Levistilide A ameliorates neuroinflammation via inhibiting JAK2/STAT3 signaling for neuroprotection and cognitive improvement in scopolamine-induced Alzheimer’s disease mouse model

Article

Author: Ni, Haojie ; Dong, Yan ; Zhang, Yifan ; Wang, Zihao ; Lu, Huinian ; Huang, Fengming ; Huang, Yujie ; Liao, Yanfang ; Huang, Zhiju ; Zhang, Zhende

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with cognitive impairment and dementia, which has become a major public health problem. There are no effective therapeutic agents used to treat AD in clinic for the extremely complex pathogenesis. Here we identify Levistilide A (LA), one of the major active natural terpene lactone constituents from Chinese herbal medicine Angelicae sinensis and Chuanxiong Rhizoma, as a potent neuroinflammation inhibitor for neuroprotection and cognitive improvement of AD. We show that LA suppresses neuronal apoptosis, restores cholinergic system function, and lowers neuroinflammation in vivo to improve scopolamine (SCOP)-induced learning and memory deficits. In addition, LA inhibits the release of IL-1β, IL-6 and TNF-α, while increasing the production of IL-4 and IL-10 for anti-inflammatory effects in LPS or Aβ-induced BV2 and HMC3 cells. Furthermore, the conditioned medium (CM) from LA-treated BV2 or HMC3 cells enhances the viability of SH-SY5Y and HT-22 cells, and LA reverses M1 to M2 phenotype transformation of BV2 and HMC3 cells accompanied by the inhibited Iba-1 expression and mRNA level of IL-1β, IL-6, TNF-α and NOS2, and the increased expression of ARG1, CD206 and CD163. Mechanistically, we analyze JAK2/STAT3 signaling as possible targets of LA using network pharmacology approaches, and further experimentally validate that LA inhibits the phosphorylation of JAK2 and STAT3, and STAT3 expression within nucleus both in vitro and in vivo. Collectively, we identify LA as a potential neuroinflammation inhibitor for neuroprotection and cognitive improvement, which is expected to be a candidate for AD therapy.

22 Jun 2021·BrainQ1 · MEDICINE

Erratum to: Gamma subunit of complement component 8 is a neuroinflammation inhibitor

Q1 · MEDICINE

03 Mar 2021·BrainQ1 · MEDICINE

Gamma subunit of complement component 8 is a neuroinflammation inhibitor

Q1 · MEDICINE

Article

Author: Hwang, Eun Mi ; Choe, Youngshik ; Afridi, Ruqayya ; Ryu, Hoon ; Shim, Hyun Soo ; Kim, Jong-Heon ; Han, Jin ; Kim, Seung-Chan ; Hoe, Hyang-Sook ; Suk, Kyoungho ; Jung, Hyun-Gug

AbstractThe complement system is part of the innate immune system that comprises several small proteins activated by sequential cleavages. The majority of these complement components, such as components 3a (C3a) and C5a, are chemotactic and pro-inflammatory. However, in this study, we revealed an inhibitory role of complement component 8 gamma (C8G) in neuroinflammation. In patients with Alzheimer's disease, who exhibit strong neuroinflammation, we found higher C8G levels in brain tissue, CSF, and plasma. Our novel findings also showed that the expression level of C8G increases in the inflamed mouse brain, and that C8G is mainly localized to brain astrocytes. Experiments using recombinant C8G protein and shRNA-mediated knockdown showed that C8G inhibits glial hyperactivation, neuroinflammation, and cognitive decline in acute and chronic animal models of Alzheimer’s disease. Additionally, we identified sphingosine-1-phosphate receptor 2 (S1PR2) as a novel interaction protein of C8G and demonstrated that astrocyte-derived C8G interacts with S1PR2 to antagonize the pro-inflammatory action of S1P in microglia. Taken together, our results reveal the previously unrecognized role of C8G as a neuroinflammation inhibitor. Our findings pave the way towards therapeutic containment of neuroinflammation in Alzheimer’s disease and related neurological diseases.

100 Deals associated with Neuroinflammation(Exscientia)

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Indication	Highest Phase	Country/Location	Organization	Date
Neuroinflammation	Preclinical	GB	Exscientia AI Ltd.	20 Sep 2023
Neuroinflammation	Preclinical	DE	Merck & Co., Inc.	20 Sep 2023

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