title: Peripheral immunomodulation with ginsenoside Rg1 ameliorates neuroinflammation-induced behavioral deficits in rats.
abstract: Neuroinflammatory disturbances have been closely associated with depression and many other neuropsychiatric diseases. Although targeting neuroinflammatory mediators with centrally acting drugs has shown certain promise, its translation is faced with several challenges especially drug delivery and safety concerns. Here, we report that neuroinflammation-induced behavioral abnormality could be effectively attenuated with immunomodulatory agents that need not to gain brain penetration. In a rat model with intracerebral lipopolysaccharide (LPS) challenge, we validated that ginsenoside Rg1 (Rg1), a well-established anti-inflammatory agent, was unable to produce a direct action in the brain. Interestingly, peripherally restricted Rg1 could effectively attenuate the weight loss, anorexic- and depressive-like behavior as well as neurochemical disturbances associated with central LPS challenge. Biochemical assay of neuroimmune mediators in the periphery revealed that Rg1 could mitigate the deregulation of the hypothalamic-pituitary-adrenal axis and selectively blunt the increase in circulating interleukin-6 levels. Furthermore, these peripheral regulatory effects were accompanied by dampened microglial activation, mitigated expression of pro-inflammatory mediators and neurotoxic species in the central compartment. Taken together, our work suggested that targeting the peripheral immune system may serve as a novel therapeutic approach to neuroinflammation-induced neuropsychiatric disorders. Moreover, our findings provided the rationale for employing peripherally active agents like Rg1 to combat mental disturbances.
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, PR China; Department of Pharmaceutical Preparation, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, PR China.
authors.forename: X
authors.initials: X
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, PR China; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China.
authors.forename: A
authors.initials: A
authors.lastname: Kang
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: S-J
authors.initials: SJ
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: L
authors.initials: L
authors.lastname: Xing
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Y-Y
authors.initials: YY
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: C
authors.initials: C
authors.lastname: Dai
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: H
authors.initials: H
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: L
authors.initials: L
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: guangjiwang@hotmail.com.
authors.forename: G-J
authors.initials: GJ
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: hhp_770505@yahoo.com.cn.
authors.forename: H-P
authors.initials: HP
authors.lastname: Hao
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002491:Central Nervous System Agents / Q000627:therapeutic use*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D004660:Encephalitis / Q000139:chemically induced / Q000150:complications*; D004797:Enzyme-Linked Immunosorbent Assay; D005518:Food Preferences / Q000187:drug effects; D036145:Ginsenosides / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D001523:Mental Disorders / Q000188:drug therapy* / Q000209:etiology* / Q000276:immunology; D008911:Minocycline / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism
chemical_list: D002491:Central Nervous System Agents; D016207:Cytokines; D036145:Ginsenosides; D008070:Lipopolysaccharides; D012701:Serotonin; D008911:Minocycline; C035054:ginsenoside Rg1
keywords: 5-HIAA; 5-HT; 5-hydroxyindoleacetic acid; BBB; BDNF; CNS drug discovery; COX-2; EDTA; ELISA; HPA; ICAM-1; IL; Iba-1; KA; KYN; LC–MS; LPS; MMPs; MPO; Mino; Myeloperoxidase; Rg1; TNF; blood–brain barrier; brain-derived neurotrophin factor; cyclooxygenase-2; depression; enzyme-linked immunosorbent assay; ethylenediaminetetraacetic acid; ginsenoside Rg1; hypothalamic–pituitary–adrenal; iNOS; inducible nitric oxide synthase; interleukin; intracellular adhesion molecule 1; ionized calcium-binding adaptor molecule-1; kynurenic acid; kynurenine; lipopolysaccharide; liquid chromatography–mass spectrometry; matrix metalloproteinases; microglia; minocycline; neuroinflammation; peripheral target; qPCR; quantitative PCR; serotonin; tumor necrosis factor