Immune basis for hippocampal cholinergic deficits in pyridostigmine-treated rats

Veterans Health Administration, Decatur PA

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Abstract

Following return from the Gulf War (GW), veterans have experienced a constellation of symptoms, designated Gulf War Illness (GWI), that cannot be associated with a single disease, including structural and functional deficits in the central nervous system (CNS), along with alterations in stress reactivity and cardiovascular complications. One of the more insidious aspects of GWI is that it is a chronic and progressive disorder; indeed, the number of veterans diagnosed with GWI continues to rise in the post- deployment period. Although the mechanisms responsible for GWI remain unclear, studies have determined that GWI veterans exhibit exaggerated immune responses to physiological stressors, which supports the concept that neuroinflammation is a key component in the etiology and progression of GWI. We have developed and validated a model of GWI in which rats are administered the acetylcholinesterase (AChE) inhibitor pyridostigmine bromide (PB) alone and in combination with repeated restraint stress (RRS). Studies performed in the previous funding period demonstrated that PB-treated rats consistently exhibit exacerbated vagal, neuroimmune, neurochemical, and behavioral responses to an immune or stress challenge. These observations support the hypothesis that dysregulation of the cholinergic anti-inflammatory network is a key mechanistic mediator of GWI pathology. These observations also support the concept that restoration of the cholinergic anti-inflammatory network would inhibit the exacerbated responses exhibited by PB-treated in response to immune or stress challenges. Nicotinic acetylcholine receptors (nAChRs) that express α7 subunits have been shown to be critical regulators of the cholinergic anti-inflammatory network. As such, drugs which activate α7-containing nAChRs may represent a novel approach to restore the activity of this network and thereby inhibit the exacerbated immune and stress responses that are characteristic of GWI. Positive allosteric modulators (PAMs) of α7 nAChRs have previously been shown to block neuroinflammation and enhance behavioral performance in rodents and non-human primates, thereby providing rationale for examining the ability of α7 PAMs to inhibit the exacerbated stress and immune responses that are characteristic of GWI. Accordingly, the goal of this project is to directly test our overarching hypothesis that the α7 PAM PNU-120596 can restore the activity of the cholinergic anti-inflammatory network and thereby reverse the neuroimmune, neurochemical, vagal and behavioral deficits in an animal model of Gulf War Illness. This hypothesis will be directly tested in the following Aims: Aim 1 will examine the ability of PNU-120596 to restore cardiovascular and peripheral immune responses in PB-treated rats. Aim 2 will examine the ability of PNU-120596 to restore appropriate CNS immune responses in the hippocampus of PB-treated rats. Aim 3 will examine the ability of the 120596 to block behavioral deficits in our rat model of GWI. Successful completion of these studies will demonstrate that restoration of the cholinergic anti-inflammatory network effectively inhibits exacerbated vagal and neurological responses to immune challenges and stressful stimuli. Most importantly, these studies will identify α7 nAChRs as a potential therapeutic intervention for Veterans with GWI.