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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gulf War Syndrome (GWS) remains a contentious diagnosis with conflicting laboratory investigation and lack of a biologically plausible aetiology. This paper discusses the potential role of maxadilan, a potent sandfly vasoactive peptide, in causing autoimmune responses in susceptible individuals through possible molecular mimicry with pituitary adenylate cyclase activating polypeptide (PACAP) and the PAC1R receptor. Gulf War Syndrome may share some causative pathology with Chronic Fatigue Syndrome (CFS), a disorder characterised by prolonged fatigue and debility mostly associated with post-infection sequelae although ongoing infection is unproven. Immunological aberration associated with an expanding group of vasoactive neuropeptides in the context of molecular mimicry and inappropriate immunological memory has been recently raised as possible cause of CFS. Vasoactive neuropeptides act as hormones, neurotransmitters, immune modulators and neurotrophes. They are readily catalysed to small peptide fragments. They and their binding sites are immunogenic and are known to be associated with a range of autoimmune conditions. Maxadilan, while not sharing substantial sequence homology with PACAP is a known agonist of the PACAP specific receptor (PAC1R) and therefore emulates these functions. Moreover a specific amino acid sequence peptide deletion within maxadilan converts it to a PACAP receptor antagonist raising the possibility of this substance provoking a CFS like response in humans exposed to it. This paper describes a biologically plausible mechanism for the development of a GWS-like chronic fatigue state based on loss of immunological tolerance to the vasoactive neuropeptide PACAP or its receptor following bites of the sandfly Phlebotomus papatasi and injection of the vasodilator peptide maxadilan. Exacerbation of this autoimmune response as a consequence of recent or simultaneous multiple vaccination exposures deserves further investigation. While the possible association between the relatively recently discovered vasoactive neuropeptides and chronic fatigue conditions has only recently been reported in the literature, this paper explores links for further research into GWS and CFS.
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PMID:Is Gulf War Syndrome an autoimmune disorder of endogenous neuropeptides, exogenous sandfly maxadilan and molecular mimicry? 1508 85

Vasoactive neuropeptides such as pituitary adenylate cyclase activating polypeptide (PACAP), calcitonin gene related peptide (CGRP) and vasoactive intestinal peptide (VIP) have been implicated in a number of fatigue-related conditions. Associations of these vasoactive neuropeptides with heat shock proteins (hsps) and cytosine-guanosine dinucleotide (CpG) DNA fragments in autoimmune phenomena have been postulated to interfere with receptor signal activation for adenylate cyclase and other vital cellular processes. However, a specific mechanism for receptor dysfunction has not been explored to date. G protein-coupled receptors (GPCRs) constitute a high proportion of biological receptor mechanisms and serve a wide range of substances including nucleosides, nucleotides, catecholamines, calcium, histamine, serotonin and prostaglandins. They are complex transmembrane hepta-helical serpentine structures with specific binding capabilities resulting in conformational changes that activate cognate cyclic GMP (G proteins). GPCRs adapt to certain stimuli through desensitisation and changes in phosphorylation and are subject to distortions of signalling processes. Hence, these vital signalling structures are susceptible to impairment of function through a range of mechanisms. One of their vital functions is signalling through adenylate cyclase, a vital step in cyclic AMP metabolism. This step involves ATP metabolism and therefore is a crucial mediator of cellular energy pathways. Some GPCRs act to inhibit adenylate cyclase (Gi proteins). Also vasoactive neuropeptides, such as PACAP display a number of receptor isotypes including null variants. Overexpression of Gi proteins and null variant receptors may account for major disruptions of signal transduction and ATP/cAMP metabolism. This paper examines the possible role of GPCR dysfunction in contributing to fatigue-related vasoactive neuropeptide autoimmune disorders which may include chronic fatigue syndrome (CFS), Gulf War syndrome (GWS) and even sudden infant death syndrome (SIDS).
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PMID:Are vasoactive neuropeptide autoimmune fatigue-related disorders mediated via G protein-coupled receptors? 1589 12

Autoimmune dysfunction of certain vasoactive neuropeptides (e.g., vasoactive intestinal peptide, pituitary adenylate cyclase activating polypeptide) may be implicated in a range of disorders associated with fatigue-like states (chronic fatigue syndrome, Gulf War syndrome) and even sudden infant death syndrome (SIDS). The important roles of these vasoactive neuropeptides make them a vulnerable target for autoimmune dysfunction. They are known to be associated with heat shock proteins for intracellular functioning with which they may form immunostimulating complexes. Cytosine guanine dinucleotide (CpG) fragments are potently immunogenic DNA fragments which serve as friend or foe recognition systems between bacterial (hypomethylated) and mammalian (methylated) DNA and are being assessed for suitability for use in human vaccines as adjuvants. Interactions between CpG fragments, heat shock proteins and vasoactive neuropeptides may be associated with fatigue-related autoimmune conditions.
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PMID:Do cytosine guanine dinucleotide (CpG) fragments induce vasoactive neuropeptide mediated fatigue-related autoimmune disorders? 1592 14

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.
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PMID:Do vasoactive neuropeptide autoimmune disorders explain pyridostigmine's association with Gulf War syndrome? 1600 38

Autoimmune dysfunction of certain vasoactive neuropeptides (VNs) has been postulated as a contributing cause of sudden infant death syndrome (SIDS), chronic fatigue syndrome (CFS), Gulf War syndrome (GWS) and other fatigue-related disorders. This family of VNs includes pituitary adenylate cyclase activating polypeptide (PACAP), vasoactive intestinal peptide (VIP) and calcitonin gene related peptide (CGRP). The postulated mechanism is compromise of adenylate cyclase activation, a vital and unique step in cyclic AMP production from ATP, through autoimmune dysfunction of VNs, their receptors or their genes possibly involving cytosine-phosphate-guanine (CpG) fragments. CpG fragments are immunomodulatory dinucleotides serving as 'friend or foe' recognition systems to differentiate bacterial and viral (hypomethylated CpG) from mammalian (methylated CpG) DNA. However hypomethylation disorders affecting these fragments in mammals may convert them to dysfunctional states by promoting autoimmune inflammatory reactions. Epigenetic mechanisms acting on gene promoter regions may contribute to the development of VN autoimmune fatigue-related disorders through CpG fragments located in vital segments of VN/receptor genes by causing signalling defects with profound implications for VN function. Neurotransmitter dysfunction particularly glutamatergic transmission could also result with disruption of neuronal cellular biochemical functions such as ammonia regulation. Endosomal acidity and mitochondrial membrane potential modifiers such as chloroquine, together with immunoregulatory therapies, may have therapeutic implications in protecting against these apparent autoimmune disorders. This paper examines specific epigenetic and biochemical mechanisms possibly mediated by VN or receptor genes resulting in postulated VN autoimmune fatigue-related disorders. These mechanisms may have implications for treatment and prevention options for VN autoimmune disorders. VN autoimmune processes have implications for military medicine where radiological, chemical and biological agents may play an important role in pathogenesis.
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PMID:Does dysregulation of key epigenetic and biochemical pathways occur in postulated vasoactive neuropeptide autoimmune disorders? 1602 37

Disorders such as chronic fatigue syndrome (CFS) and gulf war syndrome (GWS) are characterised by prolonged fatigue and a range of debilitating symptoms of pain, intellectual and emotional impairment, chemical sensitivities and immunological dysfunction. Sudden infant death syndrome (SIDS) surprisingly may have certain features in common with these conditions. Post-infection sequelae may be possible contributing factors although ongoing infection is unproven. Immunological aberration may prove to be associated with certain vasoactive neuropeptides (VN) in the context of molecular mimicry, inappropriate immunological memory and autoimmunity. Adenylate cyclase-activating VNs including pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP) and calcitonin gene-related peptide (CGRP) act as hormones, neurotransmitters, neuroregulators, immune modulators and neurotrophic substances. They and their receptors are potentially immunogenic. VNs are widely distributed in the body particularly in the central and peripheral nervous systems and have been identified in the gut, adrenal gland, blood cells, reproductive system, lung, heart and other tissues. They have a vital role in maintaining cardio-respiratory function, thermoregulation, memory, concentration and executive functions such as emotional responses including social cues and appropriate behaviour. They are co-transmitters for a number of neurotransmitters including acetylcholine and gaseous transmitters, are potent immune regulators with primarily anti-inflammatory activity, and have a significant role in protection of the nervous system against toxic assault as well as being important in the maintenance of homeostasis. This paper describes a biologically plausible mechanism for the development of certain fatigue-related syndromes based on loss of immunological tolerance to these VNs or their receptors following infection, other events or de novo resulting in significant pathophysiology possibly mediated via CpG fragments and heat shock (stress) proteins. These conditions extend the public health context of autoimmunity and VN dysregulation and have implications for military medicine where radiological, biological and chemical agents may have a role in pathogenesis. Possible treatment and prevention options are considered.
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PMID:Postulated vasoactive neuropeptide autoimmunity in fatigue-related conditions: a brief review and hypothesis. 1660 42

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are the members of the glucagon superfamily and bind to common receptors while PACAP also acts via the PACAP-specific receptor, PAC1. The aim of the present study was to investigate whether intracerebroventricular (i.c.v.) injection of VIP and PACAP acts in a similar or different manner to affect body temperature and energy expenditure in the domestic chick. I.c.v. injection of VIP did not significantly affect rectal temperature, but decreased energy expenditure. On the other hand, i.c.v. injection of PACAP significantly increased both body temperature and energy expenditure. These specific actions of PACAP could be explained by an interaction with the PAC1 receptor, since they were partly, but not entirely, attenuated by PACAP (6-38), a PAC1 receptor antagonist. In addition, it was observed that central administration of both VIP and PACAP induced a reduction in respiratory quotient and increased plasma non-esterified fatty acid concentrations. This suggests that both peptides act centrally to regulate a catabolic response. In summary, brain VIP and PACAP both appear to exert generally catabolic effects on energy metabolism in the chick, but their influence on body temperature and glucose metabolism differs and their central effects do not appear to be mediated by the same receptors.
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PMID:Central administration of vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide differentially regulates energy metabolism in chicks. 1729 2

Parkinson's disease (PD) is a motor disease including disorders of mobility, fine tremor, rigidity and posture caused by a relentless deterioration of dopaminergic cells in the substantia nigra (SN). Disorders of affect and a range of other symptoms including fatigue, cognitive dysfunction and mental confusion, sleep disorder and addictions are also seen as other CNS sites are also affected. Idiopathic and genetic causes together with inflammatory and degenerative disorders of ageing have been postulated as contributing to PD. Autoimmunity affecting certain vasoactive neuropeptides (VNs) has been postulated as contributing to certain fatigue-related conditions in humans and may be consistent with compromise of receptors associated with VNs and including receptors for vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP). Pro-inflammatory responses are seen in PD patients consistent with apoptotic neurodegeneration. Involvement of the Th1 directed cytokine interferon-gamma has been demonstrated and Th2 directed cytokines such as IL-10 protect against inflammation-mediated degeneration of dopaminergic neurons in the SN. Nitric-oxide dysregulation is also postulated in PD by fostering dopamine depletion via nitric-oxide synthase (iNOS). Both PACAP and VIP have neuroprotective effects in PD models by inhibiting the production of inflammatory mediators. PACAP specifically protects against the neurotoxicity induced by rotenone as well as protecting against oxidative stress-induced apoptosis. These findings suggest that a defect in VN function may act adversely on SN cells and hence contribute to a clinical presentation consistent with PD. The conclusion drawn from these findings is that PD may be an autoimmune disorder of VNs, specifically PACAP and VIP. Possibly unusual or anatomically specific receptors for these VNs may be involved. If proven, this hypothesis would have significant implications for immunological and pharmacological treatment and prevention of PD.
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PMID:Is Parkinson's disease an autoimmune disorder of endogenous vasoactive neuropeptides? 1756 59

Autoimmune dysfunction of endogenous vasoactive neuropeptides (VNs) such as vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) has been postulated as a cause for some fatigue-related conditions. VN receptors are class II G protein-coupled receptors (GPCRs) which couple primarily to the adenylate cyclase (AC)-cyclic AMP (cAMP) pathway and cAMP has a central role in neurological metabolism including influencing blood-brain barrier (BBB) and blood-spinal barrier (BSB) permeability, coordinating neuroregulatory pathways, and protecting against neuronal apoptosis. Complex clinical signs occur in multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). While traditionally viewed as diseases of the motor system, the clinical picture of these conditions is considerably more complex. Disturbances of cognition and memory, as well as emotional lability occur along with fatigue and motor dysfunction. This paper explores the hypothesis that autoimmune dysfunction of VNs may contribute to MS and ALS. While MS and ALS differ in important respects, they have common pathogenic features including inflammation, oxidative stress and mitochondrial dysfunction. Apoptotic mechanisms are associated with activation of caspase pathways and functional interplay between proinflammatory cytokines, interferon gamma and nitric oxide is suggested associated with oxidative stress and glial activation. Diseases such as MS and ALS may represent related conditions resulting from variation in expression of different receptor subtypes of the VN family. Anatomical differences of these receptors, perhaps in areas overly dependent on a specific VN receptor sub-type, may predispose to autoimmune susceptibility to these conditions, either in impaired expression of receptors or antibody and cellular immune targeting of them. Further studies are required to determine if such VN receptor sub-types of significant specificity exist and if they are susceptible to compromise. This hypothesis, if proven, may have implications for the development of treatment and preventive strategies.
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PMID:Are multiple sclerosis and amyotrophic lateral sclerosis autoimmune disorders of endogenous vasoactive neuropeptides? 1758 95

Neuropsychiatric symptoms occur in a number of neurological fatigue-related conditions including multiple sclerosis (MS), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and chronic fatigue syndrome (CFS). These conditions have been attributed variably to neuroinflammatory and neurodegenerative processes. While autoimmune pathology, at least in part, has long been suspected in these conditions proof has been elusive. Autoimmune pathomechanisms affecting the blood-brain barrier (BBB) or blood-spinal barrier (BSB) may predispose the BBB/BSB to 'leakiness' and be a precursor to additional autoimmune events resulting in neuroinflammatory or neurodegenerative processes. The aim of the paper is to postulate immunopathology of the cerebrospinal perivascular compartment involving certain vasoactive neuropeptides, specifically pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP), in the etiology of certain neuropsychiatric fatigue-related conditions such as MS, ALS, PD, and CFS. Vasoactive neuropeptides (VNs) such as PACAP and VIP have critical roles as neurotransmitters, vasodilators including perfusion and hypoxia regulators, and immune and nociception modulators. PACAP and VIP are widely distributed in the central nervous system (CNS) and have key roles in CNS blood vessels including maintaining functional integrity of the BBB and BSB. Autoimmunity affecting these VNs would likely have a detrimental effect on BBB and BSB functioning arguably predisposing to further pathological processes. Virchow-Robin spaces (VRS) are perivascular compartments surrounding small vessels within the CNS which contribute to the BBB and BSB integrity and contain PACAP and VIP receptors. Autoimmunity of these receptors would likely affect BBB and VRS function and therefore may contribute to the etiology of these conditions by affecting CNS and immunological homeostasis, including promoting neuropsychological symptomatology. PACAP and VIP, as potent activators of adenylate cyclase (AC), have a key role in cyclic adenosine monophosphate (cAMP) production affecting regulatory T cell (Treg) and other immune functions. Phosphodiesterase enzymes (PDEs) catalyze cAMP and PDE inhibitors (PDEIs) maintain cAMP levels and have proven and well known therapeutic benefit in animal models such as experimental allergic encephalomyelitis (EAE). Therefore PDEIs may have a role in therapy for certain neuropsychiatric fatigue-related conditions.
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PMID:Postulated vasoactive neuropeptide immunopathology affecting the blood-brain/blood-spinal barrier in certain neuropsychiatric fatigue-related conditions: A role for phosphodiesterase inhibitors in treatment? 1955 3


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