Antidepressant effects of resveratrol in an animal model of depression

Abstract

Resveratrol (3,4',5-trihydroxy-trans-stilbene) is a natural non-flavonoid polyphenol antioxidant extracted from red grapes in the processing of wine. Initially it was studied for its potential as anticancer drug, and later was found to reduce cardiovascular disease. More recently resveratrol was shown to alleviate depressive-like symptoms induced by stress or other means in mice and rats. The major purpose of this study was to investigate whether resveratrol would manifest an antidepressant effect in Wistar-Kyoto (WKY) rats, a putative and non-induced animal model of depression, and whether this effect might be associated with an increase in hippocampal and frontal cortical brain-derived neurotrophic factor (BDNF), a protein implicated in chronic effects of many antidepressants. Adult male WKY rats were injected with two doses of resveratrol (10 and 40 mg/kg, i.p.) and their behavior in the open field locomotor activity (LMA), forced swim test (FST: a measure of helplessness), and sucrose preference test (SPT: a measure of anhedonia) was evaluated after a single acute injection or following 7 days of daily treatment. Both acute and chronic administration of resveratrol resulted in a dose-dependent decrease in FST. However, only chronic resveratrol resulted in dose-dependent increase in sucrose consumption. LMA was not affected by any treatment. Parallel to the observed behavioral effects the level of hippocampal, but not frontal cortical, BDNF was also dose-dependently elevated after chronic resveratrol administration. These findings indicate an antidepressant-like effect of resveratrol in an animal model of depression possibly via activation of hippocampal BDNF, and suggest therapeutic potential of resveratrol in at least a subpopulation of depressed patients.

Keywords: Animal model; BDNF; Depression; Hippocampus; Resveratrol.

Fig 1

Schematic of drug treatment and behavioral testing. Sucrose habituation occurred the week before testing began. BEH – Behavioral testing occurred 20 min after acute injection, after one week of daily chronic injections, and again one week after chronic injections were stopped. Animals where then rested 10 days before receiving another week of chronic injections before sacrifice for brain collection, denoted by X.

Fig 2

Effects of acute and chronic (7day) treatment with two doses of resveratrol on immobility in the forced swim test. The animals were tested 20 min after the acute injection and 18-20 h after the last chronic injection. The animals were tested again after one week of rest (post treatment). Values are mean ± SEM. N = 6/group. *p<0.05, **p<0.01 compared to control.

Fig 3

Effects of acute and chronic (7day) treatment with two doses of resveratrol on open field locomotor activity (distance travelled cm). The animals were tested 20 min after the acute injection and 18-20 h after the last chronic injection. The animals were tested again after one week of rest (post treatment). Values are mean ± SEM. N = 6/group.

Fig 4

Effects of acute and chronic (7day) treatment with two doses of resveratrol on sucrose preference (% sucrose/total liquid consumption). The animals were tested for 12 h after acute or chronic injections. The animals were tested again after one week of rest (post treatment). Values are mean ± SEM. N = 6/group. *p<0.05, **p<0.01 compared to control.

Fig 5

Effects of chronic (7day) treatment with two doses of resveratrol on BDNF levels in the hippocampal and frontal cortex. The animals were sacrificed 18-20 h after the last injection. The upper panel depicts the immunoblots in Western assay. Values are mean ± SEM. N = 6/group. *p<0.05, **p<0.01 compared to control.

Fig 5

Effects of chronic (7day) treatment with two doses of resveratrol on BDNF levels in the hippocampal and frontal cortex. The animals were sacrificed 18-20 h after the last injection. The upper panel depicts the immunoblots in Western assay. Values are mean ± SEM. N = 6/group. *p<0.05, **p<0.01 compared to control.