mandag den 16. juli 2012


Professor Don Staines has for several years worked on a hypothesis, that the development of ME is based on loss of immunological tolerance to vasoactive neuropeptides (VIP and PACAP) or their receptor binding sites:

Is chronic fatigue syndrome an autoimmune disorder of endogenous neuropeptides, exogenous infection and molecular mimicry?
“All documented symptoms of CFS are explained by vasoactive neuropeptide compromise, namely fatigue and nervous system dysfunction through impaired acetylcholine activity, myalgia through nitric oxide and endogenous opioid dysfunction, chemical sensitivity through peroxynitrite and adenosine dysfunction, and immunological disturbance through changes in immune modulation.”

Professor Don Staines and colleagues have elaborated the theory in this article:
Novel pathomechanisms in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: Do purinergic signalling perturbations and gliosis play a role?

But let us take a closer look on these neuropeptides to better understand the ME articles:

VIP = Vasoactive Intestinal Peptide
PACAP = Pituitary Adenylate Cyclase Activating Polypeptide
PACAP-27, PACAP-38 = two forms of PACAP, respectively a 27 and a 38 amino acid peptide
VIPR1 = VPACR1 = VPAC1  receptor = Vasoactive Intestinal Peptide Receptor 1
VIPR2 = VPACR2 = VPAC2  receptor = Vasoactive Intestinal Peptide Receptor 2
ADCYAP1R1 = PAC1R = PAC1 receptor = Adenylate Cyclase Activating Polypeptide 1 (pituitary) receptor

VPAC1 receptor responds to VIP and PACAP with comparable affinity.
VPAC2 receptor also responds to VIP and PACAP with comparable affinity.
PAC1 receptor recognises PACAP-27 and PACAP-38 with much higher potency than VIP.

VIP is a vasodilator and has many other actions as a neuroendocrine hormone, putative neurotransmitter and cytokine. The presence of VIP and specific VIP binding sites in defined pathways in the brain indicate that it may play an important role in central nervous system function. VIP is now widely accepted as a co-transmitter, with nitric oxide and carbon monoxide, of nonadrenergic, noncholinergic relaxation of both vascular and nonvascular smooth muscle. VIP stimulates prolactin secretion from the pituitary and catecholamine release from the adrenal medulla. In the immune system, VIP regulates T cell traffic and inhibits mitogen-activated proliferation of T cells by inhibiting interleukin-2 production. Other actions of VIP include stimulation of electrolyte secretion and protection against oxidant injury.

PACAP and the mRNA encoding its precursor are most abundant in the hypothalamus, with lower levels in many other brain regions. PACAP is also present in a number of peripheral tissues, including the gastrointestinal tract, adrenal gland and testis. PACAP is expressed in sympathetic neurons and in the cholinergic innervation of the adrenal medulla, where it is thought to facilitate prolonged secretion of catecholamines under conditions of high stress. PACAP is also thought to regulate exocrine and endocrine secretion from the pancreas.
Reference: IUPHAR Database. VIP and PACAP receptors: Introduction

I had hoped to find an abundance of articles with measurements of VIP, PACAP and expression of their receptors – but all I could find was this:

Immunological abnormalities as potential biomarkers in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis
“This is the first study to show significantly higher levels of VPACR2 receptors, CD4+CD25+Tregs and FoxP3 +Treg expression in CFS/ME patients compared to healthy controls.”

But I found something else interesting. At Glostrup Hospital in Denmark researchers have shown that PACAP-38 provokes a significant headache, while VIP only gives a small headache. Danish reference  
Poster in English about PACAP and headache

Further reading about VIP and PACAP:
VIP and PACAP. Recent insights into their functions/roles in physiology and disease from molecular and genetic studies

Immunomodulation of innate immune responses by vasoactive intestinal peptide (VIP): its therapeutic potential in inflammatory disease

Emerging roles of vasoactive intestinal peptide: a new approach for autoimmune therapy

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