examined the causal effects of 91 circulating inflammatory cytokines on CRC. A series of MR methods, including bidirectional MR, replication sample MR, and multivariable MR, were employed to provide more robust causal estimates. After the validation with 3 MR methods and a series of sensitivity analyses, 2 circulating inflammatory factors were found to be significantly associated with the risk of CRC at the genetic level. Specifically, genetically predicted circulating levels of glial cell line-derived neurotrophic factor (GDNF) (OR = 1.12; 95% CI: 1.05-1.19; P = 2.72 × 10-4) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (OR = 0.93; 95% CI: 0.91-0.99; P = 1.00 × 10-2) exerted causal effects on CRC risk. In conclusion, this study suggests that increased circulating levels of GDNF and TRAIL are associated with a higher and lower risk of CRC, respectively. GDNF and TRAIL may be 2 potential therapeutic targets that deserve future investigation.

Relationship between klotho, neurotrophic factors (BDNF, NGF, GDNF) and cognitive functions in patients with bipolar disorder

BackgroundKlotho and neurotrophic factors, including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and glial cell line-derived neurotrophic factor (GDNF), have been shown to play a role in cognitive functions. However, these molecules have not been investigated in bipolar disorder simultaneously to assess the interactions among them and their relationships with cognitive functions. This study investigated the relationships among cognitive function, klotho, and neurotrophic factors in patients with bipolar disorder in the remission period.MethodsMale, bipolar disorder (BD) patients (patient group, n = 48) in the remission period and healthy volunteers (control group, n = 48) were included in the study. The Stroop test and Wechsler Memory Scale–Visual Production Subtest were applied, and the serum levels of Klotho, BDNF, GDNF, and NGF were measured with an ELISA reader.ResultsThe klotho protein levels (0.12 ± 0.15 and 0.17 ± 0.16) and NGF levels (34.36 ± 41.99 and 48.54 ± 41.06) in the patient group were significantly lower than those in the control group (Z = -3.071, p = 0.002 and Z = -2.217, p = 0.027, respectively). In the patient group, there was a positive correlation between the klotho and NGF levels (p = 0.003, rs = 0.413), and a negative correlation was detected between the NGF and GDNF levels (p = 0.013, rs = -0.355). Klotho and NGF were predictors of Weshler 40-min test results (adjusted R2 = 0.467), and Klotho and BDNF were predictors of Stroop test colour word reading time (adjusted R2 = 0.391) with other variables.ConclusionIn BD patients, klotho, BDNF, GDNF and NGF are associated with cognitive functions and exhibit different characteristics from those of the control group. Nevertheless, the differences related to these molecules seem to be associated with a regulatory system rather than merely an increase or decrease in serum levels.

Urine miRNA signature as potential non-invasive diagnostic biomarker for Hirschsprung's disease.

Hirschsprung's disease (HSCR) is characterized by congenital absence of ganglion cells in the gastrointestinal tract, which leads to impaired defecation, constipation and intestinal obstruction. The current diagnosis of HSCR is based on Rectal Suction Biopsies (RSBs), which could be complex in newborns. Occasionally, there is a delay in diagnosis that can increase the risk of clinical complications. Consequently, there is room for new non-invasive diagnostic methods that are objective, more logistically feasible and also deliver a far earlier base for a potential surgical intervention. In recent years, microRNA (miRNA) has come into the focus as a relevant early marker that could provide more insights into the etiology and progression of diseases. Therefore, in the search of a non-invasive HSCR biomarker, we analyzed miRNA expression in urine samples of HSCR patients. Results from 5 HSCR patients using microarrays, revealed hsa-miR-378 h, hsa-miR-210-5p, hsa-miR-6876-3p, hsa-miR-634 and hsa-miR-6883-3p as the most upregulated miRNAs; while hsa-miR-4443, hsa-miR-22-3p, hsa-miR-4732-5p, hsa-miR-3187-5p, and hsa-miR-371b-5p where the most downregulated miRNAs. Further search in miRNAwalk and miRDB databases showed that certainly most of these dysregulated miRNAs identified target HSCR associated genes, such as RET, GDNF, BDNF, EDN3, EDNRB, ERBB, NRG1, SOX10; and other genes implied in neuronal migration and neurogenesis. Finally, we could also validate some of these miRNA changes in HSCR urine by RT-qPCR. Altogether, our analyzed HSCR cohort presents a dysregulated miRNA expression presents that can be detected in urine. Our findings open the possibility of using specific urine miRNA signatures as non-invasive HSCR diagnosis method in the future.

Molecular and Functional Significance of Growth Differentiation Factor-15: A Review on Cardiovascular-Kidney-Metabolic Biomarker.

Cardiovascular-kidney-metabolic (CKM) syndrome is the association between obesity, diabetes, CKD (chronic kidney disease), and cardiovascular disease. GDF-15 mainly acts through the GFRAL (Glial cell line-derived neurotrophic factor Family Receptor Alpha-Like) receptor. GDF-15 and GDFRAL complex act mainly through RET co-receptors, further activating Ras and phosphatidylinositol-3-kinase (PI3K)/Akt pathways through downstream signaling. GDF-15 decreases cardiac dysfunction and hypertrophy by inducing HIF-α (hypoxia-inducible factor-1α). It causes increased fractional shortening and a significant decrease in ventricular dilation through the induction of the SMAD 2/3. GDF-15 prevents hyperglycemia-induced apoptosis in diabetes mellitus. GDF-15 causes anorexia by influencing the central systems regulating metabolism and appetite. Therefore, targeting GDF-15 can be useful for the treatment of anorexia caused by cancer as well as the prevention of resulting weight loss. GDF-15 has an important role in predicting mortality in acute kidney injury. Its high levels are related to eGFR decline and also have a prognostic role in CKD patients. Growth differentiation factor-15 (GDF-15) is a vital biomarker for diagnosis, treatment, and prognosis of CKM syndrome. Elevated GDF-15 levels can be utilised as a biomarker to determine the suitable metformin dosage. In light chain amyloidosis, a raised level of GDF-15 predicts early death in heart failure and renal disease patients. In vivo, studies using GDF-15 analogs and antibodies against GFRAL to affect metabolic parameters and ventricular dilatation have shown potential for GDF-15-based therapeutic interventions. This review aims to study the role of GDF-15 in CKM syndrome and establish it as a CKM biomarker.

The Association of Vitamin D, Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF), and Glial Cell-Derived Neurotrophic Factor (GDNF) with Development in Children.

Short stature remains a global problem and is associated with vitamin D status. Vitamin D is also a neurosteroid with regard to neurotrophic factors but its role in development is unclear. Therefore, this study analyzed the relationships between vitamin D, NGF, GDNF, and BDNF and developmental status in children with a history of short stature (<2 years). This research is a prospective cross-sectional study conducted in March 2022. The vitamin D, NGF, GDNF, and BDNF levels were measured in stored biological materials from children aged 2-4 years, and their Ages and Stages Questionnaire (ASQ-3) scores were also assessed. The results were analyzed via the chi-square test, Fisher's exact test, Mann-Whitney test for NGF, unpaired t-test, and Spearman rank correlation. Among the 85 study subjects, 41.2% were short in stature, with 37% having developmental deviation. Male sex (p = 0.038) and low maternal education (p = 0.024) were associated with short stature. The mean vitamin D level was lower (p = 0.041) in children with short stature (27.65 ng/dL). The risk factors associated with short stature were vitamin D levels ≤ 32.7 ng/dL, GDNF levels ≤ 12.99 ng/mL, male sex, and low maternal education. Children with short stature (<2 years old) also demonstrated impaired problem-solving as assessed by the ASQ-3 (p = 0.005). Vitamin D was also associated with gross motor skills (p = 0.035) and personal social development (p = 0.038). There was no association of vitamin D with NGF, GDNF, or BDNF levels. Vitamin D levels are associated with short stature and development in children, especially gross motor skills, personal social development, and problem solving.

The Role of Vitamin D in the Disease Stage of Parkinson's Patients

Parkinson's disease (PD) is a disorder of brain function that is pathologically characterized by degeneration of nerve cells in the brain, specifically the basal ganglia. Additionally, there is a loss of pigmentation in the substantia nigra, the presence of cytoplasmic inclusions called Lewy bodies, and a decrease in dopamine in the Substantia nigra Pars Compacta (SNC) and corpus striatum. Vitamin D may provide neuroprotection through the action of neurotrophic factors, which regulate neuronal growth, or through protection against cytotoxicity. In some studies, the synthesis of neurotrophic factors, including Neurotrophin 3 (NT3) and Glial Cell Line-derived Neurotrophic Factor (GDNF), was found to be upregulated by 1,25(OH)2D3. A number of studies have demonstrated a higher prevalence of vitamin D deficiency in individuals with Parkinson's disease (PD) compared to healthy controls. Following the discovery that Vitamin D Receptor (VDR) and 1α-hydroxylase, an enzyme responsible for converting vitamin D into its active form, are highly expressed in the substantia nigra, it was postulated that insufficient circulating vitamin D may contribute to the dysfunction or cell death observed in this region. Keywords: Parkinson Disease, Substantia Nigra Pars Compacta, Glial Cell Line-derived Neurotrophic Factor, Vitamin D Receptor

Function of Brain-Derived Neurotrophic Factor in the Vestibular-Cochlear System.

Brain-derived neurotrophic factor (BDNF) is essential for the development and functioning of the vestibular system. BDNF promotes the growth, differentiation, and synaptic plasticity of vestibular neurons, ensuring their normal operation and maintenance. According to research, BDNF is pivotal during vestibular compensation, aiding in the recovery of neuron function by remodeling the spontaneous resting potentials of damaged vestibular neurons. Additionally, BDNF exhibits dose-dependent and age-dependent characteristics during vestibular system development, with its deficiencies leading to the degeneration of vestibular neurons. BDNF dynamically interacts with other neurotrophic factors, such as fibroblast growth factor-2 (FGF-2) and glial cell line-derived neurotrophic factor (GDNF), synergistically enhancing neuron survival and functionality. This review outline the function of BDNF in the vestibulocochlear system and explores its potential therapeutic applications, offering fresh perspectives and guidance for future research and treatment of vestibulocochlear system disorders.

Glial Derived Neurotrophic Factor and Schizophrenia Spectrum Disorders: A Scoping Review.

Psychotic disorders, characterized by altered brain function, significantly impair reality perception. The neurodevelopmental hypothesis suggests these disorders originate from early brain development disruptions. Glial-derived neurotrophic factor (GDNF) is crucial for neuronal survival and differentiation, especially in dopaminergic neurons, and shows promise in neurodegenerative and neuropsychiatric conditions. This scoping review aims to examine the role of GDNF in schizophrenia spectrum disorders and substance-induced psychoses, integrating knowledge on the neurobiological mechanisms and therapeutic potential of GDNF. A comprehensive literature search was conducted using PubMed and Scopus databases from January 2001 onwards. Data extraction focused on GDNF levels, cognitive function, antipsychotic treatment effects, and genetic studies. The review included 25 studies (18 human, 7 animal). While some studies demonstrated inconsistent results regarding GDNF serum levels in schizophrenic patients, the majority reported correlations between GDNF levels and cognitive functions. Animal studies underscored GDNF's role in stress response, drug-induced neurotoxicity, and dopamine signaling abnormalities. Genetic studies revealed potential associations between GDNF gene polymorphisms and schizophrenia susceptibility, though findings were mixed. GDNF plays a significant role in cognitive functions and neuroprotection in schizophrenia. The variability in study results underscores the complexity of GDNF's involvement. The therapeutic potential of GDNF in psychotic disorders remains unclear, necessitating further research to clarify its efficacy and safety. This review emphasizes the importance of integrated biomarker strategies, gene therapy approaches, and precision medicine in advancing the understanding and treatment of psychotic disorders.

Fundamental research and practical application of GDNF as a neuroprotective agent in neurodegenerative diseases

Glial cell line-derived neurotrophic factor (GDNF) is under extensive investigation as a therapeutic agent for treating age-related neurodegenerative diseases and traumatic neuronal injury. The compelling results from preclinical studies contrast with the disappointing outcomes of phase II clinical trials in Parkinson’s disease, highlighting the need for further fundamental research. Several hypotheses have been proposed to explain these discrepancies, including challenges with the delivery of high molecular weight drugs, GDNF’s high affinity for heparin and heparin-like molecules, which limits its biodistribution in the brain parenchyma, the use of protein forms differing from the native GDNF, and the existence of multiple isoforms of the protein. These issues underscore the necessity for further investigation into GDNF at the genetic, RNA, and protein levels. This review aims to consolidate the latest data on GDNF, address the challenges identified, and explore its potential for therapeutic application in human neurodegenerative diseases.

Comparative analysis of the effects of different hypoxia mimetic agents on the secretome contents of conditioned medium obtained from mesenchymal stem/stromal cells cultured in 2 or 3-dimensional cell culture systems.

Paracrine factors secreted by mesenchymal stem/stromal cells (MSCs) have been demonstrated to have significant therapeutic potential. The secretome profiles of MSCs variate depending on culture conditions. Generally, the effects of a single preconditioning strategy on secretome profiles of MSCs were investigated. However, until now, there has been no study examining the combinatory effects of different preconditioning strategies in a comparative manner. This study aimed to evaluate the secretome contents of conditioned media obtained from human umbilical cord-derived MSCs cultured in 2- or 3-dimensional (D) culture systems preconditioned with deferoxamine (DFS) or dimethyloxalylglycine (DMOG). Immunocytochemical analysis showed that MSCs preconditioned with DFS or DMOG have increased nuclear hypoxia-inducible factor-1α expression. Transmission electron microscopic analysis showed that cells preconditioned with DFS or DMOG have increased autophagic vesicles, which could be attributed to altered energy metabolism under hypoxic conditions. It was revealed that hypoxia-mimetic agents added to the 2D-, or 3D-culture environment raised total protein concentrations per cell along with vascular endothelial growth factor. The concentrations of glial cell-derived neurotrophic factor (GDNF) and nerve growth factor (NGF) were differentially regulated in 2D-, and 3D-culture system, that the secretions of GDNF and NGF per cell were more prominent in 3D- and 2D-culture systems, respectively. These findings indicate that hypoxic conditions alone significantly elevate total protein concentrations, while the contribution of the 3D environment is more modest than initially anticipated. However, concentrations of secreted growth factors may be affected differently depending on the topography of the culture condition and the types of hypoxia mimetic agents.

Lineage-specific intersection of endothelin and GDNF signaling in enteric nervous system development.

Two major ligand-receptor signaling axes - endothelin Edn3 and its receptor Ednrb, and glial-derived neurotrophic factor (GDNF) and its receptor Ret - are required for migration of enteric nervous system (ENS) progenitors to the hindgut. Mutations in either component cause colonic aganglionosis, also called Hirschsprung disease. Here, we have used Wnt1Cre and Pax2Cre in mice to show that these driver lines label distinct ENS lineages during progenitor migration and in their terminal hindgut fates. Both Cre lines result in Hirschsprung disease when combined with conditional Ednrb or conditional Ret alleles. In vitro explant assays and analysis of lineage-labeled mutant embryos show that GDNF but not Edn3 is a migration cue for cells of both lineages. Instead, Edn3-Ednrb function is required in both for GDNF responsiveness albeit in different ways: by expanding the Ret+ population in the Pax2Cre lineage, and by supporting Ret function in Wnt1Cre-derived cells. Our results demonstrate that two distinct lineages of progenitors give rise to the ENS, and that these divergently utilize endothelin signaling to support migration to the hindgut.

Filbertone-Induced Nrf2 Activation Ameliorates Neuronal Damage via Increasing BDNF Expression

Neurotrophic factors are endogenous proteins that promote the survival of various neuronal cells. Increasing evidence has suggested a key role for brain-derived neurotrophic factor (BDNF) in the dopaminergic neurotoxicity associated with Parkinson’s Disease (PD). This study explores the therapeutic potential of filbertone, a bioactive compound found in hazelnuts, in neurodegeneration, focusing on its effects on neurotrophic factors and the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. In our study, filbertone markedly elevated the expression of neurotrophic factors, including BDNF, Glial cell line-Derived Neurotrophic Factor (GDNF), and Nerve Growth Factor (NGF), in human neuroblastoma SH-SY5Y cells, mouse astrocyte C8-D1A cells, and mouse hypothalamus mHypoE-N1 cells. Moreover, filbertone effectively countered neuroinflammation and reversed the decline in neurotrophic factors and Nrf2 activation induced by a high-fat diet (HFD) in neurodegeneration models. The neuroprotective effects of filbertone were further validated in models of neurotoxicity induced by palmitic acid (PA) and the neurotoxin MPTP/MPP+, where it was observed to counteract PA and MPTP/MPP+-induced decreases in cell viability and neuroinflammation, primarily through the activation of Nrf2 and the subsequent upregulation of BDNF and heme oxygenase-1 expression. Nrf2 deficiency negated the neuroprotective effects of filbertone in MPTP-treated mice. Consequently, our finding suggests that filbertone is a novel therapeutic agent for neurodegenerative diseases, enhancing neuronal resilience through the Nrf2 signaling pathway and upregulation of neurotrophic factors.Graphical s

Synthetic conduits efficacy in neural repair: a comparative study of dip-coated polycaprolactone and electrospun polycaprolactone/polyurethane conduits.

Objectives.Peripheral nerve injuries (PNI) represent the most common type of nervous system injuries, resulting in 5 million injuries per year. Current gold standard, autografts, still carry several limitations, including the inappropriate type, size, and function matches in grafted nerves, lack of autologous donor sites, neuroma formation, and secondary surgery incisions. Polymeric nerve conduits, also known as nerve guides, can help overcome the aforementioned issues that limit nerve recovery and regeneration by reducing tissue fibrosis, misdirection of regenerating axons, and the inability to maintain long- distance axonal growth. Polymer-based double-walled microspheres (DWMSs) are designed to locally and in a sustainable fashion deliver bioactive agents. Lysozyme is a natural antimicrobial protein that shares similar physical and chemical properties to glial cell line-derived neurotrophic factor, making it an ideal surrogate molecule to evaluate the release kinetics of encapsulated bioagent from polymeric biodegradable microspheres embedded in polycaprolactone and polycaprolactone/polyurethane blend nerve conduits.Approach.Lysozyme was encapsulated in poly(lactic-co-glycolic acid)/poly(L-lactide) DWMSs fabricated through a modified water-oil-water emulsion solvent evaporation method. Lysozyme-loaded DWMS were further embedded in PCL and PCL-PU based nerve guides constructed via polymer dip-coating and electrospinning method respectively. Lysozyme DWMS and nerve guides were imaged using scanning electron microscopy (SEM). Released lysozyme concentration was determined by using a colorimetric micro-BCA protein assay and spectrophotometric quantitation. Tensile and suture pull-out tests were utilized to evaluate the mechanical properties of both dip-coated and electrospun nerve guides, embedded and free of lysozyme DWMS.Main results.The study revealed significant distinctions in the lysozyme release profiles, and mechanical properties of the manufactured polymer nerve guides. Both PCL dip-coated and PCL/PU electrospun DWMS-embedded nerve guides revealed biphasic protein release profiles. PCL/PU electrospun and PCL dip-coated nerve guides released 16% and 29% of the total protein concentration within 72 h, plateauing at week 16 and week 8, respectively. SEM analysis of the nerve guides confirmed the homogeneity and integrity of the polymer nerve guides' structures. The electrospun guides were found to be more flexible with a higher extension under stress bending, while the dip-coated PCL nerve guides displayed more rigid behavior.Significance.This study provides useful insights on how to optimize nerve guide design and fabrication to enhance recovery progress of PNI.

Impaired Basal Forebrain Cholinergic Neuron GDNF Signaling Contributes to Perioperative Sleep Deprivation-Induced Chronicity of Postsurgical Pain in Mice Through Regulating Cholinergic Neuronal Activity, Apoptosis, and Autophagy.

This study investigated the roles of lateral basal forebrain glial cell line-derived neurotrophic factor (GDNF) signaling and cholinergic neuron activity, apoptosis, and autophagy dysfunction in sleep deprivation-induced increased risk of chronic postsurgical pain (CPSP) in mice. Sleep deprivation (6 h per day from -1 to 3 days postoperatively) was administered to mice receiving skin/muscle incision and retraction (SMIR) to determine whether perioperative sleep deprivation induces mechanical and thermal pain hypersensitivity, increases the risk of chronic pain, and causes changes of basal forebrain neurons activity (c-Fos immunostaining), apoptosis (cleaved Caspase-3 expression), autophagy (LC3 and p62 expression) and GDNF expression. Adeno-associated virus (AAV)-GDNF was microinjected into the basal forebrain to see whether increased GDNF expression could reverse sleep deprivation-induced changes in pain duration and cholinergic neuron apoptosis and autophagy. Cholinergic neurons were further depleted by mu p75-SAP to examine whether the pain-prolonging effects of sleep deprivation still exist. Perioperative sleep deprivation enhanced pain sensation and prolonged pain duration in SMIR mice, which was accompanied by decreased cholinergic neuron activity and GDNF expression, increased apoptosis, and autophagy dysfunction in the substantia innominata (SI), magnocellular preoptic nucleus (MCPO), and horizontal diagonal band Broca (HDB) (hereafter lateral basal forebrain). Normalizing cholinergic neuron GDNF expression by AAV-GDNF in the lateral basal forebrain inhibited apoptosis and autophagy dysfunction and mitigated sleep deprivation-induced pain maintenance. Mice with selective lesion of lateral basal forebrain cholinergic neurons were resistant to the pain-enhancing and prolonging effects of sleep deprivation and the pain-alleviating effects of AAV-GDNF therapy. Perioperative sleep deprivation promotes chronicity of postsurgical pain possibly through decreasing basal forebrain GDNF signaling and causing cholinergic neuronal apoptosis and autophagy dysfunction.

Targeting the GDF15 Signalling for Obesity Treatment: Recent Advances and Emerging Challenges.

The growth differentiation factor 15 (GDF15)-glial cell-derived neurotrophic factor family receptor alpha-like (GFRAL) pathway plays a crucial role in the regulation of metabolism, appetite and body weight control. Obesity is an increasingly prevalent chronic disease worldwide, necessitating effective treatment strategies. Recent preclinical and clinical studies have highlighted that targeting the GDF15-GFRAL signalling pathway is a promising approach for treating obesity, particularly because it has minimal impact on skeletal muscle mass, which is essential to preserve during weight loss. Given its distinctive mechanisms, the GDF15-GFRAL axis represents an attractive target for addressing various metabolic disorders, especially obesity. In this review, we will explore how the GDF15-GFRAL axis is regulated, its distribution in the body and its role in the regulation of metabolism, appetite and obesity. Additionally, we will discuss recent advances and potential challenges in targeting the GDF15-GFRAL axis for obesity treatment.

Oligodendrocyte Progenitor Cell Transplantation Reduces White Matter Injury in a Fetal Goat Model.

Preterm white matter injury (PWMI) is the most common type of brain injury in preterm infants, in which, oligodendrocyte progenitor cells (OPCs) are predominantly damaged. In this study, human OPCs (hOPCs) were administered to a fetal goat model of PWMI to examine the differentiation potential and therapeutic effects of the cells on PWMI. Preterm goat fetuses were subjected to hypoxic-ischemia (HI) via intermittent umbilical cord occlusion (5 min × 5). Twenty million hOPCs were administered via a nasal catheter 12 h after an HI insult, and brain tissues were collected 14 or 21 days after the HI insult. Myelin basic protein (MBP) and myelin-associated glycoprotein (MAG) were detected by immunofluorescence and western blotting techniques. The percentage of myelinated nerve fibers and g-ratio were examined using transmission electron microscopy. Inflammatory cells were detected by immunohistochemistry. Inflammatory and neurotrophic factors were measured using enzyme-linked immunosorbent assay. Our results showed that intermittent umbilical cord occlusion induced PWMI in fetal goats. Transplanted hOPCs can survive in periventricular and subcortical white matter. Further, transplanted hOPCs expressed markers of mature oligodendrocytes (MBP and MAG) and few cells expressed markers of preoligodendrocytes (NG2 and A2B5), suggesting that these cells can differentiate into mature oligodendrocytes in the brain. In addition, hOPCs administration increased MBP and MAG levels, percentage of myelinated nerve fibers, and thickness of the myelin sheath, indicating a reduction in PWMI. Furthermore, hOPCs did not increase the inflammatory response after HI. Interestingly, hOPC administration decreased tumor necrosis factor-alpha and increased glial-derived neurotrophic factor and brain-derived neurotrophic factor levels after HI, suggesting that additional mechanisms mediate the inflammatory microenvironment and neuroprotective effects. Exogenous hOPCs can differentiate into mature oligodendrocytes in fetal goats and alleviate HI-induced PWMI. Transplantation of hOPCs is a promising strategy for treating PWMI.

Diversity of Microglia-Derived Molecules with Neurotrophic Properties That Support Neurons in the Central Nervous System and Other Tissues.

Microglia, the brain immune cells, support neurons by producing several established neurotrophic molecules including glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF). Modern analytical techniques have identified numerous phenotypic states of microglia, each associated with the secretion of a diverse set of substances, which likely include not only canonical neurotrophic factors but also other less-studied molecules that can interact with neurons and provide trophic support. In this review, we consider the following eight such candidate cytokines: oncostatin M (OSM), leukemia inhibitory factor (LIF), activin A, colony-stimulating factor (CSF)-1, interleukin (IL)-34, growth/differentiation factor (GDF)-15, fibroblast growth factor (FGF)-2, and insulin-like growth factor (IGF)-2. The available literature provides sufficient evidence demonstrating murine cells produce these cytokines and that they exhibit neurotrophic activity in at least one neuronal model. Several distinct types of neurotrophic activity are identified that only partially overlap among the cytokines considered, reflecting either their distinct intrinsic properties or lack of comprehensive studies covering the full spectrum of neurotrophic effects. The scarcity of human-specific studies is another significant knowledge gap revealed by this review. Further studies on these potential microglia-derived neurotrophic factors are warranted since they may be used as targeted treatments for diverse neurological disorders.

Neuroprotective Effect of Maresin-1 in Rotenone-Induced Parkinson’s Disease in Rats: The Putative Role of the JAK/STAT Pathway

Exposure to rotenone results in similar pathophysiological features as Parkinson’s disease. Inflammation and oxidative stress are essential to PD pathogenesis. Maresin-1 has potent anti-inflammatory properties and promotes the regression of inflammation function. The current study aimed to evaluate the protective effects of Maresin-1 (MaR1) in rotenone (ROT)-induced PD and whether this protective role is associated with the initiation of the Janus kinase (JAK)-signal transducers and activator of transcription (STAT) signaling pathway. Thirty male Wister rats were classified into control, ROT-treated, and ROT + MaR1-treated groups. Rats underwent rotarod, open field, grip strength, and stepping tests as part of their motor behavioral evaluation. Serum glial cell-derived neurotrophic factor (GDNF) and striatal dopamine, acetylcholine, malondialdehyde (MDA), reduced glutathione (GSH), TNF-α, IL-6, and IL-1β were evaluated. Expression of JAK1 and STAT3 genes was assessed in striatum. Then, the tissue was subjected to histological and immunohistochemical evaluation for caspase-3, GFAP, and NF-kB. The administrated group with rotenone showed significant motor behavioral impairment. This was accompanied by reduced levels of GDNF and dopamine and increased levels of acetylcholine, as well as augmented oxidative stress and inflammatory biomarkers and reduced antioxidant activity. Inflammatory pathways (JAK1/STAT3, caspase-3, and NF-kB) were upregulated. Histopathological changes and upregulation in GFAP immunopositive reaction were observed. Remarkably, MaR1 treatment effectively alleviated behavior, histopathological changes, and biochemical alterations induced by ROT. MaR1 exerts protective effects against ROT-induced PD by its anti-inflammatory, antiapoptotic, and antioxidant properties. MaR1 mechanisms of action may involve modulation of pathways such as JAK/STAT.

Astrocyte Dysfunction Reflected in Ischemia-Induced Astrocyte-Derived Extracellular Vesicles: A Pilot Study on Acute Ischemic Stroke Patients.

Extracellular vesicles (EVs) secreted by astrocytes (ADEVs) mediate numerous biological processes, providing insights into damage, repair, and protection following ischemic stroke (IS). This pilot study aimed to broaden the current knowledge on the astrocyte response to ischemia by dynamically assessing the aquaporin-4 (AQP4) and glial cell line-derived neurotrophic factor (GDNF) as cargo proteins of these vesicles in eighteen acute IS patients and nine controls. EV proteins were detected by Western blotting and followed 24 h (D1), 7 days (D7), and one month (M1) after symptoms onset. The post-ischemic ADEV AQP4 and GDNF levels were higher at D1 compared to the control group (p = 0.006 and p = 0.023). Significant differences were observed in ADEV AQP4 during the three evaluated time points (n = 12, p = 0.013) and between D1 and D7 (z = 2.858, p = 0.012), but not in EV GDNF. There was a positive relationship between the severity of stroke at D1 according to the National Institutes of Health Stroke Scale, and ADEV AQP4 at D1 (r = 0.50, p = 0.031), as well as ADEV GDNF at D1 and D7 (r = 0.49, p = 0.035 and r = 0.53, p = 0.021, respectively). The release of EVs with distinct protein profiles can be an attractive platform for the development of biomarkers in IS.

Neuroprotective and inflammatory biomarkers in pediatric drug-resistant epilepsy: Interplay between GDNF, IL-1β and vitamin D 25-OH.

Drug-resistant epilepsy in pediatric patients is associated with neuroinflammation and neurodegeneration. Vitamin D 25-OH exerts neuroprotective effects, while glial cell line- derived neurotrophic factor (GDNF) and the proinflammatory cytokine interleukin-1β (IL-1β) are implicated in the mechanisms of neuroinflammation and epileptogenesis. The aim of this study was to investigate the relationship between vitamin D 25-OH, IL-1β, and GDNF levels with seizure severity and frequency in children with drug-resistant epilepsy. A cross-sectional study was conducted at Adam Malik Hospital, Medan, Indonesia, among children with drug-resistant epilepsy. Vitamin D 25-OH, IL-1β and GDNF levels were measured using enzyme-linked immunosorbent assay (ELISA). Epilepsy severity was assessed using the Hague Seizure Severity Scale (HASS), while seizure frequency was assessed using the Global Assessment of Severity of Epilepsy (GASE). The present study identified a significant correlation between GDNF levels and epilepsy severity, as measured by the HASS score (r=0.318; p=0.006). However, no significant correlation was observed between vitamin D 25-OH or IL-1β levels and epilepsy severity or seizure frequency (p>0.05). IL-1β levels correlated significantly with GDNF levels (r=0.525; p=0.001), but IL-1β did not directly correlate with seizure frequency or epilepsy severity. In conclusion, GDNF levels significantly correlated with epilepsy severity, suggesting that GDNF may serve as a potential biomarker for assessing epilepsy severity. However, further studies investigating the role of GDNF as a potential neurotrophic factor in the pathophysiology of epilepsy and its possible application as a therapeutic target are important.