Yang Li, Yin Peng, Guangning Nie, Fangping Cheng, Yuling Zhou, Jian Liu, Hongyan Yang
{"title":"虎阳养坤方通过GAT-1/GABA/GABAAR2影响下丘脑GnRH/LH脉冲释放，增强卵巢功能，延缓生殖衰老","authors":"Yang Li, Yin Peng, Guangning Nie, Fangping Cheng, Yuling Zhou, Jian Liu, Hongyan Yang","doi":"10.2147/DDDT.S504610","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Huyang Yangkun Formula (HYF), based on Yin and Yang principles, is effective in treating Premature Ovarian Insufficiency (POI) and enhancing reproduction, but its mechanism needs to be clarified.</p><p><strong>Aim: </strong>This study investigates HYF's impact on enhancing ovarian follicles development via GABA/GnRH neuron regulation.</p><p><strong>Materials and methods: </strong>The chemical components of water extract of HYF were analyzed by combining the ultra-high performance liquid chromatography coupled with Q-Exactive mass spectrum analysis (UHPLC-QE-MS). Female SD rats received HYF for 90 days to assess changes in the ovarian function. In addition, female SD rats underwent ovariectomy to evaluated the impact of HYF or GABA treatments on LH release induced by E2 to address age-related neuroendocrine damage. Reproductive neuroendocrine markers were analyzed through immunohistochemistry and immunofluorescence.</p><p><strong>Results: </strong>HYF treatment improved the disrupted estrous cycle in aged female rats, breaking the continuous keratinized epithelial cell state and alternating between estrous periods. Aging reduces ovarian volume and follicle numbers, but after 3 months of HYF treatment, ovarian follicle development increased, and mature follicle and luteum numbers changed significantly. HYF improved sex hormone levels, advancing and enhancing the LH peak in older rats, thus boosting total 24-hour LH release. GABA injection into the lateral ventricle increased GnRH release in aging rats, highlighting GABA's excitatory role. HYF also increased GnRH secretion by reducing GAT-1, leading to more GABA release, which activates GABAAR2 receptors in GnRH neurons, enhancing their function in the hypothalamic arcuate nucleus of elderly rats.</p><p><strong>Conclusion: </strong>HYF shows promise as a treatment for improving ovarian and reproductive neuroendocrine function in early reproductive aging, providing insights into its effects on hypothalamic GnRH/LH pulse release via the GAT-1/GABA/GABAAR2/GnRH pathway.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"2677-2691"},"PeriodicalIF":4.7000,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11994086/pdf/","citationCount":"0","resultStr":"{\"title\":\"Huyang Yangkun Formula Enhances Ovarian Function and Delays Reproductive Aging by Influencing Hypothalamic GnRH/LH Pulse Release Through GAT-1/GABA/GABAAR2.\",\"authors\":\"Yang Li, Yin Peng, Guangning Nie, Fangping Cheng, Yuling Zhou, Jian Liu, Hongyan Yang\",\"doi\":\"10.2147/DDDT.S504610\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Huyang Yangkun Formula (HYF), based on Yin and Yang principles, is effective in treating Premature Ovarian Insufficiency (POI) and enhancing reproduction, but its mechanism needs to be clarified.</p><p><strong>Aim: </strong>This study investigates HYF's impact on enhancing ovarian follicles development via GABA/GnRH neuron regulation.</p><p><strong>Materials and methods: </strong>The chemical components of water extract of HYF were analyzed by combining the ultra-high performance liquid chromatography coupled with Q-Exactive mass spectrum analysis (UHPLC-QE-MS). Female SD rats received HYF for 90 days to assess changes in the ovarian function. In addition, female SD rats underwent ovariectomy to evaluated the impact of HYF or GABA treatments on LH release induced by E2 to address age-related neuroendocrine damage. Reproductive neuroendocrine markers were analyzed through immunohistochemistry and immunofluorescence.</p><p><strong>Results: </strong>HYF treatment improved the disrupted estrous cycle in aged female rats, breaking the continuous keratinized epithelial cell state and alternating between estrous periods. Aging reduces ovarian volume and follicle numbers, but after 3 months of HYF treatment, ovarian follicle development increased, and mature follicle and luteum numbers changed significantly. HYF improved sex hormone levels, advancing and enhancing the LH peak in older rats, thus boosting total 24-hour LH release. GABA injection into the lateral ventricle increased GnRH release in aging rats, highlighting GABA's excitatory role. HYF also increased GnRH secretion by reducing GAT-1, leading to more GABA release, which activates GABAAR2 receptors in GnRH neurons, enhancing their function in the hypothalamic arcuate nucleus of elderly rats.</p><p><strong>Conclusion: </strong>HYF shows promise as a treatment for improving ovarian and reproductive neuroendocrine function in early reproductive aging, providing insights into its effects on hypothalamic GnRH/LH pulse release via the GAT-1/GABA/GABAAR2/GnRH pathway.</p>\",\"PeriodicalId\":11290,\"journal\":{\"name\":\"Drug Design, Development and Therapy\",\"volume\":\"19 \",\"pages\":\"2677-2691\"},\"PeriodicalIF\":4.7000,\"publicationDate\":\"2025-04-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11994086/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Drug Design, Development and Therapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.2147/DDDT.S504610\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug Design, Development and Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2147/DDDT.S504610","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Huyang Yangkun Formula Enhances Ovarian Function and Delays Reproductive Aging by Influencing Hypothalamic GnRH/LH Pulse Release Through GAT-1/GABA/GABAAR2.
Background: Huyang Yangkun Formula (HYF), based on Yin and Yang principles, is effective in treating Premature Ovarian Insufficiency (POI) and enhancing reproduction, but its mechanism needs to be clarified.
Aim: This study investigates HYF's impact on enhancing ovarian follicles development via GABA/GnRH neuron regulation.
Materials and methods: The chemical components of water extract of HYF were analyzed by combining the ultra-high performance liquid chromatography coupled with Q-Exactive mass spectrum analysis (UHPLC-QE-MS). Female SD rats received HYF for 90 days to assess changes in the ovarian function. In addition, female SD rats underwent ovariectomy to evaluated the impact of HYF or GABA treatments on LH release induced by E2 to address age-related neuroendocrine damage. Reproductive neuroendocrine markers were analyzed through immunohistochemistry and immunofluorescence.
Results: HYF treatment improved the disrupted estrous cycle in aged female rats, breaking the continuous keratinized epithelial cell state and alternating between estrous periods. Aging reduces ovarian volume and follicle numbers, but after 3 months of HYF treatment, ovarian follicle development increased, and mature follicle and luteum numbers changed significantly. HYF improved sex hormone levels, advancing and enhancing the LH peak in older rats, thus boosting total 24-hour LH release. GABA injection into the lateral ventricle increased GnRH release in aging rats, highlighting GABA's excitatory role. HYF also increased GnRH secretion by reducing GAT-1, leading to more GABA release, which activates GABAAR2 receptors in GnRH neurons, enhancing their function in the hypothalamic arcuate nucleus of elderly rats.
Conclusion: HYF shows promise as a treatment for improving ovarian and reproductive neuroendocrine function in early reproductive aging, providing insights into its effects on hypothalamic GnRH/LH pulse release via the GAT-1/GABA/GABAAR2/GnRH pathway.
期刊介绍：
Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications.
The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas.
Specific topics covered by the journal include:
Drug target identification and validation
Phenotypic screening and target deconvolution
Biochemical analyses of drug targets and their pathways
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Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes)
Structural or molecular biological studies elucidating molecular recognition processes
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Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products**
Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development
Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing)
Preclinical development studies
Translational animal models
Mechanisms of action and signalling pathways
Toxicology
Gene therapy, cell therapy and immunotherapy
Personalized medicine and pharmacogenomics
Clinical drug evaluation
Patient safety and sustained use of medicines.
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