Acetylcholinesterase inhibitor exposures as an initiating factor in the development of Gulf War Illness, a chronic neuroimmune disorder in deployed veterans

Abstract

Gulf War Illness (GWI) is a chronic multi-symptom disorder, characterized by symptoms such as fatigue, pain, cognitive and memory impairment, respiratory, skin and gastrointestinal problems, that is experienced by approximately one-third of 1991 Gulf War veterans. Over the nearly three decades since the end of the war, investigators have worked to elucidate the initiating factors and underlying causes of GWI. A significant portion of this research has indicated a strong correlation between GWI and exposure to a number of different acetycholinesterase inhibitors (AChEIs) in theater, such as sarin and cyclosarin nerve agents, chlorpyrifos and dichlorvos pesticides, and the anti-nerve agent prophylactic pyridostigmine bromide. Through studying these exposures and their relationship to the symptoms presented by ill veterans, it has become increasingly apparent that GWI is the likely result of an underlying neuroimmune disorder. While evidence indicates that AChEIs are a key exposure in the development of GWI, particularly organophosphate AChEIs, the mechanism(s) by which these chemicals instigate illness appears to be related to "off-target", non-cholinergic effects. In this review, we will discuss the role of AChEI exposure in the development and persistence of GWI; in particular, how these chemicals, combined with other exposures, have led to a chronic neuroimmune disorder. This article is part of the special issue entitled 'Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield'.

Keywords: Acetylcholinesterase inhibitor; Gulf war illness; Neuroimmune; Neuroinflammation.

Fig. 1.. Mechanism of acetylcholinesterase inhibitor-induced neuroimmune dysfunction in Gulf War Illness.

Acetylcholinesterase inhibitors (AChEIs), in particular the organophosphate (OP) chemicals, can instigate illness in two ways: (1) acute toxicity that results in cholinergic crisis (salivation, lacrimation, urination, defecation, gastrointestinal upset, emesis, miosis [SLUDGEM]; seizures) and carries a higher risk of mortality; (2) long-term illness in the absence of an acute cholinergic crisis. The latter condition is proposed to be the result of chronic low-level AChEI exposure with or without concurrent exposure to physiological stress. The myriad of cellular and molecular effects that have been demonstrated in the brain as a result of these exposures are hypothesized to be the consequences of organophosphorylation of non-cholinergic targets, e.g. neuroinflammatory signaling mediators. Ultimately, these effects culminate into a state of chronic neuroimmune dysfunction, the underlying cause of Gulf War Illness (GWI).