Diene Valepotriates from Valeriana glechomifolia Prevent Lipopolysaccharide-Induced Sickness and Depressive-Like Behavior in Mice

Abstract

Valeriana glechomifolia, a native species from southern Brazil, presents antidepressant-like activity and diene valepotriates (VAL) contribute to the pharmacological properties of the genus. It is known that depression can develop on an inflammation background in vulnerable patients and antidepressants present anti-inflammatory properties. We investigated the effects of VAL (10 mg/kg, p.o.) on sickness and depressive-like behaviors as well as proinflammatory cytokines (IL-1β and TNF-α) and BDNF expression in the cortex of mice exposed to a 5 min swimming session (as a stressful stimulus) 30 min before the E. coli LPS injection (600 µg/kg, i.p.). The forced swim + LPS induced sickness and depressive-like behaviors, increased the cortical expression of IL-1β and TNF-α, and decreased BDNF expression. VAL was orally administered to mice 1 h before (pretreatment) or 5 h after (posttreatment) E. coli LPS injection. The pretreatment with VAL restored the behavioral alterations and the expression of cortical proinflammatory cytokines in LPS-injected animals but had no effects on BDNF expression, while the posttreatment rescued only behavioral alterations. Our results demonstrate for the first time the positive effects of VAL in an experimental model of depression associated with inflammation, providing new data on the range of action of these molecules.

Figure 1

Experimental timeline and design. OFT: open field test; TST: tail suspension test.

Figure 2

Diene valepotriates found in Valeriana glechomifolia.

Figure 3

Effects of diene valepotriates from V. glechomifolia (VAL) pretreatment on sickness and depressive-like behavior induced by a stressful stimulus (6 min forced swimming session) + E. coli LPS injection in mice. The animals were orally treated with VAL (10 mg/kg, p.o.) or imipramine (IMI, used as a positive control, 20 mg/kg, p.o.) 1 hour before being exposed to the forced swim + LPS and were evaluated in the open field and tail suspension tests 6 h (Panels (a) and (b)) and 24 h after (Panels (c) and (d)) the immune challenge. Each column represents the mean ± S.E.M (n = 8–12 mice/group). Two-way ANOVA, post hoc Student-Newman-Keuls test. ^∗ p < 0.05; ^∗∗ p < 0.01; ^∗∗∗ p < 0.001.

Figure 4

Effects of diene valepotriates from V. glechomifolia (VAL) posttreatment on sickness and depressive-like behavior induced by a stressful stimulus (6 min forced swimming session) + E. coli LPS injection in mice. The animals were orally treated with VAL (10 mg/kg, p.o.) or imipramine (IMI, used as a positive control, 20 mg/kg, p.o.) 5 hours after being exposed to the forced swim + LPS and were evaluated in the open field and tail suspension tests 6 h (Panels (a) and (b)) and 24 h after (Panels (c) and (d)) the immune challenge. Each column represents the mean ± S.E.M (n = 8–12 mice/group). Two-way ANOVA, post hoc Student-Newman-Keuls test. ^∗ p < 0.05; ^∗∗ p < 0.01.

Figure 5

Effects of diene valepotriates from V. glechomifolia (VAL) pretreatment on the alterations in the cortical expression of IL1-β (Panel (a)), TNF-α (Panel (b)), and BDNF (Panel (c)) induced by a stressful stimulus (6 min forced swimming session) + E. coli LPS injection in mice. The animals were orally treated with VAL (10 mg/kg, p.o.) or imipramine (IMI, used as a positive control, 20 mg/kg, p.o.) 1 hour before being exposed to the forced swim + LPS and the tissues were collected 25 h later. Each column represents the mean (n = 4 mice/group). One-way ANOVA, post hoc Student-Newman-Keuls test. ^∗∗ p < 0.01; ^∗∗∗ p < 0.001 versus Naïve group; ### versus Vehicle+LPS-treated group.

Figure 6

Effects of diene valepotriates from V. glechomifolia (VAL) posttreatment on the alterations in the cortical expression of IL1-β (Panel (a)), TNF-α (Panel (b)), and BDNF (Panel (c)) induced by a stressful stimulus (6 min forced swimming session) + E. coli LPS injection in mice. The animals were orally treated with VAL (10 mg/kg, p.o.) or imipramine (IMI, used as a positive control, 20 mg/kg, p.o.) 5 hours after being exposed to the forced swim + LPS and the tissues were collected 25 h later. Each column represents the mean (n = 4 mice/group). One-way ANOVA, post hoc Student-Newman-Keuls test. ^∗∗∗ p < 0.001 versus Naïve group; ^# p < 0.05 versus Vehicle + LPS-treated group.