Study 16

Modulation of cytokine expression by hypericum extract

AU: Thiele-B; Brink-I; Ploch-M

AD: Medizinische Fakultat (Charite) der Humboldt Universitat zu Berlin, Germany.

SO: J-Geriatr-Psychiatry-Neurol. 1994 Oct; 7 Suppl 1: S60-2

Introduction

Recent research suggests that except for the well known role of neurotransmitters like serotonin and norepinephrine, there might also be other important physiological mechanisms involved in the patophysiology of depression.

One of these is the possible indirect actions via the immune system.

The immune system and the nervous system are the only known biological structures possessing a memory capacity.

How these memory functions actually work is still largely unknown, but we know that there is a lot of interaction between the CNS and the immune system. Part of this is due to production and secretion of certain molecules, including endorphins, ACTH (adreno-cortico-trope hormone), ADH (anti-diuretical hormone) and in particular certain cytokines. Cytokines are heavily involved in the communication between cells inside and outside the immune system, especially in the nervous system. Virtually all systematic manifestations of immune system activation are mediated either directly or indirectly by the brain or the endocrine organs. Activation of the immune system is causally associated with extensive changes in neural and/or endocrine functions.

These changes include fever, somnolence, loss of appetite, activation of the hypothalamic-hypophyseal-adrenal axis and suppression of the hypothalamic-hypophyseal-gonadal axis and that of the hypothalamic-hypophyseal-thyroid.

It cannot be ruled out that, in subjects with an appropriate disposition, monocyteinterleukins (monokines) are capable of inducing all the signs of depressive illness. According to this hypothesis, a large variety of white blood mononuclear cells (stimulated by infection, allergy, estrogen) would lead to increased levels of interleukins, resulting in changes in mental state.

The aim of this pilot study was to determine whether hypericum extract LI 160 exerts effects on the immune system in vitro, compatible with the "mediator theory" of its antidepressant effect.

Description

The effect of hypericum extract LI 160 on the stimulated cytokine expression was investigated in vitro in a whole blood culture system on non-immune-stimulated cells and on cells stimulated by phytohemagglutinin (PHA) or lipopolysaccharides (LPS). Blood samples were taken from five healthy volunteers and four depressive patients.

The release of the cytokines interleukin-6 (IL-6), interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) was measured quantitatively after an incubation time of 24 hours on microtiter plates.

The hypericin concentration was 2 microl/200 microl = 10 microl/ml = 10mg/ml =120 000 ng/ml hypericin.

Steady state concentration of hypericin during treatment with hypericin was measured to 5 ng/ml by Staffeldt et al.

Results

• IL-6 levels in the stimulated group were significantly and almost completely suppressed by hypericum, both in healthy and depressed subjects.
• IL-1B and TNF-a were less affected.
• There was no effect on nonstimulated cells (i.e., under resting conditions)
• Mononuclear cells showed a different reaction pattern in their cytokine production after stimulation with PHA or LPS when exposed to hypericum extract.
• Two of the four patients with depression and none of the healthy subjects showed suppression of production and release of IL-1B in the presence of hypericin compared to controls.

Researchers' comments

Cytokines affect the nervous system both directly and indirectly.

IL-1 had the following direct effects:

• prolongation of slow-wave sleep, appetite loss
• inhibition of gastric acid and gastric secretion
• a strong analgesic component
• a central inhibition of GRH, TRH, vasopressin and oxytocin.

IL-1B and IL-6 have the following effects:

• induced CRH, ACTH and cortisol production
• CRH in turn stimulates the production of IL-6; thus a vicious circle can be created.

Other facts:

• Patients with depression often have an oversecretion of CRH
• Patients with depression also seem to have a reduced amount of central CRH receptors.

Hypericum appears to reduce the interleukin-6 excretion, which in turn reduces the CRH, ACTH and corticosteroid secretion.