Journal of IiME Volume 5 Issue 1 (May 2011) International Science Symposium on ME continued induce neuronal damage and leukocyte infiltration into the CNS. Noradrenaline regulates glial inflammatory responses, exerts neuroprotective effects and helps maintain the integrity of the blood brain barrier (BBB). Dysregulation of noradrenaline signalling could exacerbate disease. The supposed reductions of noradrenaline increase inflammatory responses, the amyloid burden and neurotropic factors. Noradrenaline is mainly produced in the locus coeruleus (LC). This part of the brain is damaged in Alzheimer‟s and Parkinsonism. LC loss correlates with plaque and tangle numbers. The question was asked “does increasing noradrenaline in the CNS improve things?” The drug Droxidopa is a precursor of noradrenaline. This drug is in phase 3 trials for neurogenic orthostatic hyopotension. In mice the drug leads to improvement in plaques and learning. This drug used in MS and experimental autoimmune encephalmyelitis (EAE) showed stabilisation compared to controls. This trial indicates that the LC is significantly damaged in MS and EAE. Noradrenaline directed therapies need to be considered if there is perhaps also LC disturbance in CFS. Doina Ganea (Philadelphia,USA) spoke about Vasoactive Intestinal Peptide (VIP) – an endogenous and exogenous immunomodlator. VIP downregulates the innate immune response by inhibiting the release of pro-inflammatory cytokines, chemokines and nitric oxide by activated macrophages, microglia and dendritic cells. It also affects the adaptive immune response by reducing the co-stimulatory capacity of antigen-presenting cells, and by inducing Th2 type responses. She had looked at several diseases, such as collagen-induced arthritis and autoimmune encephalmyelitis. She had used dendritic cells generated in the presence of VIP/PACAP as immunomodulatory agents, with positive results. Monica Carson (California,USA) had studied the CNS expression of the classic chemokine Invest in ME (Charity Nr. 1114035) CCL21. This is a predisposing factor for autoimmunity due to the proliferation induced preactivation. It thus contributes to chronic inflammatory disease and auto-immunity. Experimental work was done using mice. Resulting data indicated that CCL21 expression within the CNS has the potential to contribute to T-cell mediated CNS pathology. This could occur via homeostatic priming of CD4+T cell lymphocytes outside the CNS, and CD4+T cell migration into parenchymal site after infection with organisms such as toxoplasma. Donald Staines (Gold Coast, Australia) rounded off the formal papers with a presentation looking at novel treatments in CFS. He considered whether auto-immunity affecting vaso-active neuropeptides suggest a pathomechanism. ME/CFS may be associated with auto-immunity affecting the function of vaso-active neuropeptides, such as VIP and PACAP (pituitary adenylate cyclase activating peptide). Upsets in adenylate cyclase (AC) signalling and cAMP functioning possibly involving ATP toxicity may be a feature of VN auto-immunity. Purinergic receptors such as ATP negatively regulate AC. He outlined some basic biochemical principles to clarify things; AC amplifies incoming intracellular signals; PACAP is an acetylcholine co-transmitter; AC is involved in long term potentiation and enhanced maintenance of neuronal activity. VIP/PACAP synergism is involved with potentiation of cardiac firing, anti-apoptosis function, cAMP and insulin control, hypoxia regulation and glutamate metabolism. Purinergic signalling is involved in centrally mediated pain (neuropathic pain). He then went on to describe some likely treatment possibilities based on these principles. These included purigenic signalling modulators, VIP/PACAP mimics/analogues, phosphodiesterase inhibitors: eg Rolipram (toxic), Ibudilast, Roflumilast; B cell depletors (Rituximab); chondroitinase; VIP liposomes and Continued page 28 www.investinme.org Page 27/58

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