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[Preprint]. 2024 Dec 20:rs.3.rs-5611378.
doi: 10.21203/rs.3.rs-5611378/v1.

Targeting NLRP3 signaling with a novel sulfonylurea compound for the treatment of vascular cognitive impairment and dementia

Adnan Akif  1 , Thi Thanh My Nguyen  1 , Langni Liu  2 , Xiaotian Xu  3 , Amol Kulkarni  4 , Jianxiong Jiang  5 , Yang Zhang  1 , Jiukuan Hao  1
Affiliations

Targeting NLRP3 signaling with a novel sulfonylurea compound for the treatment of vascular cognitive impairment and dementia

Adnan Akif et al. Res Sq. .

Update in

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.

Keywords: Inflammasome; Inflammation; Ischemia; NLRP3; Vascular Dementia.

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Figures

Figure 1
Figure 1
AMS-17 improves memory function in VaD mice.
Figure 2
Figure 2
AMS-17 reduces neuron degeneration and demyelination in the cortical regions in VaD mice.
Figure 3
Figure 3
AMS-17 reduces fibrinogen deposition in the cortical regions of the brain in VaD mice.
Figure 4
Figure 4
AMS-17 increases tight junction protein expressions in the cortical regions of the brain in VaD mice.
Figure 5
Figure 5
AMS-17 inhibits microglial NLRP3 and ASC expression in the cortical regions of the brain in VaD mice.
Figure 6
Figure 6
AMS-17 inhibits NLRP3, Cleaved caspase-1 and P-MST1 expression in the cortical regions of the brain in VaD mice.
Figure 7
Figure 7
AMS-17 regulates cytokines release
See this image and copyright information in PMC

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