Pharmacological Inhibition of Spleen Tyrosine Kinase Suppressed Neuroinflammation and Cognitive Dysfunction in LPS-Induced Neurodegeneration Model

Min Woo Kim; Kyonghwan Choe; Jun Sung Park; Hyeon Jin Lee; Min Hwa Kang; Riaz Ahmad; Myeong Ok Kim

doi:10.3390/cells11111777

Pharmacological Inhibition of Spleen Tyrosine Kinase Suppressed Neuroinflammation and Cognitive Dysfunction in LPS-Induced Neurodegeneration Model

Cells. 2022 May 28;11(11):1777. doi: 10.3390/cells11111777.

Authors

Min Woo Kim¹, Kyonghwan Choe^{1

2}, Jun Sung Park¹, Hyeon Jin Lee¹, Min Hwa Kang¹, Riaz Ahmad¹, Myeong Ok Kim^{1

3}

Affiliations

¹ Division of Life Sciences and Applied Life Science (BK 21 Four), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea.
² Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, 6229ER Maastricht, The Netherlands.
³ Alz-Dementia Korea Co., Jinju 52828, Korea.

Abstract

Tyrosine-protein kinase (Syk) plays a potential role in neuroinflammation and adaptive immune responses in several neurodegenerative conditions. Seeing the significant role of Syk in the pathophysiology of neurodegeneration, several pharmacological inhibitors have been developed. One of the known inhibitors of Syk is BAY61-3606, which has shown efficacies in Alzheimer's disease (AD) through regulating amyloid production. However, little is known about its efficacies in neuroinflammation and neurodegeneration. Our finding showed that Syk expression was up-regulated by lipopolysaccharide (LPS)-dependent manner, and BAY61-3606 significantly suppressed the activated microglia (ionized calcium-binding adaptor molecule 1 [Iba-1]) and the inflammatory cytokines (tumor necrosis factor-alpha [TNF-α], interleukin 1-beta [IL-1β], IL-6) and other inflammatory mediators (nuclear factor kappa B [NF-κB], cyclooxygenase-2 [Cox-2], and inducible nitric axide synthase [iNOS]) in the lipopolysaccharide (LPS)-treated in vivo and in vitro models. Moreover, BAY61-3606 significantly reduced microglia-mediated neuronal cell death by regulating the expression of Cytochrome C and Bim (B-cell lymphoma 2 [BCL-2] interacting mediator of cell death) in the LPS-treated mice brain and HT22 cells. Furthermore, the expression of synaptic markers, synaptosomal-associated protein, 25 kDa (SNAP25), synaptophysin (Syp), and postsynaptic density protein-95 (PSD95) in LPS-challenged mice showed that BAY61-3606 significantly recovered the synaptic markers. Finally, we have analyzed the effects of BAY61-3606 against memory and cognitive dysfunctions in the LPS injected mice. The Y-maze test and Passive avoidance test suggested that BAY61-3606 significantly protected against LPS-induced cognitive and memory dysfunctions. The current findings not only highlight the mechanisms of Syk in the pathophysiology of neuro-inflammation, but also support the therapeutic efficacy of BAY61-3606 in the management of neurodegeneration.

Keywords: Syk; cognitive and memory dysfunctions; lipopolysaccharide; microglia; neurodegeneration; neuroinflammation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cognitive Dysfunction* / metabolism
Lipopolysaccharides* / metabolism
Lipopolysaccharides* / pharmacology
Mice
Microglia / metabolism
Neuroinflammatory Diseases
Syk Kinase / metabolism

Substances

Lipopolysaccharides
Syk Kinase

Grants and funding

This research was supported by the Neurological Disorder Research Program of the National Research Foundation (NRF) funded by the Korean Government (MSIT) (2020M3E5D9080660).