title: Inhibition of Src tyrosine kinase activity by squamosamide derivative FLZ attenuates neuroinflammation in both in vivo and in vitro Parkinson's disease models.
abstract: The participation of neuroinflammation in the pathogenesis of Parkinson's disease (PD) has long been validated. Excessive activated microglia release a large number of pro-inflammatory factors, damage surrounding neurons and eventually induce neurodegeneration. Inhibition of microglial over-activation might be a promising strategy for PD treatment. FLZ (formulated as: N-(2-(4-hydroxy-phenyl)-ethyl)-2-(2, 5-dimethoxy-phenyl)-3-(3-methoxy-4-hydroxy-phenyl)-acrylamide, the code name: FLZ), a natural squamosamide derivative from a Chinese herb, has been shown to inhibit over-activated microglia and protect dopaminergic neurons in previous studies, but the mechanism remains unclear. In the present study, we further investigated the mechanism in lipopolysaccharide (LPS)-induced in vivo and in vitro PD models. FLZ treatment significantly improved the motor dysfunction of PD model rats induced by intra-nigral injection of LPS and this beneficial effect of FLZ attributed to the inhibition of microglial over-activation and the protection on dopaminergic neurons in the substantia nigra (SN). In vitro mechanistic study revealed that the inhibitive effect of FLZ on microglia was mediated by suppressing Src kinase related inflammatory signaling pathway activation and subsequent NF-κBp65 nuclear translocation, inhibiting nitric oxide (NO) and reactive oxygen species (ROS) production, decreasing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation. In conclusion, the present study supports that FLZ exerts neuroprotection against LPS-induced dopaminergic neurodegeneration through its anti-inflammatory effect, which is mediated by suppressing Src tyrosine kinase and the downstream inflammatory signaling pathway. Furthermore, this study defines a critical role of Src tyrosine kinase in neuroinflammation, and suggests that particular tyrosine kinase inhibition may be a potential anti-inflammatory approach for PD treatment.
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, China.
authors.forename: Wenjiao
authors.initials: W
authors.lastname: Tai
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, China.
authors.forename: Xiuqi
authors.initials: X
authors.lastname: Bao
authors.affiliation: Section of Dermatology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Baozhong
authors.initials: B
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, China.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, China. Electronic address: danzhang@imm.ac.cn.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D044482:Benzeneacetamides / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000188:drug therapy* / Q000209:etiology; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000737:chemistry / Q000494:pharmacology*; D005106:Exploratory Behavior / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010300:Parkinson Disease / Q000150:complications* / Q000209:etiology; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D044482:Benzeneacetamides; D018491:Dopamine Agonists; D020536:Enzyme Activators; D008070:Lipopolysaccharides; D010636:Phenols; C084439:squamosamide; D019061:src-Family Kinases; D001058:Apomorphine
keywords: DA; DOPAC; HVA; Iba-1; LPS; NADPH; NADPH oxidase; NF-κB; NO; Neuroinflammation; ORP; PD; PI3K; Parkinson's disease; ROS; SN; Src tyrosine kinase; TH; TLRs; dihydroxyphenylacetic acid; dopamine; homovanillic acid; ionized calcium binding adaptor molecule-1; lipopolysaccharide; nicotinamide adenine dinucleotide phosphate; nitric oxide; nuclear factor κB; overall rod performance; phosphorylated phosphoinositide 3-kinase; reactive oxygen species; substantia nigra; toll-like receptors; tyrosine hydroxylase