Antidepressant-like effect of a Ginkgo biloba extract (EGb761) in the mouse forced swimming test: Role of oxidative stress
Highlights
► EGb761 produces antidepressant-like effect in the forced swimming test. ► Protection by EGb761 is not related to excitatory or inhibitory effects. ► Antidepressant-like effect is associated to a reduction of lipid peroxidation. ► Protection is also related to a downregulation of Mn-superoxide dismutase activity. ► EGb761 has antioxidant effect against oxidative stress in this animal model.
Introduction
Depression is one of the most prevalent, serious, recurrent, incapacitating and costly psychopathologies worldwide. Depression is characterized by altered mood and cognitive functions, and recurrent thoughts of death or suicide with a lifetime incidence of 15–25% (Paykel, 2006). The World Health Organization predicts that depression will be the second cause of loss in human disability-adjusted life years worldwide. Although the mechanism provoking depression has not been clearly elucidated oxidative stress, via free radical production, may play an important role in its pathophysiology (Ng et al., 2008).
Free radicals are produced constitutively under normal physiological conditions. Organisms have developed various defense mechanisms to protect themselves against injury from free radicals including antioxidant enzymes (catalase, glutathione peroxidase, and superoxide dismutase), free radical scavengers, and metal chelating agents (Reiter, 1995). Normally, there is a balance between the generation of free radicals and antioxidant defense system activity. When this balance is altered to favour production of free radicals due to depletion of antioxidant-system components or increased generation of free radicals, oxidative stress occurs (Halliwel, 1992). Oxidative stress leads to damage of polyunsaturated lipids by lipid peroxidation (LP), a chain-reaction that results in numerous degradation products (Niki et al., 1993). In particular, a number of oxidative disturbances in depressed patients have been reported, including enhanced oxidative damage and decreased antioxidant enzyme levels (Ng et al., 2008, Sarandol et al., 2007). Moreover, preclinical studies have suggested that antioxidants (radical scavengers) may have antidepressant properties (Eren et al., 2007, Zafir et al., 2009). It appears reasonable to propose that exogenous antioxidants may be effective in treating depression. Many available synthetic chemical antidepressants have low rates of response, remission and severe adverse effects (Nestler et al., 2002). There are several phytomedicines that have been introduced into psychiatric practice because of greater compliance and milder side effects (Thachil et al., 2007).
The Ginkgo biloba extract termed EGb761 has become one of the most widely used medicinal plant products in Europe. It has been used in clinics for the treatment of cerebrovascular insufficiency, degenerative dementia, peripheral vascular disturbances, and neurosensory disorders (DeFeudis and Drieu, 2000). EGb761 is a well-known extract obtained from leaves of the Ginkgo biloba tree according to a standardized procedure (Drieu, 1986). The patented extract EGb761 contains two main groups of active compounds, flavonoid glycosides (24%) and terpene lactones (6%) of low molecular weight that permit their penetration of the blood–brain barrier (DeFeudis and Drieu, 2000). The flavonoid fraction is composed of three flavonoids: quercetin, kaempferol, and isorhamnetin, which are linked to a sugar. The terpenoid fraction is composed of ginkgolides A, B, C, M, J and bilobalides (Drieu, 1986). EGb761 exhibits a broad spectrum of pharmacological actions in the central nervous system (DeFeudis and Drieu, 2000). It has been proposed that EGb761 has neuroprotective effects, via its potent antioxidant action (Droy-Lefaix et al., 1995, Rojas et al., 2001, Rojas et al., 2008), and as a free radical scavenger (Maitra et al., 1995, Marcocci et al., 1994a, Ni et al., 1996). We have shown that EGb761 could be used as an antioxidant in an animal model of Parkinson’s disease (Rojas et al., 2001, Rojas et al., 2008).
The forced swimming test (FST) is a well-established preclinical animal model for depression and represents an acute stressful event (Porsolt et al., 1977). The existence of oxidative stress in this depression model has been reported (Akhtar et al., 2005). The aim of this study was to investigate the antidepressant-like effect of EGb761 due to its antioxidant role against oxidative stress induced in the forced swimming test. We analyzed spontaneous locomotor activity, serotonin and dopamine turnover ratio, LP, and different antioxidant enzyme activities such as Mn-superoxide dismutase (Mn-SOD), Cu, Zn-superoxide dismutase (Cu, Zn-SOD), glutathione peroxidase, and glutathione reductase.
Section snippets
Materials
EGb761 was provided by Schwabe Pharmaceuticals (Karlsruhe, Germany). Sodium octyl sulfate, sodium metabisulfite, glutathione reductase, NADPH, homovanillic acid, dopamine, serotonin, 5-HIAA, and imipramine hydrochloride were obtained from Sigma–Aldrich (St. Louis, MO, USA). Perchloric acid, thiobarbituric acid, EDTA (Merck, Darmstadt, Germany), polyclonal anti-Cu, Zn-SOD and polyclonal anti-Mn-SOD antibodies (Stressgen Biotechnologies Co., Victoria, BC, Canada), a chemiluminescence detection
EGb761 produces antidepressant-like effect in the FST
EGb761 (10 mg/kg) and imipramine (classical antidepressant) significantly reduced the duration of immobility (41% and 40%, respectively) in the FST (Fig. 1) as compared to the vehicle-treated control group (F2,109 = 22.865, P < 0.001), suggesting an antidepressant-like effect of EGb761.
In the EGb761 dose-response study the degree of antidepressant-like effect was reduced at 5 mg/kg (30%) when compared to the vehicle-treated control group. However, doses of 20 and 40 mg/kg of EGb761 differences were
Discussion
There is an increasing interest in the study of the antidepressant effect of herbs, since treatment of depression with conventional antidepressants results in complete remission in almost 50% of individuals (Nestler et al., 2002). Several research groups have shown that Ginkgo biloba extracts have diverse effects on improvement of mood and cognitive performance, and protection against memory deficits and central nervous system disorders (DeFeudis and Drieu, 2000, Polich and Gloria, 2001, Trick
Acknowledgements
This study was partially supported by the National Council of Science and Technology of Mexico (CONACyT) CB-2008-01, No. 106619. We thank Dr. Robyn Elizabeth Hudson for her valuable comments and Alberto Julio for his technical assistance.
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