Alkaloids in Uncaria rhynchophylla improves AD pathology by restraining CD4+ T cell-mediated neuroinflammation via inhibition of glycolysis in APP/PS1 mice

Ying Kuang; Mengyu Zhu; Hongting Gu; Yue Tao; Hao Huang; Lei Chen

doi:10.1016/j.jep.2024.118273

Alkaloids in Uncaria rhynchophylla improves AD pathology by restraining CD4⁺ T cell-mediated neuroinflammation via inhibition of glycolysis in APP/PS1 mice

J Ethnopharmacol. 2024 May 3:331:118273. doi: 10.1016/j.jep.2024.118273. Online ahead of print.

Authors

Ying Kuang¹, Mengyu Zhu¹, Hongting Gu¹, Yue Tao¹, Hao Huang¹, Lei Chen²

Affiliations

¹ National Engineering Research Center for Modernization of Traditional Chinese Medicine-Hakka Medical Resources Branch, School of Pharmacy, Gannan Medical University, Ganzhou, 341000, China.
² National Engineering Research Center for Modernization of Traditional Chinese Medicine-Hakka Medical Resources Branch, School of Pharmacy, Gannan Medical University, Ganzhou, 341000, China. Electronic address: kuangsunlight@163.com.

PMID: 38703874
DOI: 10.1016/j.jep.2024.118273

Abstract

Ethnopharmacological relevance: Uncaria rhynchophylla (Miq.) Miq.ex Havil. was a classical medicinal plant exhibiting the properties of extinguishing wind, arresting convulsions, clearing heat and pacifying the liver. Clinically, it could be utilized for the treatment of central nervous system-related diseases, such as Alzheimer's disease. U. rhynchophylla (UR) and its major ingredient alkaloid compounds (URA) have been proved to exert significant neuroprotective effects. However, the potential mechanism aren't fully understood.

Aim of the study: This study systematically examined the therapeutic effects of URA on AD pathology in APP-PS1 mice, and revealed the potential mechanism of action.

Materials and methods: The cognitive ability was evaluated by morris water maze test in APP-PS1 mice. The H&E staining was used to observe the tissue pathological changes. The ELISA kits were used to detect the level of inflammatory factors. The flow cytometry was used to analyze the percentage of CD4⁺ effector T cells (Teffs) in spleen. The immunofluorescent staining was performed to count the Teffs and microglia in brain. The protein expression was analyzed by western blot. In vitro, the lymphocyte proliferation induced by ConA was performed by CCK-8 kits. The IFN-γ, IL-17, and TNF-α production were detected by ELISA kits. The effects of URA on glycolysis and the involvement of PI3K/Akt/mTOR signaling pathway was analyzed by Lactic Acid assay kit and western blot in ConA-induced naive T cell.

Results: URA treatment improved AD pathology effectively as demonstrated by enhanced cognitive ability, decreased Aβ deposit and Tau phosphorylation, as well as reduced neuron apoptosis. Also, the neuroinflammation was significantly alleviated as evidenced by decreased IFN-γ, IL-17 and increased IL-10, TGF-β. Notably, URA treatment down-regulated the percentage of Teffs (Th1 and Th17) in spleen, and reduced the infiltration of Teffs and microglia in brain. Meanwhile, the Treg cell was up-regulated both in spleen and brain. In vitro, URA was capable of attenuating the spleen lymphocyte proliferation and release of inflammatory factors provoked by ConA. Interestingly, glycolysis was inhibited by URA treatment as evidenced by the decrease in Lactic Acid production and expression of HK2 and GLUT1 via regulating PI3K/Akt/mTOR signaling pathway in ConA-induced naive T cell.

Conclusion: This study proved that URA could improve AD pathology which was possibly attributable to the restraints of CD4⁺ T cell mediated neuroinflammation via inhibiting glycolysis.

Keywords: Alzheimer's disease; CD4(+) T cell; Glycolysis; Neuroinflammation; Uncaria rhynchophylla.