Targeting NLRP3 signaling with a novel sulfonylurea compound for the treatment of vascular cognitive impairment and dementia
Abstract Background As a key inflammatory factor, the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in neuroinflammation and the progression of neurodegenerative diseases. Dysregulation of NLRP3 signaling can trigger various inflamm...
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| Language: | English |
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BMC
2025-06-01
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| Series: | Fluids and Barriers of the CNS |
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| Online Access: | https://doi.org/10.1186/s12987-025-00665-6 |
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| author | Adnan Akif Thi Thanh My Nguyen Langni Liu Xiaotian Xu Amol Kulkarni Jianxiong Jiang Yang Zhang Jiukuan Hao |
| author_facet | Adnan Akif Thi Thanh My Nguyen Langni Liu Xiaotian Xu Amol Kulkarni Jianxiong Jiang Yang Zhang Jiukuan Hao |
| author_sort | Adnan Akif |
| collection | DOAJ |
| description | Abstract Background As a key inflammatory factor, the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in neuroinflammation and the progression of neurodegenerative diseases. Dysregulation of NLRP3 signaling can trigger various inflammatory responses in the brain, contributing to the development of neurodegenerative diseases such as ischemic stroke, vascular dementia (VaD), Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). Therefore, the NLRP3 signaling pathway is a promising therapeutic target for the treatment of neurodegenerative diseases, including VaD. Methods In this study, we investigated the therapeutic effects of a synthetic sulfonylurea NLRP3 inhibitor, AMS-17, in a VaD mouse model using bilateral common carotid artery stenosis (BCAS) and elucidated the underlying mechanisms. All mice were randomly divided into three groups: Sham, VaD + Vehicle, and VaD + AMS-17. Cognitive function was assessed using the Y-maze and Morris water maze (MWM) on the 50th day after BCAS. Brain sections and blood serum samples were collected for biomarker analysis and immunohistochemistry. Neurodegeneration, expressions of the molecules involved in the NLRP3 signaling pathways, tight junction proteins, and myelination were assessed using western blotting and immunofluorescence (IF). The levels of Interleukin-1 beta (IL-1β), Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-4 (IL-4) in the blood were measured using ELISA. Results AMS-17 treatment improved cognitive function, enhanced blood-brain barrier (BBB) integrity, and promoted remyelination in VaD mice. Additionally, AMS-17 reduced neurodegeneration and decreased the expression of NLRP3 and its associated proteins, Apoptosis-associated speck-like protein (ASC), and cleaved caspase-1 in the brain. It also lowered pro-inflammatory TNF-α and IL-1β levels, while increasing the anti-inflammatory IL-4 level in the blood. Conclusions The findings of this study provide the first promising evidence for the use of AMS-17 in VaD treatment in mice. This study introduces AMS-17 as a novel chemical scaffold with NLRP3 inhibitory activity, which can be further developed for the treatment of VaD in humans. Clinical trial number Not applicable. Graphical Abstract |
| format | Article |
| id | doaj-art-4b0b236df9f547f58e336c13a83403ee |
| institution | OA Journals |
| issn | 2045-8118 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Fluids and Barriers of the CNS |
| spelling | doaj-art-4b0b236df9f547f58e336c13a83403ee2025-08-20T02:30:59ZengBMCFluids and Barriers of the CNS2045-81182025-06-0122111610.1186/s12987-025-00665-6Targeting NLRP3 signaling with a novel sulfonylurea compound for the treatment of vascular cognitive impairment and dementiaAdnan Akif0Thi Thanh My Nguyen1Langni Liu2Xiaotian Xu3Amol Kulkarni4Jianxiong Jiang5Yang Zhang6Jiukuan Hao7Department of Pharmacological and Pharmaceutical Sciences, University of HoustonDepartment of Pharmacological and Pharmaceutical Sciences, University of HoustonCenter for Neuroimmunology and Glial Biology, Institute of Molecular Medicine, University of Texas Health Science CenterDepartment of Neurology, The Affiliated Hospital of Yangzhou UniversityDepartment of Chemistry and Biochemistry, University of Texas at El PasoDepartment of Pharmaceutical Sciences and Drug Discovery Center, College of Pharmacy, University of Tennessee Health Science CenterDepartment of Pharmacological and Pharmaceutical Sciences, University of HoustonDepartment of Pharmacological and Pharmaceutical Sciences, University of HoustonAbstract Background As a key inflammatory factor, the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in neuroinflammation and the progression of neurodegenerative diseases. Dysregulation of NLRP3 signaling can trigger various inflammatory responses in the brain, contributing to the development of neurodegenerative diseases such as ischemic stroke, vascular dementia (VaD), Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). Therefore, the NLRP3 signaling pathway is a promising therapeutic target for the treatment of neurodegenerative diseases, including VaD. Methods In this study, we investigated the therapeutic effects of a synthetic sulfonylurea NLRP3 inhibitor, AMS-17, in a VaD mouse model using bilateral common carotid artery stenosis (BCAS) and elucidated the underlying mechanisms. All mice were randomly divided into three groups: Sham, VaD + Vehicle, and VaD + AMS-17. Cognitive function was assessed using the Y-maze and Morris water maze (MWM) on the 50th day after BCAS. Brain sections and blood serum samples were collected for biomarker analysis and immunohistochemistry. Neurodegeneration, expressions of the molecules involved in the NLRP3 signaling pathways, tight junction proteins, and myelination were assessed using western blotting and immunofluorescence (IF). The levels of Interleukin-1 beta (IL-1β), Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-4 (IL-4) in the blood were measured using ELISA. Results AMS-17 treatment improved cognitive function, enhanced blood-brain barrier (BBB) integrity, and promoted remyelination in VaD mice. Additionally, AMS-17 reduced neurodegeneration and decreased the expression of NLRP3 and its associated proteins, Apoptosis-associated speck-like protein (ASC), and cleaved caspase-1 in the brain. It also lowered pro-inflammatory TNF-α and IL-1β levels, while increasing the anti-inflammatory IL-4 level in the blood. Conclusions The findings of this study provide the first promising evidence for the use of AMS-17 in VaD treatment in mice. This study introduces AMS-17 as a novel chemical scaffold with NLRP3 inhibitory activity, which can be further developed for the treatment of VaD in humans. Clinical trial number Not applicable. Graphical Abstracthttps://doi.org/10.1186/s12987-025-00665-6InflammasomeInflammationIschemiaNLRP3Vascular dementia |
| spellingShingle | Adnan Akif Thi Thanh My Nguyen Langni Liu Xiaotian Xu Amol Kulkarni Jianxiong Jiang Yang Zhang Jiukuan Hao Targeting NLRP3 signaling with a novel sulfonylurea compound for the treatment of vascular cognitive impairment and dementia Fluids and Barriers of the CNS Inflammasome Inflammation Ischemia NLRP3 Vascular dementia |
| title | Targeting NLRP3 signaling with a novel sulfonylurea compound for the treatment of vascular cognitive impairment and dementia |
| title_full | Targeting NLRP3 signaling with a novel sulfonylurea compound for the treatment of vascular cognitive impairment and dementia |
| title_fullStr | Targeting NLRP3 signaling with a novel sulfonylurea compound for the treatment of vascular cognitive impairment and dementia |
| title_full_unstemmed | Targeting NLRP3 signaling with a novel sulfonylurea compound for the treatment of vascular cognitive impairment and dementia |
| title_short | Targeting NLRP3 signaling with a novel sulfonylurea compound for the treatment of vascular cognitive impairment and dementia |
| title_sort | targeting nlrp3 signaling with a novel sulfonylurea compound for the treatment of vascular cognitive impairment and dementia |
| topic | Inflammasome Inflammation Ischemia NLRP3 Vascular dementia |
| url | https://doi.org/10.1186/s12987-025-00665-6 |
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