Antisecretory factor in inflammation and secretion disorders

Antisecretory Factor (AF) is a 43 kD endogenous protein expressed in most tissues in the body. AF was identified and cloned in our group 1995. Our aims since then are to investigate the functions of AF and its mechanisms of action. AF reduces inflammation and regulates secretory processes, and can be a part of the innate immune system. In a healthy person AF is to a large extent inactive. AF can be activated by exposure of the small intestine to bacterial toxins or through intake of certain food components. We have shown that intake of specially processed cereals (SPC-Flakes®) increases AF-activity in plasma. Preformed active AF can be given as an egg drink (Salovum®), prepared from egg yolk from hens fed an AF-activating feed.  Clinical studies have shown that AF-therapy decreases symptoms in patients with inflammatory bowel disease (IBD, and diarrhoea of different genesis. AF-therapy has also been effective in reducing vertigo in patients with Meniere´s disease, an inner ear disease caused by secretory disturbances in the cochlear and vestibular systems. Patients with chronic diseases or small children can have problems activating endogenous AF by intake of SPC-Flakes. These categories can be treated with preformed active AF in the form of Salovum. Clinical studies in Pakistan have shown that Salovum effectively stops infant diarrhoea, independent of infecting agent, indicating that this simple therapy can be used in low-income countries. Both SPC-Flakes® and Salovum® have been classified by Läkemedelsverket as food addition, Food for Specific Medical Purposes. They can be included in the usual diet as an addition without change in the basal medical treatment.  No adverse effects of medical importance have been reported so far,

The active sequence of AF is an 8 amino acid long peptide in the N-terminal part of AF. A slightly longer peptide, AF-16, is more stable and useful for preclinical work. Animal studies have shown that AF-16, given iv or intranasally decreases the tissue pressure in solid tumours and increases the perfusion of the tumour, potentially increasing the effect of antitumour treatment. In a model for traumatic brain injury, it was found the AF-16 reduced the oedema induced high intracranial pressure. This finding led to an open clinical study at the department of Neurosurgery Sahlgrenska University hospital, in which patients with high intracranial pressure due to a traumatic brain injury were treated with Salovum in addition to standard medical treatment. AF in this form was found to significantly reduce the intracranial pressure. However, a more defined method for AF-treatment is desirable. In this aim a phase I study with AF-16 is terminated and a Phase II study of treatment with AF-16 in patients with traumatic brain injury has started.

We and also other groups have shown that AF-therapy is of clinical value in a number of common diseases. However, so far, the mode of action for the beneficial effects are unknown. Our work is now focused on this aspect.  The results from preclinical and clinical studies indicate that GABA and GABA receptors are involved in the mode of action. Autoradiography with 14C-AF-16 in rats showed that AF-16 preferentially binds to pancreas, peripheral ganglia, hippocampus and plexus choroideus in the CNS, and to the pituitary gland. All these organs express GABA-A receptors. Electophysiological studies on hippocampus slices from rats indicate that AF-16 modifies the effects GABA-A receptors. A similar effect is seen in hippocampus slices from rats fed an AF-activating diet. In collaboration with Aroldo Cupello in Genua, we have identified the α6-subunit of the GABA-A receptor as a binding site for AF-16 in granular cells from rat cerebellum. Immunohistochemistry show that these cells have a high expression of receptor with the α6-subunit. We and other groups have shown that AF-therapy decreases the symptoms in patients with Meniere’s disease, especially reducing vertigo. It is possible that the positive effects of AF in these patients is mediated through interacting with α6-subunit on granular cells which are regulating the balance system. Further studies are necessary to investigate if, and to what extent, interaction between AF and the α6-subunit of the GABA-A receptor can explain known effects of AF in various experimental systems.