Potential Therapeutic Approach using Aromatic l-amino Acid Decarboxylase and Glial-derived Neurotrophic Factor Therapy Targeting Putamen in Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative illness characterized by specific loss of dopaminergic neurons, resulting in impaired motor movement. Its prevalence is twice as compared to the previous 25 years and affects more than 10 million individuals. Lack of treatment still uses levodopa and other options as disease management measures. Treatment shifts to gene therapy (GT), which utilizes direct delivery of specific genes at the targeted area. Therefore, the use of aromatic L-amino acid decarboxylase (AADC) and glial-derived neurotrophic factor (GDNF) therapy achieves an effective control to treat PD. Patients diagnosed with PD may experience improved therapeutic outcomes by reducing the frequency of drug administration while utilizing provasin and AADC as dopaminergic protective therapy. Enhancing the enzymatic activity of tyrosine hydroxylase (TH), glucocorticoid hormone (GCH), and AADC in the striatum would be useful for external L-DOPA to restore the dopamine (DA) level. Increased expression of glutamic acid decarboxylase (GAD) in the subthalamic nucleus (STN) may also be beneficial in PD. Targeting GDNF therapy specifically to the putaminal region is clinically sound and beneficial in protecting the dopaminergic neurons. Furthermore, preclinical and clinical studies supported the role of GDNF in exhibiting its neuroprotective effect in neurological disorders. Another Ret receptor, which belongs to the tyrosine kinase family, is expressed in dopaminergic neurons and sounds to play a vital role in inhibiting the advancement of PD. GDNF binding on those receptors results in the formation of a receptor-ligand complex. On the other hand, venous delivery of recombinant GDNF by liposome-based and encapsulated cellular approaches enables the secure and effective distribution of neurotrophic factors into the putamen and parenchyma. The current review emphasized the rate of GT target GDNF and AADC therapy, along with the corresponding empirical evidence.

Unraveling the role of glial cell line-derived neurotrophic factor in the treatment of Parkinson's disease.

Parkinson's disease is the second most common neurodegenerative condition with its prevalence projected to 8.9 million individuals globally in the year 2019. Parkinson's disease affects both motor and certain non-motor functions of an individual. Numerous research has focused on the neuroprotective effect of the glial cell line-derived neurotrophic factor (GDNF) in Parkinson's disease. Discovered in 1993, GDNF is a neurotrophic factor identified from the glial cells which was found to have selective effects on promoting survival and regeneration of certain populations of neurons including the dopaminergic nigrostriatal pathway. Given this property, recent studies have focused on the exogenous administration of GDNF for relieving Parkinson's disease-related symptoms both at a pre-clinical and a clinical level. This review will focus on enumerating the molecular connection between Parkinson's disease and GDNF and shed light on all the available drug delivery approaches to facilitate the selective delivery of GDNF into the brain paving the way as a potential therapeutic candidate for Parkinson's disease in the future.

Modulating Effects of Zingiberaceae Phenolic Compounds on Neurotrophic Factors and Their Potential as Neuroprotectants in Brain Disorders and Age-Associated Neurodegenerative Disorders: A Review.

The Zingiberaceae family possess various phenolic compounds that have significant systemic bioactivities in the brain, including in age-related neurodegenerative diseases. Neurotrophins are growth factors that protect neurons from oxidative stress, and dysregulation of the neurotrophic system may result in neurocognitive disease. Phenolic compounds from the Zingiberaceae family have been used in traditional and complementary medicine (TCM) to improve cognitive functions. These compounds may affect the expression of neurotrophic agents, but their underlying molecular mechanisms require further investigation. Therefore, the goal of this review is to determine the expression and functional roles of phenolic compounds from the Zingiberaceae family in brain disorders and age-related neurodegenerative disorders. While previous studies have proposed various mechanisms for the neuroprotective activity of these compounds, their precise mechanism of action remains complex and poorly understood. Despite some promising findings, there are still shortcomings in the therapeutic use of these herbs, and current interventions involving the Zingiberaceae family appear to be clinically insufficient. This article aims to summarize recent discoveries of phenolic compounds from several Zingiberaceae family members and their use as neuroprotectants and provide the first review of evidence-linked neuroprotective activity of bioactive ingredients from prominent members of the Zingiberaceae family.

High expression of the RET receptor tyrosine kinase and its ligand GDNF identifies a high-risk subset of estrogen receptor positive breast cancer.

PURPOSE: Resistance to endocrine therapy is the primary cause of treatment failure and death in patients with ER-positive (ER +)/luminal breast cancer. Expression and activation of the RET receptor tyrosine kinase may be driving poor outcomes. We aim to identify high-risk patients and druggable pathways for biomarker-based clinical trials. METHODS: We obtained batch-normalized mRNA expression data from Breast Invasive Carcinoma-The Cancer Genome Atlas, PanCancer Atlas (BRCA-TCGA). To determine clinically significant cutoffs for RET expression, patients were grouped at different thresholds for Kaplan-Meier plotting. Differential gene expression (DGE) analysis and enrichment for gene sets was performed. transcriptomic dataset of antiestrogen-treated ER + tumors stratified by clinical response was then analyzed. RESULTS: High RET expression was associated with worse outcomes in patients with ER + tumors, and stratification was enhanced by incorporating GDNF expression. High RET/GDNF patients had significantly lower overall survival (HR = 2.04, p = 0.012), progression-free survival (HR = 2.87, p < 0.001), disease-free survival (HR = 2.67, p < 0.001), and disease-specific survival (HR = 3.53, p < 0.001) than all other ER + patients. High RET/GDNF tumors were enriched for estrogen-independent signaling and targetable pathways including NTRK, PI3K, and KRAS. Tumors with adaptive resistance to endocrine therapy were enriched for gene expression signatures of high RET/GDNF primary tumors. CONCLUSION: Expression and activation of the RET receptor tyrosine kinase may be driving poor outcomes in some patients with ER + breast cancer. ER + patients above the 75th percentile may benefit from clinical trials with tyrosine kinase inhibitors.

Biodegradable Nerve Guide with Glial Cell Line-Derived Neurotrophic Factor Improves Recovery After Facial Nerve Injury in Rats.

Background: Bioengineered nerve guides with glial cell line-derived neurotrophic factor (GDNF) support recovery after facial nerve injury by acting as regenerative scaffolds. Objective: To compare functional, electrophysiological, and histological outcomes after repair of rat facial nerve transection in control, empty nerve guide, and nerve guide with GDNF conditions. Methods: Rats underwent transection and primary repair of the buccal branch of the facial nerve and were divided into (1) transection and repair only, (2) transection and repair augmented with empty guide, (3) transection and repair augmented with GDNF-guide groups. Weekly measurements of the whisking movements were recorded. At 12 weeks, compound muscle action potentials (CMAPs) at the whisker pad were assessed, and samples were collected for histomorphometric analysis. Results: Rats in GDNF-guide group displayed the earliest peak in normalized whisking amplitude. CMAPs were significantly higher after GDNF-guide placement. Mean fiber surface area of the target muscle, axonal count of the injured branch, and the number of Schwann cells were highest with GDNF guides. Conclusion: The biodegradable nerve guide containing double-walled GDNF microspheres enhanced recovery after facial nerve transection and primary repair.

Effect of Growth Hormone Treatment on the Concentration of Selected Metabolic Markers in Girls With Turner Syndrome.

Background: As Turner syndrome (TS) predisposes to obesity and metabolic disorders, and their complications, such as cardiovascular diseases, are the main causes of shortened life expectancy in patients with TS, new metabolic markers that could serve as early predictors of dysmetabolic state are sought. Objective: Assessment of MMP-1 (matrix metalloproteinase-1), MMP-2 (matrix metalloproteinase-2), MMP-9 (matrix metallopeptidase-9), BDNF (brain-derived neurotrophic factor), GDNF (glial cell line-derived neurotrophic factor), and VEGF (vascular endothelial growth factor) before the onset of growth hormone (GH) therapy and then during GH treatment as well as markers assessment during GH medication in girls with TS to establish marker stability and repeatability, and the impact of GH on markers concentration. Method: The concentrations of circulating MMP-1, MMP-2, MMP-9, BDNF, GDNF, and VEGF were measured in nine girls with TS before the onset of GH therapy and then after at least 3 months of treatment period. Subsequently, markers concentration was determined in 17 girls during GH medication, with the first determination after at least a 3-month treatment period. The patients' clinical and biochemical phenotypes were determined by weight, height, BMI, total cholesterol, HDL cholesterol, triglycerides, and glucose concentration. Results: Comparison of markers concentration revealed a significantly higher concentration of MMP-2 in patients undergoing GH treatment (132.1 ± 42.05) than before the onset of therapy (105.0 ± 45.5, p=0.045). The values of the first measurement of VEGF in girls with TS undergoing GH therapy were significantly higher than those during the second measurement (30.9 ± 33.4 vs. 12.5 ± 11.7, p=0.029). There were no statistically significant differences between the measurements of the remaining markers concentration at any stage of the analysis. Conclusion: Increase in MMP-2 concentration is visible during GH therapy in comparison to the pre-GH period in girls with TS which demands confirmation in subsequent tests. The role of VEGF requires further studies in the context of carbohydrate-lipid disturbances in girls with TS and its association with GH treatment.

Glial cell line-derived neurotrophic factor contributes to alcoholic-induced liver injury by regulating the NF-κB pathway.

BACKGROUND: Alcoholic liver disease (ALD) is associated with high morbidity and mortality worldwide. The pathogenesis of ALD is not completely understood. Although accumulating evidence suggests an important role of glial cell line-derived neurotrophic factor (GDNF) in several diseases, there are no data concerning its role in ALD. This study compared patients with ALD with control subjects and used a mouse model and a cell culture model to investigate the function of GDNF in ALD and its mechanism of action in hepatocyte injury. METHODS: Serum levels of GDNF were measured in 25 patients with ALD and 25 healthy control subjects. A 4-week Lieber-DeCarli ethanol (EtOH) liquid diet combined with the Gao-Binge model was used in the mouse study. Mouse primary hepatocytes and Huh-7 cells were used for cell experiments. The parameters of liver injury, inflammatory cytokines, and lipid metabolism were measured. RESULTS: Patients with alcoholic hepatitis had higher serum GDNF than control subjects. Expression of GDNF mRNA and protein was markedly increased in mice in the chronic-plus-binge ALD mouse model. The level of GDNF mRNA was upregulated in primary hepatic stellate cells isolated from ethanol-fed mouse liver. Ethanol induced GDNF expression in LX2 cells. The levels of inflammatory cytokines (tumor necrosis factor α, interleukin 1ß, and monocyte chemotactic protein 1) were significantly increased after GDNF stimulation in primary hepatocytes and Huh-7 cells. After GDNF stimulation, levels of both p-AKT and p-NF-κB were significantly increased in primary hepatocytes and Huh-7 cells. The NF-κB activity induced by GDNF was significantly decreased by an NF-κB inhibitor, which limited hepatocyte injury and inflammation. CONCLUSIONS: The concentration of GDNF is increased in the circulation of ALD patients. GDNF promotes alcohol-induced liver injury and inflammation via the activation of NF-κB, which mediates hepatocyte injury and inflammatory cytokine expression. Based on these findings, GDNF is a potential therapeutic target for preventing or ameliorating liver injury in ALD.

Edaravone activates the GDNF/RET neurotrophic signaling pathway and protects mRNA-induced motor neurons from iPS cells.

BACKGROUND: Spinal cord motor neurons (MNs) from human iPS cells (iPSCs) have wide applications in disease modeling and therapeutic development for amyotrophic lateral sclerosis (ALS) and other MN-associated neurodegenerative diseases. We need highly efficient MN differentiation strategies for generating iPSC-derived disease models that closely recapitulate the genetic and phenotypic complexity of ALS. An important application of these models is to understand molecular mechanisms of action of FDA-approved ALS drugs that only show modest clinical efficacy. Novel mechanistic insights will help us design optimal therapeutic strategies together with predictive biomarkers to achieve better efficacy. METHODS: We induce efficient MN differentiation from iPSCs in 4 days using synthetic mRNAs coding two transcription factors (Ngn2 and Olig2) with phosphosite modification. These MNs after extensive characterization were applied in electrophysiological and neurotoxicity assays as well as transcriptomic analysis, to study the neuroprotective effect and molecular mechanisms of edaravone, an FDA-approved drug for ALS, for improving its clinical efficacy. RESULTS: We generate highly pure and functional mRNA-induced MNs (miMNs) from control and ALS iPSCs, as well as embryonic stem cells. Edaravone alleviates H2O2-induced neurotoxicity and electrophysiological dysfunction in miMNs, demonstrating its neuroprotective effect that was also found in the glutamate-induced miMN neurotoxicity model. Guided by the transcriptomic analysis, we show a previously unrecognized effect of edaravone to induce the GDNF receptor RET and the GDNF/RET neurotrophic signaling in vitro and in vivo, suggesting a clinically translatable strategy to activate this key neuroprotective signaling. Notably, edaravone can replace required neurotrophic factors (BDNF and GDNF) to support long-term miMN survival and maturation, further supporting the neurotrophic function of edaravone-activated signaling. Furthermore, we show that edaravone and GDNF combined treatment more effectively protects miMNs from H2O2-induced neurotoxicity than single treatment, suggesting a potential combination strategy for ALS treatment. CONCLUSIONS: This study provides methodology to facilitate iPSC differentiation and disease modeling. Our discoveries will facilitate the development of optimal edaravone-based therapies for ALS and potentially other neurodegenerative diseases.

Cerebral dopamine neurotrophic factor protects and repairs dopamine neurons by novel mechanism.

Midbrain dopamine neurons deteriorate in Parkinson's disease (PD) that is a progressive neurodegenerative movement disorder. No cure is available that would stop the dopaminergic decline or restore function of injured neurons in PD. Neurotrophic factors (NTFs), e.g., glial cell line-derived neurotrophic factor (GDNF) are small, secreted proteins that promote neuron survival during mammalian development and regulate adult neuronal plasticity, and they are studied as potential therapeutic agents for the treatment of neurodegenerative diseases. However, results from clinical trials of GDNF and related NTF neurturin (NRTN) in PD have been modest so far. In this review, we focus on cerebral dopamine neurotrophic factor (CDNF), an unconventional neurotrophic protein. CDNF delivered to the brain parenchyma protects and restores dopamine neurons in animal models of PD. In a recent Phase I-II clinical trial CDNF was found safe and well tolerated. CDNF deletion in mice led to age-dependent functional changes in the brain dopaminergic system and loss of enteric neurons resulting in slower gastrointestinal motility. These defects in Cdnf-/- mice intriguingly resemble deficiencies observed in early stage PD. Different from classical NTFs, CDNF can function both as an extracellular trophic factor and as an intracellular, endoplasmic reticulum (ER) luminal protein that protects neurons and other cell types against ER stress. Similarly to the homologous mesencephalic astrocyte-derived neurotrophic factor (MANF), CDNF is able to regulate ER stress-induced unfolded protein response (UPR) signaling and promote protein homeostasis in the ER. Since ER stress is thought to be one of the pathophysiological mechanisms contributing to the dopaminergic degeneration in PD, CDNF, and its small-molecule derivatives that are under development may provide useful tools for experimental medicine and future therapies for the treatment of PD and other neurodegenerative protein-misfolding diseases.

Mechanistic Insight from Preclinical Models of Parkinson's Disease Could Help Redirect Clinical Trial Efforts in GDNF Therapy.

Parkinson's disease (PD) is characterized by four pathognomonic hallmarks: (1) motor and non-motor deficits; (2) neuroinflammation and oxidative stress; (3) pathological aggregates of the α-synuclein (α-syn) protein; (4) neurodegeneration of the nigrostriatal system. Recent evidence sustains that the aggregation of pathological α-syn occurs in the early stages of the disease, becoming the first trigger of neuroinflammation and subsequent neurodegeneration. Thus, a therapeutic line aims at striking back α-synucleinopathy and neuroinflammation to impede neurodegeneration. Another therapeutic line is restoring the compromised dopaminergic system using neurotrophic factors, particularly the glial cell-derived neurotrophic factor (GDNF). Preclinical studies with GDNF have provided encouraging results but often lack evaluation of anti-α-syn and anti-inflammatory effects. In contrast, clinical trials have yielded imprecise results and have reported the emergence of severe side effects. Here, we analyze the discrepancy between preclinical and clinical outcomes, review the mechanisms of the aggregation of pathological α-syn, including neuroinflammation, and evaluate the neurorestorative properties of GDNF, emphasizing its anti-α-syn and anti-inflammatory effects in preclinical and clinical trials.

Neuroinductive properties of mGDNF depend on the producer, E. Coli or human cells.

The glial cell line-derived neurotrophic factor (GDNF) is involved in the survival of dopaminergic neurons. Besides, GDNF can also induce axonal growth and creation of new functional synapses. GDNF potential is promising for translation to treat diseases associated with neuronal death: neurodegenerative disorders, ischemic stroke, and cerebral or spinal cord damages. Unproductive clinical trials of GDNF for Parkinson's disease treatment have induced to study this failure. A reason could be due to irrelevant producer cells that cannot perform the required post-translational modifications. The biological activity of recombinant mGDNF produced by E. coli have been compared with mGDNF produced by human cells HEK293. mGDNF variants were tested with PC12 cells, rat embryonic spinal ganglion cells, and SH-SY5Y human neuroblastoma cells in vitro as well as with a mouse model of the Parkinson's disease in vivo. Both in vitro and in vivo the best neuro-inductive ability belongs to mGDNF produced by HEK293 cells. Keywords: GDNF, neural differentiation, bacterial and mammalian expression systems, cell cultures, model of Parkinson's disease.

Combination of Drugs and Cell Transplantation: More Beneficial Stem Cell-Based Regenerative Therapies Targeting Neurological Disorders.

Cell transplantation therapy using pluripotent/multipotent stem cells has gained attention as a novel therapeutic strategy for treating neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, ischemic stroke, and spinal cord injury. To fully realize the potential of cell transplantation therapy, new therapeutic options that increase cell engraftments must be developed, either through modifications to the grafted cells themselves or through changes in the microenvironment surrounding the grafted region. Together these developments could potentially restore lost neuronal function by better supporting grafted cells. In addition, drug administration can improve the outcome of cell transplantation therapy through better accessibility and delivery to the target region following cell transplantation. Here we introduce examples of drug repurposing approaches for more successful transplantation therapies based on preclinical experiments with clinically approved drugs. Drug repurposing is an advantageous drug development strategy because drugs that have already been clinically approved can be repurposed to treat other diseases faster and at lower cost. Therefore, drug repurposing is a reasonable approach to enhance the outcomes of cell transplantation therapies for neurological diseases. Ideal repurposing candidates would result in more efficient cell transplantation therapies and provide a new and beneficial therapeutic combination.

Low-Intensity Pulsed Ultrasound Enhances Neurotrophic Factors and Alleviates Neuroinflammation in a Rat Model of Parkinson's Disease.

Low-intensity pulsed ultrasound (LIPUS) has also been reported to improve behavioral functions in Parkinson's disease (PD) animal models; however, the effect of LIPUS stimulation on the neurotrophic factors and neuroinflammation has not yet been addressed. PD rat model was built by injection of 6-hydroxydopamine (6-OHDA) in 2 sites in the right striatum. The levels of neurotrophic factors and lipocalin-2 (LCN2)-induced neuroinflammation were quantified using a western blot. Rotational test and cylinder test were conducted biweekly for 8 weeks. When the 6-OHDA + LIPUS and 6-OHDA groups were compared, the locomotor function of the 6-OHDA + LIPUS rats was significantly improved. After LIPUS stimulation, the tyrosine hydroxylase staining density was significantly increased in the striatum and substantia nigra pars compacta (SNpc) of lesioned rats. Unilateral LIPUS stimulation did not increase brain-derived neurotrophic factor in the striatum and SNpc of lesioned rats. In contrast, unilateral LIPUS stimulation increased glial cell line-derived neurotrophic factor (GDNF) protein 1.98-fold unilaterally in the SNpc. Additionally, LCN2-induced neuroinflammation can be attenuated following LIPUS stimulation. Our data indicated that LIPUS stimulation may be a potential therapeutic tool against PD via enhancement of GDNF level and inhibition of inflammatory responses in the SNpc of the brain.

Safety Assessment of AAV2-hGDNF Administered Via Intracerebral Injection in Rats for Treatment of Parkinson's Disease.

Glial cell line-derived neurotrophic factor (GDNF) is a potent neuroprotective biologic in Parkinson's disease models. Adeno-associated viral vector serotype 2 (AAV2)-human GDNF safety was assessed in rats treated with a single intracerebral dose of vehicle, 6.8 × 108, 6.8 × 109, or 5.2 × 1010 vector genomes (vg)/dose followed by interim sacrifices on day 7, 31, 90, and 376. There were no treatment-related effects observed on food consumption, body weight, hematology, clinical chemistry, coagulation parameters, neurobehavioral parameters, organ weights, or serum GDNF and anti-GDNF antibody levels. Increased serum anti-AAV2 neutralizing antibody titers were observed in the 5.2 × 1010 vg/dose group. Histopathological lesions were observed at the injection site in the 6.8 × 109 vg/dose (day 7) and 5.2 × 1010 vg/dose groups (days 7 and 31) and consisted of gliosis, mononuclear perivascular cuffing, intranuclear inclusion bodies, and/or apoptosis on day 7 and mononuclear perivascular cuffing on day 31. GDNF immunostaining was observed in the injection site in all dose groups through day 376 indicating no detectable impacts of anti-AAV2 neutralizing antibody. There was no evidence of increased expression of calcitonin gene-related peptide or Swann cell hyperplasia in the cervical and lumbar spinal cord or medulla oblongata at the 5.2 × 1010 vg/dose level indicating lack of hyperplastic effects. In conclusion, no systemic toxicity was observed, and the local toxicity observed at the injection site appeared to be reversible demonstrating a promising safety profile of intracerebral AAV2-GDNF delivery. Furthermore, an intracerebral dose of 6.8 × 108 AAV2-GDNF vg/dose was considered to be a no observed adverse effect level in rats.

Epidural Stimulation Combined with Triple Gene Therapy for Spinal Cord Injury Treatment.

The translation of new therapies for spinal cord injury to clinical trials can be facilitated with large animal models close in morpho-physiological scale to humans. Here, we report functional restoration and morphological reorganization after spinal contusion in pigs, following a combined treatment of locomotor training facilitated with epidural electrical stimulation (EES) and cell-mediated triple gene therapy with umbilical cord blood mononuclear cells overexpressing recombinant vascular endothelial growth factor, glial-derived neurotrophic factor, and neural cell adhesion molecule. Preliminary results obtained on a small sample of pigs 2 months after spinal contusion revealed the difference in post-traumatic spinal cord outcomes in control and treated animals. In treated pigs, motor performance was enabled by EES and the corresponding morpho-functional changes in hind limb skeletal muscles were accompanied by the reorganization of the glial cell, the reaction of stress cell, and synaptic proteins. Our data demonstrate effects of combined EES-facilitated motor training and cell-mediated triple gene therapy after spinal contusion in large animals, informing a background for further animal studies and clinical translation.

Intravitreal Co-Administration of GDNF and CNTF Confers Synergistic and Long-Lasting Protection against Injury-Induced Cell Death of Retinal Ganglion Cells in Mice.

We have recently demonstrated that neural stem cell-based intravitreal co-administration of glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) confers profound protection to injured retinal ganglion cells (RGCs) in a mouse optic nerve crush model, resulting in the survival of ~38% RGCs two months after the nerve lesion. Here, we analyzed whether this neuroprotective effect is long-lasting and studied the impact of the pronounced RGC rescue on axonal regeneration. To this aim, we co-injected a GDNF- and a CNTF-overexpressing neural stem cell line into the vitreous cavity of adult mice one day after an optic nerve crush and determined the number of surviving RGCs 4, 6 and 8 months after the lesion. Remarkably, we found no significant decrease in the number of surviving RGCs between the successive analysis time points, indicating that the combined administration of GDNF and CNTF conferred lifelong protection to injured RGCs. While the simultaneous administration of GDNF and CNTF stimulated pronounced intraretinal axon growth when compared to retinas treated with either factor alone, numbers of regenerating axons in the distal optic nerve stumps were similar in animals co-treated with both factors and animals treated with CNTF only.

Gene Therapy in the Management of Parkinson's Disease: Potential of GDNF as a Promising Therapeutic Strategy.

The limitations of conventional treatment therapies in Parkinson's disorder, a common neurodegenerative disorder, lead to the development of an alternative gene therapy approach. Multiple treatment options targeting dopaminergic neuronal regeneration, production of enzymes linked with dopamine synthesis, subthalamic nucleus neurons, regulation of astrocytes and microglial cells and potentiating neurotrophic factors, were established. Viral vector-based dopamine delivery, prodrug approaches, fetal ventral mesencephalon tissue transplantation and dopamine synthesizing enzyme encoding gene delivery are significant therapies evidently supported by numerous trials. The review primarily elaborates on the significant role of glial cell-line derived neurotrophic factor in alleviating motor symptoms and the loss of dopaminergic neurons in Parkinson's disease. Neuroprotective and neuroregenerative effects of GDNF were established via preclinical and clinical study outcomes. The binding of GDNF family ligands with associated receptors leads to the formation of a receptor-ligand complex activating Ret receptor of tyrosine kinase family, which is only expressed in dopaminergic neurons, playing an important role in Parkinson's disease, via its association with the essential protein encoded genes. Furthermore, the review establishes delivery aspects, like ventricular delivery of recombinant GDNF, intraparenchymal and intraputaminal delivery using infusion catheters. The review highlights problems and challenges of GDNF delivery, and essential measures to overcome them, like gene therapy combinations, optimization of delivery vectors, newer targeting devices, motor symptoms curbing focused ultrasound techniques, modifications in patient selection criteria and development of novel delivery strategies based on liposomes and encapsulated cells, to promote safe and effective delivery of neurotrophic factor and establishment of routine treatment therapy for patients.

The impact of N-cadherin-ß-catenin signaling on the analgesic effects of glial cell-derived neurotrophic factor in neuropathic pain.

Long-term neuropathic pain can lead to anxiety, depression, and other issues, which seriously affect patients' quality of life. For this reason, it is important to find effective treatments. Studies have shown that glial cell-derived neurotrophic factor (GDNF) can relieve neuropathic pain. However, its mechanism of action is unknown. Our previous study of GDNF suggested that the N-cadherin-ß-catenin transmembrane signaling system might play a role in GDNF transmembrane signaling. Based on this, the current study aimed to produce a neuropathic pain model to confirm the activation of the N-cadherin-ß-catenin signaling system in the spinal dorsal horn under pain conditions and to study the impact of GDNF intrathecal injection on central sensitization of dorsal horn neurons. The results showed that N-cadherin expression, as well as the expression of membrane-associated ß-catenin, was reduced in the dorsal horn of the spinal cord in the chronic pain model. Intrathecal injection of GDNF could reactivate the N-cadherin-ß-catenin system, improve central sensitization, and relieve pain. Knockdown of N-cadherin or ß-catenin could significantly reduce the analgesic effect of GDNF. These results provide clear experimental evidence that the N-cadherin-ß-catenin signaling system participates in the analgesic effect of GDNF in neuropathic pain and help identify transmembrane and intracellular signal transduction mechanisms associated with GDNF's analgesic effects.

Non-viral nucleic acid delivery to the central nervous system and brain tumors.

Gene therapy is a rapidly emerging remedial route for many serious incurable diseases, such as central nervous system (CNS) diseases. Currently, nucleic acid medicines, including DNAs encoding therapeutic or destructive proteins, small interfering RNAs or microRNAs, have been successfully delivered to the CNS with gene delivery vectors using various routes of administration and have subsequently exhibited remarkable therapeutic efficiency. Among these vectors, non-viral vectors are favorable for delivering genes into the CNS as a result of their many special characteristics, such as low toxicity and pre-existing immunogenicity, high gene loading efficiency and easy surface modification. In this review, we highlight the main types of therapeutic genes that have been applied in the therapy of CNS diseases and then outline non-viral gene delivery vectors.