Comparison of hypericum extracts with imipramine and fluoxetine in animal models of depression and alcoholism

https://doi.org/10.1016/S0924-977X(99)00005-XGet rights and content

Abstract

Clinical evidence suggests that hypericum extracts (Hypericum perforatum L., St. John’s wort) have antidepressive properties and may offer an interesting alternative for the treatment of mood disorders. In addition, hypericum extracts, as well as standard antidepressants such as the tricyclic, impramine, and the selective serotonin reuptake inhibitor, fluoxetine, have been reported to be of therapeutic benefit in the treatment of alcoholism, as these compounds may reduce alcohol craving and/or intake in particular subgroups of patients. It was the aim of the present study to compare the effects of hypericum extracts with those of imipramine and fluoxetine in the rat forced swimming test (RFST), a model of depression, as well as in cAA rats, a genetic model of alcoholism. In the RFST, triple i.p. administration of imipramine (3–30 mg/kg) and fluoxetine (3–30 mg/kg) induced a dose-dependent reduction in immobility; the minimal effective dose (MED) being 30 and 10 mg/kg, and the maximal effect being 50% and 57% immobility reduction, for imipramine and fluoxetine, respectively. In this test, the hypericum extracts Ze 117 (Remotiv®) and LI 160 (Jarsin®) also induced a statistically significant reduction of immobility when administered under the same application schedule (5–40 mg/kg, i.p., triple application). In the case of the hypericum extracts the dose–response relationship was inverted U-shaped with a MED value of 20 mg/kg and a maximal effect of 41% and 32% immobility reduction, for Ze 117 and LI 160, respectively. Interestingly, the anti-immobility effects tended to be more pronounced after subacute (1 week, B.I.D.) treatment with 10 mg/kg of imipramine, fluoxetine, or Ze 117, as compared with acute treatment. This phenomenon is in accordance with clinical experience and suggests that repeated treatment is required for full development of antidepressive effects. In the alcohol-preferring cAA rats, acute i.p. administration of imipramine (3–30 mg/kg), fluoxetine (1–10 mg/kg) and Ze 117 (10–40 mg/kg) dose-dependently reduced alcohol intake in a 12-h limited access two-bottle [ethanol 10% (v/v) versus water] choice procedure; with MED values of 30, 5 and 20 mg/kg, respectively. The anti-alcohol effects of fluoxetine and Ze 117 appeared to be specific, as reductions in alcohol intake coincided with reductions in alcohol preference. The present study suggests that hypericum extracts have antidepressant-like properties which resemble those of clinically established antidepressants, and that Remotiv® may be an interesting adjunct for the treatment of alcoholism.

Introduction

Clinical evidence suggests that hypericum extracts (Hypericum perforatum L., St. John’s wort) have antidepressive properties and may offer an interesting alternative for the treatment of mood disorders (for review, see: Linde et al., 1996; Volz, 1997). Thus far, however, it remains unclear to what extent the antidepressive efficacy of hypericum extracts compares to that of standard antidepressants, such as the tricyclics (e.g., imipramine), or the selective serotonin reuptake inhibitors (SSRIs; e.g., fluoxetine). Also in preclinical studies, antidepressant-like effects of hypericum extracts have been reported. Thus, indications for antidepressive efficacy were obtained in animal models based on stress-induced behavioral deficits, such as the mouse or rat forced swimming test, the mouse tail suspension test, or the rat learned helplessness test (Butterweck et al., 1997; Gambarana et al., 1996; Öztürk, 1997; Okpanyi and Weischer, 1987; Winterhoff et al., 1993, Winterhoff et al., 1995). Unfortunately, it remains difficult to evaluate such extracts with respect to potency and efficacy, as no dose–response data comparing different hypericum extracts with each other, and with standard antidepressants, have been reported in these preclinical studies. In addition, as it is well known that, similar to the clinical situation, repeated treatment is required for full development of antidepressive efficacy of tricyclics and SSRIs in these animal models of depression (e.g., De Vry and Schreiber, 1993), it remains to be demonstrated whether such a sensitization effect also occurs in the case of hypericum extracts. The only study on the effects of repeated treatment with a hypericum extract suggests that at least no tolerance appears to develop for the antidepressant-like effects of these compounds in the rat forced swimming test (Winterhoff et al., 1995). However, the lack of an appropriate control group in the latter study precludes any conclusion on the possible development of sensitization of the antidepressant-like effects.

Recent clinical studies have indicated that antidepressants, including the tricyclic imipramine, and the SSRI fluoxetine, may be of therapeutic benefit in the treatment of alcoholism, as these compounds may reduce alcohol craving and/or intake in particular subgroups of patients (Cornelius et al., 1993; Kranzler et al., 1995; Naranjo et al., 1990; Nunes et al., 1993; for review, see: Anton, 1996). Interestingly, it has been suggested that hypericum extracts may also be beneficial for the treatment of alcoholic patients (Anonymus, 1996; Krylov and Ibatov, 1993). Both fluoxetine (e.g., De Vry et al., 1996; Maurel et al., 1999b, Maurel et al., 1998; Zabik et al., 1982) and imipramine (de Beun et al., 1996b) have previously been reported to attenuate the intake of ethanol (EtOH) in particular animal models of alcoholism. Thus far, however, no comparative study on the effects of hypericum extract and these compounds in such a model has been reported.

It was the aim of the present study to compare the efficacy of the methanolic hypericum extract LI 160 (Jarsin), with that of the ethanolic hypericum extract Ze 117 (Remotiv), as well as, with that of imipramine and fluoxetine in animal models of depression and alcoholism. Therefore, the effects of different doses of these compounds were compared in the rat forced swimming model of depression, under a standardized application schedule (i.e., three applications in 24 h; De Vry and Schreiber, 1993; Porsolt et al., 1977). In order to investigate possible sensitization effects, repeated treatment for 1 week (nine applications, B.I.D.) with Ze 117, imipramine and fluoxetine was compared with administration of these compounds under the standardized application schedule, preceeded by the appropriate vehicle control applications. In order to assess the potential anti-alcohol effects of hypericum extract, the effects of acute treatment with Ze 117 was compared with that of imipramine and fluoxetine in alcohol-preferring cAA rats (Maurel et al., 1999a). These rats derive from the Finnish alcohol-preferring AA rats (for review, see: Sinclair et al., 1989) and have been used extensively for the characterization of novel pharmacotherapies of alcoholism (e.g., De Beun et al., 1996a, De Beun et al., 1996b; De Vry et al., 1996; Maurel et al., 1999b; Schreiber et al., 1993). In this model, effects on excessive EtOH intake and EtOH preference are compared with effects on food and total fluid intake under a standardized 12-h limited access, two-bottle (EtOH 10% v/v versus water) choice procedure. This allows for an assessment of the specificity of the anti-alcohol effect of a compound (i.e., the extent to which a reduction in EtOH intake coincides with a reduction in EtOH preference); as well as its selectivity (i.e., the extent to which a reduction in EtOH intake can be dissociated from a general reduction of food or fluid intake).

Section snippets

Animals

For the rat forced swimming test, male Wistar rats were purchased from Harlan-Winkelmann (Borchen, Germany). Body weight upon arrival at the laboratory was around 200 g. Rats were individually housed in Makrolon type three cages under a normal 12-h light/dark period (light on at 7:00 a.m.), with unrestricted access to food (standard pellets; Ssniff Spezialdiäten, Soest, Germany) and water ad libitum. Ambient temperature and relative humidity were maintained at 22±1°C and at 55±5%, respectively.

Acute experiment

Effects of acute administration of imipramine, fluoxetine (both: 3–30 mg/kg) and the hypericum extracts Ze 117 and LI 160 (both: 5–40 mg/kg) on immobility scores are shown in Fig. 1. The reference antidepressants, imipramine and fluoxetine, induced a dose-dependent reduction in immobility [imipramine: F(3,20)=11.41, P<0.001; fluoxetine: F(3,20)=26.59, P<0.001]; the maximal effect being 50% and 57% immobility reduction, for imipramine and fluoxetine, respectively. Fluoxetine appeared to be

Discussion

In the present study, it was found that treatment with the hypericum extracts Ze 117 and LI 160 reduces stress-induced immobility; with a potency comparable to, and an efficacy slightly less than that of the tricyclic imipramine and the SSRI fluoxetine. Direct comparison of Ze 117 and LI 160 in this animal model of depression indicated that both extracts were generally equipotent (same MED value of 20 mg/kg); whereas the former compound was slightly more effective than the latter (i.e.,

References (46)

  • F. Borsini et al.

    Is the forced swimming test a suitable model for revealing antidepressant activity?

    Psychopharmacology

    (1988)
  • V. Butterweck et al.

    Effects of the total extract and fractions of Hypericum perforatum in animal assays for antidepressant activity

    Pharmacopsychiatry

    (1997)
  • Chatterjee, S.S., Koch, E., Nölder, M., Biber, A., Erdelmeier, C., 1996. Hyperforin and hypericum extract: interactions...
  • J.R. Cornelius et al.

    Fluoxetine trial in suicidal depressed alcoholics

    Psychopharmacol. Bull.

    (1993)
  • J.M. Cott

    In vitro receptor binding and enzyme inhibition by Hypericum perforatum extract

    Pharmacopsychiatry

    (1997)
  • R. De Beun et al.

    Relationship between emotional behavior and subsequent alcohol preference in alcohol preferring AA rats

    Alcohol Alcohol.

    (1995)
  • R. De Beun et al.

    Pharmacotherapy of alcoholism: effects of clinically evaluated compounds in alcohol-preferring AA rats

    Behav. Pharmacol.

    (1996)
  • L. Demisch et al.

    Identification of selective MAO-type-A inhibitors in Hypericum perforatum L. (Hyperforat®)

    Pharmacopsychiatry

    (1989)
  • J. De Vry et al.

    Comparison of acute and repeated treatment with the 5-HT1A receptor ligands 8-OH-DPAT and ipsapirone in animal models of anxiety and depression

    Drug Dev. Res.

    (1993)
  • J. De Vry et al.

    Identification of the 5-HT receptor subtypes involved in ethanol consumption in alcohol-preferring AA rats

    Behav. Pharmacol.

    (1996)
  • C. Gambarana et al.

    The administration of an hydro-alcoholic extract of hypericum perforatum prevents the induction of learned helplessness in rats

  • H.-D. Höltje et al.

    Molecular modeling of the antidepressive mechanism of hypericum ingredients

    Nervenheilkunde

    (1993)
  • J. Hölzl

    Inhaltsstoffe und Wirkmechanismen des Johanniskrautes

    Z. Phytother.

    (1993)
  • Cited by (78)

    • Imipramine administered before the first of two forced swim sessions results in reduced immobility in the second session 24 h later

      2019, Behavioural Brain Research
      Citation Excerpt :

      Finally, this study will provide a chance to replicate our previous results on the effect of dopamine D1-like and D2-like receptor antagonists on the FST behavioural response [34]. To this end, we examined the effects of the dopamine D1-like and D2-like receptor antagonists SCH 23390 [40] and raclopride [41] on the effect of imipramine 20 mg/kg × 3/24-h [15,42,43] administered before a 15-min FST session, followed by a 5-min session performed 24-h later. In two separate experiments, the effects of these antagonists at low dose (Experiment 1) and at high dose (Experiment 2) were examined.

    • St. John’s Wort (Hypericum perforatum)

      2018, Nonvitamin and Nonmineral Nutritional Supplements
    • Biosynthetic and Total Synthetic Approaches for (-)-Hyperforin: A Potent Antidepressant Agent From Hypericum perforatum Linn. (St. John's Wort)

      2018, Discovery and Development of Neuroprotective Agents from Natural Products: Natural Product Drug Discovery
    • Behavioral and neurochemical studies in mice pretreated with garcinielliptone FC in pilocarpine-induced seizures

      2014, Pharmacology Biochemistry and Behavior
      Citation Excerpt :

      This work proposes to study a compound isolated from species P. insignis, popularly known in Brazil as “bacuri”. Belonging to the family Clusiaceae, P. insignis is popularly used as antidepressants (Bilia et al., 2002; Viana et al., 2005), being equivalent to fluoxetine and imipramine, with reduced adverse effects (De Vry et al., 1999). This compound corresponds to a polyprenylated acylphloroglucinol benzophenone which has a core (diphenyl methanone) substituted groups isoprenylates (3-methyl-2-butenila) and 2-isopropenyl-hex-5-enyl.

    • Chronic corticosterone administration from adolescence through early adulthood attenuates depression-like behaviors in mice

      2011, Journal of Affective Disorders
      Citation Excerpt :

      Mice were individually placed in clear perspex cylinders (height = 25 cm; diameter = 20 cm) containing 15 cm depth of water at 25 ± 1 °C. The trial was conducted for 6 min (De Vry et al., 1999) and the behavior was video recorded. The total period of immobility during the final 4 min was assessed by a blinded observer.

    • Pharmacological studies in an herbal drug combination of St. John's Wort (Hypericum perforatum) and passion flower (Passiflora incarnata): In vitro and in vivo evidence of synergy between Hypericum and Passiflora in antidepressant pharmacological models

      2011, Fitoterapia
      Citation Excerpt :

      For these three psychoactive herbal extracts, the extent of the evidence of their pharmacological characteristics varies greatly with most information being available for Hypericum extracts, which is one of the most sold phytomedicines in Europe. In various models of depression, Hypericum extracts have been shown to act like conventional antidepressant drugs [1–3]. Hypericum exerts a variety of effects on central neurotransmitter systems [4,5].

    View all citing articles on Scopus
    View full text