Sex-dependent efficacy of sphingosine-1-phosphate receptor agonist FTY720 in mitigating Huntington’s disease
Huntington's disease (HD) is a debilitating neurodegenerative disorder characterized by severe motor deficits, cognitive decline and psychiatric disturbances. An early and significant morphological hallmark of HD is the activation of astrocytes triggered by mutant huntingtin, leading to the rel...
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Elsevier
2025-01-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661824005024 |
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| author | Jingyun Wu Irene Santos-Garcia Ivan Eiriz Thomas Brüning Aleš Kvasnička David Friedecký Tuula A. Nyman Jens Pahnke |
| author_facet | Jingyun Wu Irene Santos-Garcia Ivan Eiriz Thomas Brüning Aleš Kvasnička David Friedecký Tuula A. Nyman Jens Pahnke |
| author_sort | Jingyun Wu |
| collection | DOAJ |
| description | Huntington's disease (HD) is a debilitating neurodegenerative disorder characterized by severe motor deficits, cognitive decline and psychiatric disturbances. An early and significant morphological hallmark of HD is the activation of astrocytes triggered by mutant huntingtin, leading to the release of inflammatory mediators.Fingolimod (FTY), an FDA-approved sphingosine-1-phosphate (S1P) receptor agonist is used to treat multiple sclerosis (MS), a neuroinflammatory disease, and has shown therapeutic promise in other neurological conditions.Our study aimed to investigate the therapeutic potential of FTY for treating HD by utilizing a well-characterized mouse model of HD (zQ175dn) and wild-type littermates.The study design included a crossover, long-term oral treatment with 1 mg/kg to 2 mg/kg FTY from the age of 15–46 weeks (n = 128). Different motor behavior and physiological parameters were assessed throughout the study.The findings revealed that FTY rescued disease-related body weight loss in a sex-dependent manner, indicating its potential to regulate metabolic disturbances and to counteract neurodegenerative processes in HD. FTY intervention also rescued testicular atrophy, restored testis tissue structure in male mice suggesting a broader impact on peripheral tissues affected by huntingtin pathology. Histological analyses of the brain revealed delayed accumulation of activated astrocytes contributing to the preservation of the neural microenvironment by reducing neuroinflammation.The extent of FTY-related disease improvement was sex-dependent. Motor functions and body weight improved mostly in female mice with sustained estrogen levels, whereas males had to compensate for the ongoing, disease-related testis atrophy and the loss of androgen production.Our study underscores the beneficial therapeutic effects of FTY on HD involving endogenous steroid hormones and their important anabolic effects. It positions FTY as a promising candidate for therapeutic interventions targeting various aspects of HD pathology. Further studies are needed to fully evaluate its therapeutic potential in patients. |
| format | Article |
| id | doaj-art-286b7cd8648c468daa4b6f9de3a526f9 |
| institution | Kabale University |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-286b7cd8648c468daa4b6f9de3a526f92025-01-09T06:13:05ZengElsevierPharmacological Research1096-11862025-01-01211107557Sex-dependent efficacy of sphingosine-1-phosphate receptor agonist FTY720 in mitigating Huntington’s diseaseJingyun Wu0Irene Santos-Garcia1Ivan Eiriz2Thomas Brüning3Aleš Kvasnička4David Friedecký5Tuula A. Nyman6Jens Pahnke7Translational Neurodegeneration Research and Neuropathology Lab, Department of Clinical Medicine (KlinMed), Medical Faculty, University of Oslo (UiO) and Section of Neuropathology Research, Department of Pathology, Clinics for Laboratory Medicine (KLM), Oslo University Hospital (OUS), Sognsvannsveien 20, Oslo N-0372, NorwayTranslational Neurodegeneration Research and Neuropathology Lab, Department of Clinical Medicine (KlinMed), Medical Faculty, University of Oslo (UiO) and Section of Neuropathology Research, Department of Pathology, Clinics for Laboratory Medicine (KLM), Oslo University Hospital (OUS), Sognsvannsveien 20, Oslo N-0372, NorwayTranslational Neurodegeneration Research and Neuropathology Lab, Department of Clinical Medicine (KlinMed), Medical Faculty, University of Oslo (UiO) and Section of Neuropathology Research, Department of Pathology, Clinics for Laboratory Medicine (KLM), Oslo University Hospital (OUS), Sognsvannsveien 20, Oslo N-0372, NorwayTranslational Neurodegeneration Research and Neuropathology Lab, Department of Clinical Medicine (KlinMed), Medical Faculty, University of Oslo (UiO) and Section of Neuropathology Research, Department of Pathology, Clinics for Laboratory Medicine (KLM), Oslo University Hospital (OUS), Sognsvannsveien 20, Oslo N-0372, NorwayLaboratory for Inherited Metabolic Disorders, Department of Clinical Biochemistry, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacký University Olomouc, Zdravotníků 248/7, Olomouc CZ-77900, Czech RepublicLaboratory for Inherited Metabolic Disorders, Department of Clinical Biochemistry, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacký University Olomouc, Zdravotníků 248/7, Olomouc CZ-77900, Czech RepublicProteomics Core Facility (PCF), Department of Immunology, Oslo University Hospital (OUS) and University of Oslo (UiO), Faculty of Medicine, Sognsvannsveien 20, Oslo NO-0372, NorwayTranslational Neurodegeneration Research and Neuropathology Lab, Department of Clinical Medicine (KlinMed), Medical Faculty, University of Oslo (UiO) and Section of Neuropathology Research, Department of Pathology, Clinics for Laboratory Medicine (KLM), Oslo University Hospital (OUS), Sognsvannsveien 20, Oslo N-0372, Norway; Institute of Nutritional Medicine (INUM) and Lübeck Institute of Dermatology (LIED), University of Lübeck (UzL) and University Medical Center Schleswig-Holstein (UKSH), Ratzeburger Allee 160, Lübeck D-23538, Germany; Department of Neuromedicine and Neuroscience, Faculty of Medicine and Life Sciences, University of Latvia (LU), Jelgavas iela 3, Rīga LV-1004, Latvia; Department of Neurobiology, School of Neurobiology, Biochemistry and Biophysics, The Georg S. Wise Faculty of Life Sciences, Tel Aviv University (TAU), Ramat Aviv IL-6997801, Israel; Corresponding author at: Translational Neurodegeneration Research and Neuropathology Lab, Department of Clinical Medicine (KlinMed), Medical Faculty, University of Oslo (UiO) and Section of Neuropathology Research, Department of Pathology, Clinics for Laboratory Medicine (KLM), Oslo University Hospital (OUS), Sognsvannsveien 20, Oslo N-0372, Norway.Huntington's disease (HD) is a debilitating neurodegenerative disorder characterized by severe motor deficits, cognitive decline and psychiatric disturbances. An early and significant morphological hallmark of HD is the activation of astrocytes triggered by mutant huntingtin, leading to the release of inflammatory mediators.Fingolimod (FTY), an FDA-approved sphingosine-1-phosphate (S1P) receptor agonist is used to treat multiple sclerosis (MS), a neuroinflammatory disease, and has shown therapeutic promise in other neurological conditions.Our study aimed to investigate the therapeutic potential of FTY for treating HD by utilizing a well-characterized mouse model of HD (zQ175dn) and wild-type littermates.The study design included a crossover, long-term oral treatment with 1 mg/kg to 2 mg/kg FTY from the age of 15–46 weeks (n = 128). Different motor behavior and physiological parameters were assessed throughout the study.The findings revealed that FTY rescued disease-related body weight loss in a sex-dependent manner, indicating its potential to regulate metabolic disturbances and to counteract neurodegenerative processes in HD. FTY intervention also rescued testicular atrophy, restored testis tissue structure in male mice suggesting a broader impact on peripheral tissues affected by huntingtin pathology. Histological analyses of the brain revealed delayed accumulation of activated astrocytes contributing to the preservation of the neural microenvironment by reducing neuroinflammation.The extent of FTY-related disease improvement was sex-dependent. Motor functions and body weight improved mostly in female mice with sustained estrogen levels, whereas males had to compensate for the ongoing, disease-related testis atrophy and the loss of androgen production.Our study underscores the beneficial therapeutic effects of FTY on HD involving endogenous steroid hormones and their important anabolic effects. It positions FTY as a promising candidate for therapeutic interventions targeting various aspects of HD pathology. Further studies are needed to fully evaluate its therapeutic potential in patients.http://www.sciencedirect.com/science/article/pii/S1043661824005024Huntington’s diseaseSphingosin-1-phosphateFingolimodFTY720ZQ175dnS1PR1 |
| spellingShingle | Jingyun Wu Irene Santos-Garcia Ivan Eiriz Thomas Brüning Aleš Kvasnička David Friedecký Tuula A. Nyman Jens Pahnke Sex-dependent efficacy of sphingosine-1-phosphate receptor agonist FTY720 in mitigating Huntington’s disease Pharmacological Research Huntington’s disease Sphingosin-1-phosphate Fingolimod FTY720 ZQ175dn S1PR1 |
| title | Sex-dependent efficacy of sphingosine-1-phosphate receptor agonist FTY720 in mitigating Huntington’s disease |
| title_full | Sex-dependent efficacy of sphingosine-1-phosphate receptor agonist FTY720 in mitigating Huntington’s disease |
| title_fullStr | Sex-dependent efficacy of sphingosine-1-phosphate receptor agonist FTY720 in mitigating Huntington’s disease |
| title_full_unstemmed | Sex-dependent efficacy of sphingosine-1-phosphate receptor agonist FTY720 in mitigating Huntington’s disease |
| title_short | Sex-dependent efficacy of sphingosine-1-phosphate receptor agonist FTY720 in mitigating Huntington’s disease |
| title_sort | sex dependent efficacy of sphingosine 1 phosphate receptor agonist fty720 in mitigating huntington s disease |
| topic | Huntington’s disease Sphingosin-1-phosphate Fingolimod FTY720 ZQ175dn S1PR1 |
| url | http://www.sciencedirect.com/science/article/pii/S1043661824005024 |
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