Gulf War syndrome (GWS) is a perplexing multi-symptom condition comprising a constellation of signs and symptoms consistently described in the literature. These include muscle fatigue and tiredness, malaise,
myalgia, impaired cognition,
ataxia, diarrhoea, bladder dysfunction, sweating disturbances,
headaches,
fever,
arthralgia, skin rashes, and gastrointestinal and sleep disturbances. Excessive chemical sensitivity and odour intolerance is reported. Epidemiological analysis suggests association with
pyridostigmine bromide (PB) use as
nerve gas prophylaxis,
insect repellent, certain vaccination regimes, a variety of possible chemical exposures and physical and psychological stress.
Pituitary adenylate cyclase-activating polypeptide (
PACAP),
calcitonin gene-related peptide (CGRP) and
vasoactive intestinal peptide (VIP) are potent vasoactive (vasodilatory)
neuropeptides (VNs) having pleiotropic functions as
immunomodulators,
neuroregulators and
hormones. VNs also have neurotrophic and anti-apoptotic roles. VNs act on
G protein-coupled receptors (GPCRs) to activate
adenylate cyclase, an important step in
cyclic AMP metabolism. Autoimmune dysfunction of these VNs or their receptors is postulated to give rise to
fatigue-related conditions such as
chronic fatigue syndrome (CFS). Complex mechanisms involving
heat shock proteins (hsps) and
cytosine-guanine dinucleotide (CpG)
DNA fragments may also be associated with autoimmunity to VNs or their GPCRs in contributing to
fatigue-related conditions. Dysfunction of certain VNs may be the missing link in explaining the nebulous
nexus between PB and GWS. This paper explores a possible link between exposures to PB and other chemical, physical and psychological stressors in producing a
fatigue-related illness possibly related to autoimmune dysfunction of certain VNs. Treatment options involving restoration of VN function are considered in the context of analogues with other
neurotransmitter fatigue-related conditions such as
myasthenia gravis (MG). While evidence associating these conditions is thin, vasoactive
neuropeptide neurotransmitters of the VIP/
PACAP family have
acetylcholine co-transmission functions via specific GPCRs. Autoimmune reactions to these receptors may have parallels with
muscarinic (e.g.,
Sjogren's syndrome) and nicotinic (e.g., MG)
acetylcholine neurotransmission. Hence theoretically, treatment options such as
thymectomy,
corticosteroids,
plasma exchange,
anti-idiotype antibodies and receptor genomic expression reactivation/suppression may be considered. Paradoxically
pyridostigmine may prove to have a role in
therapy although VN treatment/replacement may be associated with tachyphylaxis.