title: Cucurbitacin IIa exerts antidepressant-like effects on mice exposed to chronic unpredictable mild stress.
abstract: Cucurbitacin IIa (CuIIa) is the major active component of the Helmseya amabilis root and is known to have antiviral and anti-inflammatory effects. In this study, we examined the antidepressant-like effects of CuIIa in a mouse model of chronic unpredictable mild stress (CUMS) and investigated the possible underlying mechanisms. To evaluate the antidepressant-like effects of CuIIa on depression-like behaviors, mice were subjected to the open-field test, the elevated plus-maze test, the forced-swimming test, and the tail-suspension test. We found that CuIIa treatment reversed the CUMS-induced behavioral abnormalities. Western blot analyses showed that CUMS significantly decreased brain-derived neurotrophic factor (BDNF) levels, cAMP-response element binding protein (CREB), and calcium/calmodulin-dependent protein kinase II (CaMKII) phosphorylation, and N-methyl-D-aspartate receptor subtype GluN2B and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluA1 expression in the amygdala; in addition, the expression of gamma-aminobutyric acid receptor A subunit α2 was upregulated in CUMS mice. These CUMS-induced changes were all normalized by CuIIa treatment and administration of the BDNF antagonist ANA-12 can block the antidepressant effect of CuIIa. Our findings suggest that the antidepressant-like effects of CuIIa may be exerted by regulation of the CaMKIIα-CREB-BDNF pathway and the balance between excitatory and inhibitory synaptic transmission in the amygdala.
authors.affiliation: Departments of aPharmacology bMedicinal Chemistry cPharmaceutical Analysis, School of Pharmacy dClinical medicine Cadet Brigade, Fourth Military Medical University, Xi'an, China.
authors.forename: Shi-Meng
authors.initials: SM
authors.lastname: Zhou
authors.forename: Shao-Yu
authors.initials: SY
authors.lastname: Guan
authors.forename: Le
authors.initials: L
authors.lastname: Yang
authors.forename: Liu-Kun
authors.initials: LK
authors.lastname: Yang
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Hui-Fang
authors.initials: HF
authors.lastname: Nie
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.forename: Ming-Gao
authors.initials: MG
authors.lastname: Zhao
authors.forename: Qi
authors.initials: Q
authors.lastname: Yang
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001381:Azepines / Q000627:therapeutic use; D001549:Benzamides / Q000627:therapeutic use; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D050882:CREB-Binding Protein / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002908:Chronic Disease; D054728:Cucurbitacins / Q000627:therapeutic use*; D003863:Depression / Q000188:drug therapy* / Q000209:etiology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D019417:Hindlimb Suspension; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013315:Stress, Psychological / Q000150:complications* / Q000188:drug therapy; D013550:Swimming / Q000523:psychology
chemical_list: C559317:ANA 12 compound; D000928:Antidepressive Agents; D001381:Azepines; D001549:Benzamides; D019208:Brain-Derived Neurotrophic Factor; D016194:Receptors, N-Methyl-D-Aspartate; C557526:cucurbitacin IIa; D054728:Cucurbitacins; D050882:CREB-Binding Protein; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2