The Prototypic Antidepressant Drug, Imipramine, but not Hypericum perforatum (St. John’s Wort), Reduces HPA-Axis Function in the Rat

P. Frost; S. Bornstein; M. Ehrhart-Bornstein; F. O’Kirwan; C. Hutson; D. Heber; V. Go; J. Licinio; M.-L. Wong

doi:10.1055/s-2003-43507

Hormone and Metabolic Research, Inhaltsverzeichnis

Horm Metab Res 2003; 35(10): 602-606
DOI: 10.1055/s-2003-43507

Original Clinical

The Prototypic Antidepressant Drug, Imipramine, but not Hypericum perforatum (St. John’s Wort), Reduces HPA-Axis Function in the Rat

P. Frost¹ , S. Bornstein² , M. Ehrhart-Bornstein² , F. O’Kirwan¹ , C. Hutson¹ , D. Heber³ , V. Go³ , J. Licinio¹ , M.-L. Wong¹

¹Laboratory of Pharmacogenomics, Neuropsychiatric Institute, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
²Department of Endocrinology, Heinrich-Heine University, Dusseldorf, Germany
³Center for Dietary Supplement Research Botanicals, UCLA Center for Human Nutrition, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

Abstract

Dysregulation in corticotropin-releasing hormone (CRH) secretion in the hypothalamus-pituitary-adrenal (HPA) axis may be involved in the etiology of major depressive disorder (MDD). Chronic therapy with standard antidepressant drugs, such as imipramine, can downregulate HPA axis function, indicating that the HPA axis may be an important target for antidepressant action. We tested several doses of a standardized commercial preparation of Hypericum perforatum plant extract (popularly known as St. John’s Wort), a medicinal herb used for treating mild depressive symptoms, to determine whether it also modulated HPA axis function. Chronic imipramine treatment (daily injections for 8 weeks) of male Sprague-Dawley rats significantly downregulated circulating plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone compared to animals treated with saline. However, chronic St. John’s Wort treatment (daily gavage for 8 weeks) had no effect on plasma ACTH or corticosterone, even at the highest doses tested. Our results confirm previous findings that imipramine may have significant peripheral HPA axis-mediated effects. However, our data does not support any role for H. perforatum in modulation of HPA axis function, suggesting that alternative pathways may be involved in mediating its antidepressant effects.

Key words

Major depressive disorder · Stress · ACTH · Corticosterone

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References

1 Regier D A, Narrow W E, Rae D S, Manderscheid R W, Locke B Z, Goodwin F K. The de facto US mental and addictive disorders service system. Epidemiologic catchment area prospective 1-year prevalence rates of disorders and services. Arch Gen Psychiatry. 1993; 50 85-94
2 Keith S J, Matthews S M. The value of psychiatric treatment: its efficacy in severe mental disorders. Psychopharmacol Bull. 1993; 29 427-430
3 Moller H J, Volz H P. Drug treatment of depression in the 1990s. An overview of achievements and future possibilities. Drugs. 1996; 52 625-638
4 Broekkamp C L, Leysen D, Peeters B W, Pinder R M. Prospects for improved antidepressants. J Med Chem. 1995; 38 4615-4633
5 Bilia A R, Gallori S, Vincieri F F. St. John’s wort and depression. Efficacy, safety and tolerability-an update. Life Sci. 2002; 70 3077-3096
6 Linde K, Ramirez G, Mulrow C D, Pauls A, Weidenhammer W, Melchart D. St John’s wort for depression - an overview and meta-analysis of randomised clinical trials [see comments]. Bmj. 1996; 313 253-258
7 Whiskey E, Werneke U, Taylor D. A systematic review and meta-analysis of Hypericum perforatum in depression: a comprehensive clinical review. Int Clin Psychopharmacol. 2001; 16 239-252
8 Muller W E, Rolli M, Schafer C, Hafner U. Effects of Hypericum extract (LI 160) in biochemical models of antidepressant activity. Pharmacopsychiatry. 1997; 2 102-107
9 Muller W E, Singer A, Wonnemann M, Hafner U, Rolli M, Schafer C. Hyperforin represents the neurotransmitter reuptake inhibiting constituent of hypericum extract. Pharmacopsychiatry. 1998; 1 16-21
10 Neary J T, Bu Y. Hypericum LI 160 inhibits uptake of serotonin and norepinephrine in astrocytes. Brain Res. 1999; 816 358-363
11 Wirz A, Simmen U, Heilmann J, Calis I, Meier B, Sticher O. Bisanthraquinone glycosides of Hypericum perforatum with binding inhibition to CRH-1 receptors. Phytochemistry. 2000; 55 941-947
12 Butterweck V, Winterhoff H, Herkenham M. St John’s wort, hypericin, and imipramine: a comparative analysis of mRNA levels in brain areas involved in HPA axis control following short- term and long-term administration in normal and stressed rats. Mol Psychiatry. 2001; 6 547-564
13 Butterweck V, Korte B, Winterhoff H. Pharmacological and endocrine effects of Hypericum perforatum and hypericin after repeated treatment. Pharmacopsychiatry 34 Suppl. 2001; 1 S2-7
14 Franklin M, Chi J D, Mannel M, Cowen P J. Acute effects of LI 160 (extract of Hypericum perforatum, St John’s wort) and two of its constituents on neuroendocrine responses in the rat. J Psychopharmacol. 2000; 14 360-363
15 Franklin M, Cowen P J. Researching the antidepressant actions of Hypericum perforatum (St. John’s wort) in animals and man. Pharmacopsychiatry 34 Suppl. 2001; 1 S29-37
16 Brady L S, Whitfield H J, Jr., Fox R J, Gold P W, Herkenham M. Long-term antidepressant administration alters corticotropin-releasing hormone, tyrosine hydroxylase, and mineralocorticoid receptor gene expression in rat brain. Therapeutic implications. J Clin Invest. 1991; 87 831-837
17 Brady L S, Gold P W, Herkenham M, Lynn A B, Whitfield H J, Jr.. The antidepressants fluoxetine, idazoxan and phenelzine alter corticotropin-releasing hormone and tyrosine hydroxylase mRNA levels in rat brain: therapeutic implications. Brain Res. 1992; 572 117-125
18 Wong M L, Khatri P, Licinio J, Esposito A, Gold P W. Identification of hypothalamic transcripts upregulated by antidepressants. Biochem Biophys Res Commun. 1996; 229 275-279
19 Kasper S. Hypericum perforatum - a review of clinical studies. Pharmacopsychiatry 34 Suppl. 2001; 1 S51-55
20 Manji H K, Drevets W C, Charney D S. The cellular neurobiology of depression. Nat Med. 2001; 7 541-547
21 Kaehler S T, Sinner C, Chatterjee S S, Philippu A. Hyperforin enhances the extracellular concentrations of catecholamines, serotonin and glutamate in the rat locus coeruleus [In Process Citation]. Neurosci Lett. 1999; 262 199-202
22 Gold P W. Stress-responsive neuromodulators. Biol Psychiatry. 1988; 24 371-374
23 Inder W J, Prickett T C, Mulder R T, Donald R A, Joyce P R. Reduction in basal afternoon plasma ACTH during early treatment of depression with fluoxetine. Psychopharmacology (Berl). 2001; 156 73-78
24 Chatterjee S S, Bhattacharya S K, Wonnemann M, Singer A, Muller W E. Hyperforin as a possible antidepressant component of hypericum extracts. Life Sci. 1998; 63 499-510
25 Butterweck V, Wall A, Liefländer-Wulf U, Winterhoff H, Nahrstedt A. Effects of the total extract and fractions of Hypericum perforatum in animal assays for antidepressant activity. Pharmacopsychiatry 30 Suppl. 1997; 2 117-124

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