title: Cytokines and glucocorticoid receptors are associated with the antidepressant-like effect of alarin.
abstract: Little is known about the physiological or pharmacological properties of alarin, a new neuropeptide belonging to the galanin family. We previously showed that alarin has an antidepressant-like effect and is associated with a decrease in the hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis that is observed in patients with depression using unpredictable chronic mild stress (UCMS) mouse model of depression. However, the mechanisms underlying these effects have not been uncovered. Inflammatory cytokines are reportedly associated with depression. Animal studies and cytokine immune therapy in humans suggest that pro-inflammatory cytokines induce depressive symptomatology and potently activate the HPA axis, whereas anti-inflammatory cytokines may decrease activation. Thus, we first determined the levels of inflammatory cytokines in the blood and brain to evaluate whether the antidepressant-like effect of alarin in UCMS-treated mice is related to its regulation of these inflammatory cytokines. Pro-inflammatory cytokines disrupt the function and/or expression of glucocorticoid receptors (GRs), which mediate the negative feedback of glucocorticoids on the HPA axis to keep it from being overactivated. We next explored the expression level of GRs in the brains of mice subjected to UCMS and to the administration of alarin. We found that intracerebroventricular administration of alarin significantly ameliorated depression-like behaviors in the UCMS-treated mice. Alarin restored the UCMS-induced an increase in the levels of the pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor α and a decrease in the anti-inflammatory cytokine IL-10 level in the blood, prefrontal cortex, hippocampus and hypothalamus. Alarin also reversed the UCMS-induced down-regulation of GR expression in these brain regions. Thus, the antidepressant-like effects of alarin may be mediated by restoring altered pro-inflammatory and anti-inflammatory cytokine levels and GR expression to decrease HPA axis hyperactivity. Our findings provide additional knowledge to interpret the pathophysiology of depression.
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Department of Pharmacology, Xuzhou Medical College, Xuzhou 221004, China.
authors.forename: Fuzhi
authors.initials: F
authors.lastname: Zhuang
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Department of Pharmacology, Xuzhou Medical College, Xuzhou 221004, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Department of Pharmacology, Xuzhou Medical College, Xuzhou 221004, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Gao
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Department of Pharmacology, Xuzhou Medical College, Xuzhou 221004, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Lou
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Department of Pharmacology, Xuzhou Medical College, Xuzhou 221004, China.
authors.forename: Xuesheng
authors.initials: X
authors.lastname: Bi
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Department of Pharmacology, Xuzhou Medical College, Xuzhou 221004, China.
authors.forename: Shoujun
authors.initials: S
authors.lastname: Qin
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Department of Pharmacology, Xuzhou Medical College, Xuzhou 221004, China.
authors.forename: Chuxiao
authors.initials: C
authors.lastname: Sun
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Department of Pharmacology, Xuzhou Medical College, Xuzhou 221004, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Ye
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Department of Pharmacology, Xuzhou Medical College, Xuzhou 221004, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Department of Pharmacology, Xuzhou Medical College, Xuzhou 221004, China.
authors.forename: Tengfei
authors.initials: T
authors.lastname: Ma
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Department of Pharmacology, Xuzhou Medical College, Xuzhou 221004, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Department of Pharmacology, Xuzhou Medical College, Xuzhou 221004, China. Electronic address: gushling@aliyun.com.
authors.forename: Shuling
authors.initials: S
authors.lastname: Gu
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003863:Depression / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical; D044089:Galanin-Like Peptide / Q000008:administration & dosage / Q000494:pharmacology*; D015870:Gene Expression; D008297:Male; D008810:Mice, Inbred C57BL; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D016207:Cytokines; D044089:Galanin-Like Peptide; D011965:Receptors, Glucocorticoid; C581934:alarin
keywords: Alarin; Depression; Glucocorticoid receptor; HPA axis; Inflammatory cytokines