GDNF Expression Research Articles

Unveiling the Therapeutic Potential of Small Molecule of SVAK-12: A Comprehensive In Silico, In Vitro, and In Vivo Studies on its Neuroprotective Effects and Molecular Interactions in Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder associated with a progressive loss of dopaminergic cells and as of now, there is no established definitive treatment available for this condition. In this study, the focus was on investigating the impact of SVAK-12, a small molecule that can cross the blood-brain barrier and remain stable without structural changes. The effect of SVAK-12 was investigated in vitro on neurotoxicity, in vivo model of Parkinson's Diseases and in silico. Through in vitro and in vivo experiments, as well as molecular docking simulations, it was found that SVAK-12 (375 ng.ml) led to increased cell viability, reduced cellular damage, and decreased production of NO and ROS. Additionally, it boosted levels of important neurotrophic factors like BDNF (130.49%) and GDNF (116.38%), potentially aiding in alleviating motor disability and depression. The study also highlighted SVAK-12's potential as a therapeutic candidate for neurological disorders due to its ability to increase tyrosine hydroxylase expression and dopamine levels (4.84 times). While it did not significantly improve motor symptoms in vivo, it did enhance motor asymmetry in the forelimbs and gene expression related to brain regions. Besides, it induced significant BMP-2 gene expression in substantial nigra regions without significant changes in GDNF and Nurr1 gene expression in the striatum expression. The docking of SVAK-12, Levodopa, Amantadine, Biperiden, Selegiline, and Rasagiline to the binding site of GFRα1, sortilin, and TrkB showed that SVAK-12 had greater MolDock score than Selegiline and Amantadine for GFRα1 and greater than amantadine for Sortilin and TrKB. Overall, the study suggests that SVAK-12's neuro-biocompatibility, ability to reduce free radicals, and enhanced neurotrophic factors make it a promising candidate as a neuroprotective drug.

PMMA-induced biofilm promotes Schwann cells migration and proliferation mediated by EGF/Tnc/FN1 to improve sciatic nerve defect

ObjectiveThe purpose of this study is to investigate the role of PMMA-induced biofilm in nerve regeneration compared with silicone-induced biofilm involved in the mechanism. MethodsPMMA or silicon rods were placed next to the sciatic nerve to induce a biological membrane which was assayed by PCR, Western blot, immunohistochemistry, immunofluorescence and proteomics. A 10 mm sciatic nerve gaps were repaired with the autologous nerve wrapped in an induced biological membrane. The repair effects were observed through general observation, functional evaluation of nerve regeneration, ultrasound examination, neural electrophysiology, the wet weight ratio of bilateral pretibial muscle and histological evaluation. Cell proliferation and migration of Schwann cells co-cultured with EGF-treated fibroblasts combined with siRNA were investigated. ResultsThe results indicated that expression of GDNF, NGF and VEGF along with neovascularization was similar in the silicone and PMMA group and as the highest at 6 weeks after operation. Nerve injury repair mediated by toluidine blue and S100β/NF200 expression, the sensory and motor function evaluation, ultrasound, target organ muscle wet-weight ratio, percentage of collagen fiber, electromyography and histochemical staining were not different between the two groups and better than blank group. EGF-treated fibroblasts promoted proliferation and migration may be Tnc expression dependently. ConclusionOur study suggested that PMMA similar to silicon induced biofilm may promote autogenous nerve transplantation to repair nerve defects through EGF/Tnc/FN1 to increase Schwann cells proliferation and migration.

Neuroprotective effects of pink lotus oil in kainic acid-induced epilepsy

Excitotoxicity-induced oxidative stress results in neuronal cell death. Pink lotus essential oil (PLO) is a concentrated volatile oil from lotus blossoms widely used in traditional medicine. This study aimed to explore the possible therapeutic effects of PLO and its underlying mechanisms on kainic acid (KA)-induced oxidative stress and hippocampal cell death in a mouse model of epilepsy. Mice were treated with 100 mg/kg or 200 mg/kg PLO to ameliorate neurodegeneration and seizure-induced behavior induced by KA injection. Pre- and post-treatment of PLO increased antioxidant activities, reduced the seizure score, prevented oxidative stress by increasing GSH and CAT levels, and reduced MDA (malondialdehyde) levels after KA-induced status epilepticus. KA injection created neuronal cell death in the pyramidal layers of CA1 and CA3 subfields of the hippocampus, and affected interneurons in the hilus of the dentate gyrus. PLO treatment notably diminished KA-induced neuronal cell death in these areas through activation of the Akt signaling pathway, increasing reactive astrogliosis, and up-regulation of GDNF expression. Moreover, caspase-3 expression, and microglia activation were significantly decreased in PLO treatments. Taken together, these results suggest that PLO possesses antiepileptic, anti-apoptosic, and neuroprotective effects on KA-induced epileptogenesis indicating that PLO may serve as a dietary supplement option in the treatment of epilepsy or of other neurodegenerative disorders.

Assessment of CRISPRa-mediated gdnf overexpression in an In vitro Parkinson's disease model.

Parkinson's disease (PD) presents a significant challenge in medical science, as current treatments are limited to symptom management and often carry significant side effects. Our study introduces an innovative approach to evaluate the effects of gdnf overexpression mediated by CRISPRa in an in vitro model of Parkinson's disease. The expression of gdnf can have neuroprotective effects, being related to the modulation of neuroinflammation and pathways associated with cell survival, differentiation, and growth. We have developed a targeted delivery system using a magnetite nanostructured vehicle for the efficient transport of genetic material. This system has resulted in a substantial increase, up to 200-fold) in gdnf expression in an In vitro model of Parkinson's disease using a mixed primary culture of astrocytes, neurons, and microglia. The delivery system exhibits significant endosomal escape of more than 56%, crucial for the effective delivery and activation of the genetic material within cells. The increased gdnf expression correlates with a notable reduction in MAO-B complex activity, reaching basal values of 14.8μU/μg of protein, and a reduction in reactive oxygen species. Additionally, there is up to a 34.6% increase in cell viability in an In vitro Parkinson's disease model treated with the neurotoxin MPTP. Our study shows that increasing gdnf expression can remediate some of the cellular symptoms associated with Parkinson's disease in an in vitro model of the disease using a novel nanostructured delivery system.

Impact of early refined nursing program on prognosis of middle-aged and elderly patients with cognitive dysfunction combined with cerebral infarction.

Cerebral infarction is a local or extensive necrosis of brain tissue. Subsequently, the corresponding neurological deficits appear. The incidence of cerebrovascular diseases in China is increasing gradually. After the onset of cerebrovascular disease, the most common sequelae include movement disorders, language disorders, and cognitive dysfunction. To investigate the effect of early refined nursing program on the prognosis of middle-aged and elderly patients with cerebral infarction combined with cognitive dysfunction. A retrospective study was conducted to divide 60 patients with cerebral infarction and cognitive impairment into an experimental group (n = 32) and a control group (n = 28). The experimental group received early intensive care every day, and the control group received daily routine care. The scores of the Mini-Mental State Examination (MMSE) and the Trail Making Test (TMT), as well as the latency and amplitude of the event-related potential P300, were used as main indicators to evaluate changes in cognitive function, and changes in BDNF, TGF-β, and GDNF expression were used as secondary indicators. Both groups experienced notable enhancements in MMSE scores, with the experimental group demonstrating higher scores than the control group (experimental: 28.75 ± 2.31; control: 25.84 ± 2.87). Moreover, reductions in TMT-A and TMT-B scores were observed in both groups (experimental: TMT-A 52.36 ± 6.18, TMT-B 98.47 ± 10.23; control: TMT-A 61.48 ± 7.92, TMT-B 112.63 ± 12.55), with the experimental group displaying lower scores. P300 Latency decreased (experimental: 270.63 ms ± 14.28 ms; control: 285.72 ms ± 16.45 ms), while amplitude increased (experimental: 7.82 μV ± 1.05 μV; control: 6.35 μV ± 0.98 μV) significantly in both groups, with superior outcomes in the experimental cohort. Additionally, the levels of the growth factors BDNF, TGF-β1, and GDNF surged (experimental: BDNF 48.37 ng/mL ± 5.62 ng/mL, TGF-β1 52.14 pg/mL ± 4.28 pg/mL, GDNF 34.76 ng/mL ± 3.89 ng/mL; control: BDNF 42.58 ng/mL ± 4.73 ng/mL, TGF-β1 46.23 pg/mL ± 3.94 pg/mL, GDNF 30.25 ng/mL ± 2.98 ng/mL) in both groups, with higher levels in the experimental group. For middle-aged and elderly patients with cerebral infarction and cognitive dysfunction, early refined nursing can significantly improve their cognitive function and prognosis.

Clusterin attenuates blood-brain barrier damage and cognitive impairment by inhibiting astrocyte aging in mice with sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE) is a severe complication of sepsis, however, its exact mechanism remains unknown. This study aimed to evaluate whether clusterin is essential to the development of SAE during the aging process of astrocytes. In the study, septic mice were established with cecal ligation and puncture (CLP) and lipopolysaccharides were applied to astrocytes in vitro. Evan's blue dye was used in vivo to show blood-brain barrier (BBB) permeability. A morris water maze test was conducted to assess cognitive functions of the mice. Clusterin-knockout mice were used to examine the effect of clusterin on sepsis. The astrocytes were transfected with lentivirus expressing clusterin cDNA for clusterin overexpression or pYr-LV-clusterin small hairpin RNA for clusterin knockdown in vitro . The expression of clusterin, p-p53, p21, GDNF, and iNOS was detected. he CLP mice exhibited a higher clusterin expression in hippocampus tissue, aging astrocytes, lower GDNF expression and higher iNOS expression, accompanied with BBB damage and cognitive deficiency. Following clusterin knockout, this pathological process was further enhanced. In vitro , following lipopolysaccharides treatment, astrocytes exhibited increased clusterin, p-p53, p21, iNOS and decreased GDNF. Following clusterin knockdown, the cells exhibited a further increase in p-p53, p21, and iNOS and decrease in GDNF. Clusterin overexpression, however, helped inhibit astrocytes aging and neuroinflammation evidenced by decreased p-p53, p21, iNOS and increased GDNF. The present study has revealed that clusterin may exert its neuroprotective effect by preventing aging in astrocytes, suppressing the secretion of iNOS and promoting GNDF release.

New method to induce neurotrophin gene expression in human adipose-derived stem cells in vitro.

Rosemary leaf extract, a well-known medicinal plant, can induce neurotrophin gene expression and proliferation in stem cells. Human adipose-derived stem cells (hASCs) with high proliferation and differentiation capacity are easily accessible and can be extracted with the least damage. This study evaluated the effect of rosemary extract (RE) on neurotrophin gene expression at 48 h postinduction in hASCs. hASCs were isolated from healthy female donors, aged 28-35 years, who had undergone abdominal liposuction. Passage-4 stem cells were cultured and treated with different doses of RE (from 30 to 70 µg/ml) containing 40% carnosic acid for 48 h. Reverse transcription-polymerase chain reaction was used to check the expression of neurotrophin genes. The expression of NTF3, NTF4, and nerve growth factor genes in cells treated with 40-60 µg/ml and the expression of GDNF in cells treated with 50-70 µg/ml of RE for 48 h showed a significant increase compared to cells cultured in serum-containing medium. However, different doses of RE showed no effect on brain-derived neurotrophic factor gene expression in the treated cells. RE (50, 60 µg/ml) leads to an increase of neurotrophin gene expression in hASCs as compared to routine cell culture. Hence, this protocol can be used to prepare ideal cell sources for cell therapy.

Poly(rC)-binding protein 1 alleviates neurotoxicity in 6-OHDA-induced SH-SY5Y cells and modulates glial cells in neuroinflammation

BackgroundParkinson's disease (PD) is a debilitating neurodegenerative condition characterized by the loss of dopaminergic neurons and neuroinflammation. Previous research has identified the involvement of Poly (rC)-binding protein 1 (PCBP1) in certain degenerative diseases; however, its specific mechanisms in PD remain incompletely understood. MethodsIn this study, 6-OHDA-induced neurotoxicity in the cell lines SH-SY5Y, BV-2 and HA, was used to evaluate the protective effects of PCBP1. We assessed alterations in BDNF levels in SY5Y cells, changes in GDNF expression in glial cells, as well as variations in HSP70 and NF-κB activation. Additionally, glial cells were used as the in vitro model for neuroinflammation mechanisms. ResultsThe results indicate that the overexpression of PCBP1 significantly enhances cell growth compared to the control plasmid pEGFP/N1 group. Overexpression of PCBP1 leads to a substantial reduction in early apoptosis rates in SH-SY5Y, HA, and BV-2 cells, with statistically significant differences (p < 0.05). Furthermore, the overexpression of PCBP1 in cells results in a marked increase in the expression of HSP70, GDNF, and BDNF, while reducing NF-κB expression. Additionally, in SH-SY5Y, HA, and BV-2 cells overexpressing PCBP1, there is a decrease in the inflammatory factor IL-6 compared to the control plasmid pEGFP/N1 group, while BV-2 cells exhibit a significant increase in the anti-inflammatory factor IL-10. ConclusionOur findings suggest that PCBP1 plays a substantial role in promoting cell growth and modulating the balance of neuroprotective and inflammatory factors. These results offer valuable insights into the potential therapeutic utility of PCBP1 in mitigating neuroinflammation and enhancing neuronal survival in PD.

The Effect of Therapy Regimen on Antitumor Efficacy of the Nanosomal Doxorubicin against Rat Glioblastoma 101.8.

One of the key problems of glioblastoma treatment is the low effectiveness of chemotherapeutic drugs. Incorporation of doxorubicin into PLGA nanoparticles allows increasing the antitumor effect of the cytostatics against experimental rat glioblastoma 101.8. Animal survival, tumor volume, and oncogene expression in tumor cells were compared after early (days 2, 5, and 8 after tumor implantation) and late (days 8, 11, and 14) start of the therapy. At late start, a significant increase in the expression of oncogenes Gdnf, Pdgfra, and Melk and genes determining the development of multidrug resistance Abcb1b and Mgmt was revealed. At early start of therapy, only the expression of oncogenes Gdnf, Pdgfra, and Melk was enhanced. Early start of treatment prolonged the survival time and increased tumor growth inhibition by 141.4 and 95.7%, respectively, in comparison with the untreated group; these differences were not observed in the group with late start of therapy. The results indicate that the time of initiation of therapy is a critical parameter affecting the antitumor efficacy of DOX-PLGA.

The Relationship between Sleep Parameters Measured by Polysomnography and Selected Neurotrophic Factors.

The molecular underpinnings of insufficient sleep remain underexplored, with disruptions in the neurotrophic signaling pathway emerging as a potential explanation. Neurotrophins (NTs), including brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), neurotrophin 4 (NT4), and glial-cell-line-derived growth factor (GDNF), play crucial roles in nerve cell growth and repair. However, their associations with sleep patterns are poorly understood. This study aimed to investigate the relationship between the chosen neurotrophins and objective sleep parameters. The study involved 81 participants subjected to polysomnography (PSG). Blood samples were collected after PSG. The mRNA expression and serum protein concentrations of BDNF, GDNF, NT3, and NT4 were measured using real-time quantitative reverse-transcription PCR (qRT-PCR) or enzyme-linked immunosorbent assay (ELISA) methods, respectively. BDNF and NT3 proteins were negatively correlated with NREM events, while NT4 protein positively correlated with REM events. Electroencephalography power analysis revealed BDNF protein's negative correlation with delta waves during rapid eye movement and non-rapid eye movement sleep. The study highlights associations between neurotrophins and sleep, emphasizing BDNF's role in regulating NREM and REM sleep. The EEG power analysis implicated BDNF in delta wave modulation, shedding light on potential neurotrophic mechanisms underlying sleep effects on cognitive and mood processes.

Retracted: Effects of Pulsed Radiofrequency on Nerve Repair and Expressions of GFAP and GDNF in Rats with Neuropathic Pain.

[This retracts the article DOI: 10.1155/2021/9916978.].

Intravenously engrafted human multilineage-differentiating stress-enduring (Muse) cells rescue erectile function after rat cavernous nerve injury.

To evaluate the effect of intravenous administration of human multilineage-differentiating stress-enduring (Muse) cells on rat postoperative erectile dysfunction (ED) with cavernous nerve (CN) injury without an immunosuppressant. Male Sprague-Dawley rats were randomised into three groups after CN crush injury. Either human-Muse cells, non-Muse mesenchymal stem cells (MSCs) (both 1.0 × 105 cells), or vehicle was infused intravenously at 3 h after CN injury without immunosuppressant. Erectile function was assessed by measuring intracavernous pressure (ICP) and arterial pressure (AP) during pelvic nerve electrostimulation 28 days after surgery. At 48 h and 28 days after intravenous infusion of Muse cells, the homing of Muse cells and non-Muse MSCs was evaluated in the major pelvic ganglion (MPG) after CN injury. In addition, expressions of C-X-C motif chemokine ligand (Cxcl12) and glial cell line-derived neurotrophic factor (Gdnf) in the MPG were examined by real-time polymerase chain reaction. Statistical analyses and comparisons among groups were performed using one-way analysis of variance followed by the Tukey test for parametric data and Kruskal-Wallis test followed by the Dunn-Bonferroni test for non-parametric data. The mean (SEM) ICP/AP values at 28 days were 0.51 (0.02) in the Muse cell group, 0.37 (0.03) in the non-Muse MSC group, and 0.36 (0.04) in the vehicle group, showing a significant positive response in the Muse cell group compared with the non-Muse and vehicle groups (P = 0.013 and P = 0.010, respectively). In the MPG, Muse cells were observed to be engrafted at 48 h and expressed Schwann cell markers S100 (~46%) and glial fibrillary acidic protein (~24%) at 28 days, while non-Muse MSCs were basically not engrafted at 48 h. Higher gene expression of Cxcl12 (P = 0.048) and Gdnf (P = 0.040) was found in the MPG of the Muse group than in the vehicle group 48 h after infusion. Intravenously engrafted human Muse cells recovered rat erectile function after CN injury in a rat model possibly by upregulating Cxcl12 and Gdnf.

Exogenous GDNF promotes peripheral facial nerve regeneration in rats through the PI3K/AKT/mTOR signaling pathway.

Facial nerve regeneration still lacks a well-defined and practical clinical intervention. The survival of central facial motoneuron is a critical component in the successful peripheral facial nerve regeneration. Endogenous GDNF is vital for facial nerve regeneration according to earlier investigations. Nevertheless, the low endogenous GDNF level makes it challenging to achieve therapeutic benefits. Thus, we crushed the main trunk of facial nerve in SD rats to provide a model of peripheral facial paralysis, and we administered exogenous GDNF and Rapa treatments. We observed changes in the animal behavior scores, the morphology of facial nerve and buccinator muscle, the electrophysiological of facial nerve, and the expression of GDNF, GAP-43, and PI3K/AKT/mTOR signaling pathway-related molecules in the facial motoneurons. We discovered that GDNF could boost axon regeneration, hasten the recovery of facial paralysis symptoms and nerve conduction function, and increase the expression of GDNF, GAP-43, and PI3K/AKT/mTOR signaling pathway-related molecules in the central facial motoneurons. Therefore, exogenous GDNF injection into the buccinator muscle can enhance facial nerve regeneration following crushing injury and protect facial neurons via the PI3K/AKT/mTOR signaling pathway. This will offer a fresh perspective and theoretical foundation for the management of clinical facial nerve regeneration.

Effect of perinatal dietary protein deficiency on some neurochemicals and cytoarchitectural balance, in F1 and F2 generations of rats

ABSTRACT Protein deficiency, characterized by an inadequate intake of protein in the diet that fails to meet the body’s physiological requirements across various stages, can lead to detrimental outcomes. This is of interest due to the persistent low protein content in staple foods and suboptimal dietary patterns. The study sought to assess the intergenerational repercussions of dietary protein deficiency on specific neurochemicals and the cytoarchitecture of the brain within the F1 and F2 generations of rats. The rats were categorized into four groups based on the protein content percentage in their diets: 21% protein diet (21%PD), 10% protein diet (10%PD), 5% protein diet (5%PD), and control diet. Neurobehavior was assessed, while brain serotonin and dopamine levels were measured using HPLC. BDNF and GDNF expression in the hippocampal and prefrontal (PFC) sections, Immunohistochemical investigations of the morphological impact on the hippocampus and PFC, were also analyzed. The protein-deficient groups displayed anxiety, loss of striatal serotonin and increased dopamine levels, degenerated pyramidal cells in the hippocampus, and a prominent reduction in cellular density in the PFC. BDNF and GDNF levels in the PFC were reduced in the 5%PD group. GFAP astrocyte expression was observed to be increased in the prefrontal cortex (PFC) and hippocampal sections, indicating heightened reactivity. The density of hypertrophied cells across generations further suggests the presence of neuroinflammation. Changes in brain structure, neurotransmitter levels, and neurotrophic factor levels may indicate intergenerational alterations in critical regions, potentially serving as indicators of the brain’s adaptive response to address protein deficiency across successive generations.

A regulatory pathway model of neuropsychological disruption in Havana syndrome.

In 2016 diplomatic personnel serving in Havana, Cuba, began reporting audible sensory phenomena paired with onset of complex and persistent neurological symptoms consistent with brain injury. The etiology of these Anomalous Health Incidents (AHI) and subsequent symptoms remains unknown. This report investigates putative exposure-symptom pathology by assembling a network model of published bio-behavioral pathways and assessing how dysregulation of such pathways might explain loss of function in these subjects using data available in the published literature. Given similarities in presentation with mild traumatic brain injury (mTBI), we used the latter as a clinically relevant means of evaluating if the neuropsychological profiles observed in Havana Syndrome Havana Syndrome might be explained at least in part by a dysregulation of neurotransmission, neuro-inflammation, or both. Automated text-mining of >9,000 publications produced a network consisting of 273 documented regulatory interactions linking 29 neuro-chemical markers with 9 neuropsychological constructs from the Brief Mood Survey, PTSD Checklist, and the Frontal Systems Behavior Scale. Analysis of information flow through this network produced a set of regulatory rules reconciling to within a 6% departure known mechanistic pathways with neuropsychological profiles in N = 6 subjects. Predicted expression of neuro-chemical markers that jointly satisfy documented pathways and observed symptom profiles display characteristically elevated IL-1B, IL-10, NGF, and norepinephrine levels in the context of depressed BDNF, GDNF, IGF1, and glutamate expression (FDR < 5%). Elevations in CRH and IL-6 were also predicted unanimously across all subjects. Furthermore, simulations of neurological regulatory dynamics reveal subjects do not appear to be "locked in" persistent illness but rather appear to be engaged in a slow recovery trajectory. This computational analysis of measured neuropsychological symptoms in Havana-based diplomats proposes that these AHI symptoms may be supported in part by disruption of known neuroimmune and neurotransmission regulatory mechanisms also associated with mTBI.

Neural stem cell transplantation improves neurological function in focal cerebral ischemia through GDNF/PI3K/AKT axis.

The aim of this experiment was to analyze the ameliorating effect of neural stem cells (NSCs) on focal cerebral ischemia (FCI) through GDNF/PI3K/AKT axis, so as to provide evidence for future clinical application of NSCs. In this study, the 15 Sprague-Dawley (SD) male rats were modeled for middle cerebral artery occlusion (MCAO)-induced FCI and then grouped: NSCs group was treated with NSC transplantation, GDNF/NSCs group was transplanted with recombinant adenovirus pAdEasy-1-pAdTrackCMV-GDNF-transfedcted NSCs, and the blank group was treated with normal saline transplantation. Rats were tested by rotarod and corner turn tests at 1 week and 4 weeks after NSC transplantation, and the levels of tumor necrosis factor-α (TNF-α), interleukin-6/8 (IL-6/8), superoxide dismutase (SOD) and malondialdehyde (MDA) were quantified. Then all rats were killed and their brain tissues were HE stained for the determination of and GDNF/PI3K/AKT axis-associated protein expression. The results of the experiment showed that: at the 1st and 4th week after transplantation, the time on the rod, number of turnings and SOD were the lowest in the blank group among the three groups, while IL-6, IL-8, TNF-α and MDA were the highest (P<0.05). Increased time on the rod, number of turnings and SOD, as well as decreased IL-6, IL-8, TNF-α and MDA were observed in NSCs and GDNF/NSCs groups after transplantation, with better performance in GDNF/NSCs group (P<0.05). Based on HE staining of brain tissue, GDNF/NSCs group had the most significant improvement in tissue injury and the highest GDNF, PI3K, AKT and p-AKT protein expression among the three groups (P<0.05). In conclusions, NSC transplantation can ameliorate neurological function in MCAO-induced FCI rats through the GDNF/PI3K/AKT axis.

Analysis of Acute and Chronic Methamphetamine Treatment in Mice on Gdnf System Expression Reveals a Potential Mechanism of Schizophrenia Susceptibility.

The increase in presynaptic striatal dopamine is the main dopaminergic abnormality in schizophrenia (SCZ). SCZ is primarily treated by modulating the activity of monoamine systems, with a focus on dopamine and serotonin receptors. Glial cell line-derived neurotrophic factor (GDNF) is a strong dopaminergic factor, that recently was shown to correlate with SCZ in human CSF and in striatal tissue. A 2-3-fold increase in GDNF in the brain was sufficient to induce SCZ-like dopaminergic and behavioural changes in mice. Here, we analysed the effect of acute, chronic, and embryonic methamphetamine, a drug known to enhance the risk of psychosis, on Gdnf and its receptors, Gfra1 and Ret, as well as on monoamine metabolism-related gene expression in the mouse brain. We found that acute methamphetamine application increases Gdnf expression in the striatum and chronic methamphetamine decreases the striatal expression of GDNF receptors Gfra1 and Ret. Both chronic and acute methamphetamine treatment upregulated the expression of genes related to dopamine and serotonin metabolism in the striatum, prefrontal cortex, and substantia nigra. Our results suggest a potential mechanism as to how methamphetamine elicits individual psychosis risk in young adults-variation in initial striatal GDNF induction and subsequent GFRα1 and RET downregulation may determine individual susceptibility to psychosis. Our results may guide future experiments and precision medicine development for methamphetamine-induced psychosis using GDNF/GFRa1/RET antagonists.

Glial cell line-derived neurotrophic factor (GDNF) is essential for colonization and expansion of turbot (Scophthalmus maximus) germ cells in recipients and in vitro culture

Germ cell transplantation (GCT) is a promising biotechnology that enables the production of donor-derived gametes in surrogate recipients. It plays a crucial role in the protection of endangered species, the propagation of elite species with desired traits, and long-term preservation of genetic resources. This significance is particularly pronounced when GCT is synergistically employed with cryopreservation techniques. However, GCT often encounters challenges due to low colonization rates and, in some cases, complete loss of donor cells in recipients. Glial cell line-derived neurotrophic factor (GDNF) plays a pivotal role in sustaining the self-renewal of spermatogonial stem cells (SSCs) in mammals. Additionally, it has been shown to promote the proliferation of spermatogonia in vitro cultures in certain animal species. In turbot (Scophthalmus maximus), we found that the expressions of gdnf and gfrα1a were predominantly observed in spermatogonia rather than somatic cells, which differed from their expression patterns in mammals. The efficiency of exogenous spermatogonia transplantation in Japanese flounder (Paralichthys olivaceus) larvae could be substantially enhanced by incubating donor cells from turbot with 100 ng/ml GDNF prior to transplantation. This led to a noteworthy increase in the colonization rate, rising from 33%-50%–61.5%. Additionally, the addition of 20 ng/ml GDNF in cell medium could also promote the proliferation of turbot germ cells in vitro. These results demonstrated the gdnf in turbot testis expression characteristics and suggested that addition of GNDF could be an effective way to improve the GCT efficiency and promote the germ cells expansion during in vitro culture.

Gene Expression Profile of 3D Spheroids in Comparison with 2D Cell Cultures and Tissue Strains of Diffuse High-Grade Gliomas.

The use of relevant, accessible, and easily reproducible preclinical models of diffuse gliomas is a prerequisite for the development of successful therapeutic approaches to their treatment. Here we studied the gene expression profile of 3D spheroids in a comparison with 2D cell cultures and tissue strains of diffuse high-grade gliomas. Using real time PCR, we evaluated the expression of Gfap, Cd44, Pten, S100b, Vegfa, Hif1a, Sox2, Melk, Gdnf, and Mgmt genes playing an important role in the progression of gliomas and regulating tumor cell proliferation, adhesion, invasion, plasticity, apoptosis, DNA repair, and recruitment of tumor-associated cells. Gene expression analysis showed that 3D spheroids are more similar to tumor tissue strains by the expression levels of Gfap, Cd44, and Pten, while the expression levels of Hif1a and Sox2 in 3D spheroids did not differ from those of 2D cell cultures, the expression levels S100b and Vegfa in 3D spheroids was higher than in other models, and the expression levels of Melk, Gdnf, and Mgmt genes changed diversely. Thus, 3D spheroid model more closely mimics the tumor tissue than 2D cell culture, but still is not the most relevant, probably due to too small size of spheroids, which does not allow reproducing hypoxia and apoptotic and necrotic processes in the tumor tissue.

GDNF gene therapy for alcohol use disorder in male non-human primates.

Alcohol use disorder (AUD) exacts enormous personal, social and economic costs globally. Return to alcohol use in treatment-seeking patients with AUD is common, engendered by a cycle of repeated abstinence-relapse episodes even with use of currently available pharmacotherapies. Repeated ethanol use induces dopaminergic signaling neuroadaptations in ventral tegmental area (VTA) neurons of the mesolimbic reward pathway, and sustained dysfunction of reward circuitry is associated with return to drinking behavior. We tested this hypothesis by infusing adeno-associated virus serotype 2 vector encoding human glial-derived neurotrophic factor (AAV2-hGDNF), a growth factor that enhances dopaminergic neuron function, into the VTA of four male rhesus monkeys, with another four receiving vehicle, following induction of chronic alcohol drinking. GDNF expression ablated the return to alcohol drinking behavior over a 12-month period of repeated abstinence-alcohol reintroduction challenges. This behavioral change was accompanied by neurophysiological modulations to dopamine signaling in the nucleus accumbens that countered the hypodopaminergic signaling state associated with chronic alcohol use, indicative of a therapeutic modulation of limbic circuits countering the effects of alcohol. These preclinical findings suggest gene therapy targeting relapse prevention may be a potential therapeutic strategy for AUD.