Journal of Inflammation Research (Apr 2023)
Diminazene Ameliorates Neuroinflammation by Suppression of Astrocytic miRNA-224-5p/NLRP3 Axis in Alzheimer’s Disease Model
Abstract
XiaoJin Sun,1,* Yang Deng,2,* PengXin Ge,3,* Qiang Peng,4 Ismatullah Soufiany,4 Lin Zhu,4 Rui Duan4 1Faculty of Pharmacy, Bengbu Medical College, Anhui Engineering Technology Research Center of Biochemical Pharmaceuticals, Bengbu, Anhui, People’s Republic of China; 2School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China; 3Department of Pharmacy, Anhui Provincial Cancer Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of China; 4Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lin Zhu; Rui Duan, Email [email protected]; [email protected]: ACE2/Ang(1– 7)/Mas Receptor, the momentous component of the renin-angiotensin system, has been shown to be involved in Alzheimer’s disease (AD). We had previously found that enhancing brain ACE2 activity ameliorated cognitive impairment and attenuated brain neuroinflammation in SAMP8 mice, an animal model of AD. However, the exact mechanism of action of Diminazene (DIZE) has not been revealed.Methods: APP/PS1 mice were injected intraperitoneally with DIZE. Cognitive functions, neuronal and synaptic integrity, and inflammation-related markers were assessed by Morris water maze, Nissl staining, Western blotting and ELISA, respectively. Since astrocytes played a crucial role in AD-related neuroinflammation whilst miRNAs were reported to participate in modulating inflammatory responses, astrocytes of APP/PS1 mice were then isolated for high-throughput miRNAs sequencing to identify the most differentially expressed miRNA following DIZE treatment. Afterward, the downstream pathway of this miRNA in the anti-inflammatory action of DIZE was investigated using primary astrocytes.Results: The results showed that DIZE alleviated cognitive impairment and neuronal and synaptic damage in APP/PS1 mice. Simultaneously, DIZE suppressed the secretion of pro-inflammatory cytokines and the expression of NLRP3 inflammasome. Importantly, miR-224-5p was significantly up-regulated in the astrocytes of APP/PS1 mice treated by DIZE, and NLRP3 is one of the targets of miR-224-5p. Upregulation of miR-224-5p inhibited the expression of NLRP3 in Aβ 1– 42-stimulated cells, whereas miR-224-5p downregulation reversed this effect. Furthermore, the inhibition of miR-224-5p could reverse the inhibitory effect of DIZE on astrocytic NLRP3 inflammasome.Conclusion: These findings firstly suggested that DIZE could inhibit astrocyte-regulated neuroinflammation via miRNA-224-5p/NLRP3 pathway. Furthermore, our study reveals the underlying mechanism by which DIZE suppresses neuroinflammatory responses in AD mice and uncovers the potential of DIZE in AD treatment.Keywords: DIZE, miRNA-224-5p, astrocyte, NLRP3, neuroinflammation, Alzheimer’s disease
