An Extension Study to Assess the Safety and Efficacy of Intermittent Bilateral Intraputamenal Glial Cell Line-Derived Neurotrophic Factor (GDNF) Infusions Administered via onvection Enhanced Delivery (CED) in Subjects with Parkinson’s Disease - Intermittent Bilateral GDNF for Parkinson’s Disease

Start Date16 Sep 2013

Sponsor / Collaborator-

EUCTR2011-003866-34-GB / Not yet recruitingPhase 2

A Placebo-Controlled, Randomised, Double-Blind Trial to Assess the Safety and Efficacy of Intermittent Bilateral Intraputamenal Glial Cell Line-Derived Neurotrophic Factor (GDNF) Infusions Administered via Convection Enhanced Delivery (CED) in Subjects with Parkinson’s Disease - Intermittent Bilateral GDNF for Parkinson’s Disease

Start Date24 Sep 2012

Sponsor / Collaborator-

100 Clinical Results associated with GFRA1

100 Translational Medicine associated with GFRA1

0 Patents (Medical) associated with GFRA1

356

Literatures (Medical) associated with GFRA1

01 Oct 2024·Neuroscience

The enduring effects of antimicrobials and lipopolysaccharide on the cellular mechanisms and behaviours associated with neurodegeneration in pubertal male and female CD1 mice

Article

Author: Gandelman, Michelle ; Dubé-Zinatelli, Eleni ; Esposito, Pasquale ; Liu, Ella ; Liang, Jacky ; Ismail, Nafissa ; Cappelletti, Luna

Puberty is a sensitive developmental period during which stressors can cause lasting brain and behavioural deficits. While the acute effects of pubertal lipopolysaccharide (LPS) and antimicrobial (AMNS) treatments are known, their enduring impacts on neurodegeneration-related mechanisms and behaviours remain unclear. This study examined these effects in male and female mice. At five weeks old, mice received 200ul of either broad-spectrum antimicrobials or water through oral gavage twice daily for seven days. At six weeks of age, they received an intraperitoneal injection of either saline or LPS. Four weeks later, adult mice underwent neurodegeneration-related behavioural tests, including the rotarod, forepaw stride length, reversed grid hang, open field, and buried pellet tests. Two days after the final test, brain and ileal samples were collected. Results showed that female mice treated with both AMNS and LPS exhibited deficits in neuromuscular strength, while males treated with LPS alone showed increased anxiety-like behaviours. Males treated with AMNS alone had decreased sigma-1 receptor (S1R) expression in the cornu ammonis 1 (CA1) and dentate gyrus (DG), while females treated with both AMNS and LPS had decreased S1R expression. Additionally, males treated with either LPS or AMNS had lower glial-derived neurotrophic factor receptor alpha-1 (GFRA1) expression in the primary motor cortex (M1) than females. Mice treated with LPS alone had decreased GFRA1 expression in the DG and decreased S1R expression in the secondary motor cortex (M2). These findings suggest that pubertal AMNS and LPS treatments may lead to enduring changes in biomarkers and behaviours related to neurodegeneration.

16 Sep 2024·Biological research

PTN from Leydig cells activates SDC2 and modulates human spermatogonial stem cell proliferation and survival via GFRA1.

Article

Author: Zhu, Fang ; Zhao, Xueheng ; Zhou, Dai ; Zhang, Huan ; Liu, Lvjun ; Huang, Zenghui

BACKGROUNDSpermatogonial stem cells (SSCs) are essential for the maintenance and initiation of male spermatogenesis. Despite the advances in understanding SSC biology in mouse models, the mechanisms underlying human SSC development remain elusive.RESULTSHere, we analyzed the signaling pathways involved in SSC regulation by testicular somatic cells using single-cell sequencing data (GEO datasets: GSE149512 and GSE112013) and identified that Leydig cells communicate with SSCs through pleiotrophin (PTN) and its receptor syndecan-2 (SDC2). Immunofluorescence, STRING prediction, and protein immunoprecipitation assays confirmed the interaction between PTN and SDC2 in spermatogonia, but their co-localization was observed only in approximately 50% of the cells. The knockdown of SDC2 in human SSC lines impaired cell proliferation, DNA synthesis, and the expression of PLZF, a key marker for SSC self-renewal. Transcriptome analysis revealed that SDC2 knockdown downregulated the expression of GFRA1, a crucial factor for SSC proliferation and self-renewal, and inhibited the HIF-1 signaling pathway. Exogenous PTN rescued the proliferation and GFRA1 expression in SDC2 knockdown SSC lines. In addition, we found downregulation of PTN and SDC2 as well as altered localization in non-obstructive azoospermia (NOA) patients, suggesting that downregulation of PTN and SDC2 may be associated with impaired spermatogenesis.CONCLUSIONSOur results uncover a novel mechanism of human SSC regulation by the testicular microenvironment and suggest a potential therapeutic target for male infertility.

01 Sep 2024·Clinical and Experimental Reproductive Medicine

The effects of vitamin E supplementation on sperm parameters, chromatin integrity, and gene expression before and after freezing in aged mice

Article

Author: Majidi, Behanaz ; Vatanparast, Mahboubeh ; Abasnezhad, Farzaneh Abbas ; Mohammadihosseinabad, Saeed ; Zarei, Sadegh ; Molavi, Farnoosh ; Ranjbar, Faezeh Esmaeili

Objective: Some age-related testicular changes, such as Sertoli cell vacuolization and blood–testis barrier breakdown, reduce total sperm production and male fertility. Therefore, this study investigated the effect of vitamin E on restoring testicular function in aged mice. Sperm cryo-resistance was also assessed. Methods: Twenty-eight 48-week-old male Naval Medical Research Institute mice were divided into four groups for a daily gavage of vitamin E: the control group received distilled water, while the three treatment groups were administered 100, 200, and 400 mg/kg, respectively, for 4 weeks. Subsequently, semen analyses, DNA fragmentation index (DFI), and protamine deficiency tests were conducted. Testicular histology, tissue antioxidant enzyme activity, and gene expression levels were also assessed.Results: The two higher dosages of vitamin E were associated with a higher sperm count, greater progressive motility, and improved sperm morphology (p<0.05). These benefits were also evident after sperm freezing (p<0.05). Although chromatin abnormalities increased following vitrification, the treatment groups showed better outcomes (p<0.05). The tubular diameter, epithelium height, and luminal diameters remained unchanged with age. The tissue antioxidant capacity was greater in the groups receiving the high doses of vitamin E. Additionally, significant increases in inhibitor of DNA binding protein-4 (Id4) and GDNF family receptor alpha-1 (Gfra1) expression were observed in the higher vitamin E dosage groups, and promyelocytic leukemia zinc finger protein (Plzf) expression was notably present in the 400 mg/kg treatment group compared to the control group (p<0.05). Conclusion: Antioxidant supplementation might enhance reproductive outcomes in aging males. The observed effects included improved sperm cryo-resistance, which is advantageous for future applications such as sperm freezing or fertility preservation.

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