Cardiac arrest is a leading cause of death worldwide. While survival rates following sudden cardiac arrest remain relatively low, recent advancements in patient care have begun to increase the proportion of individuals who survive cardiac arrest. However, many of these individuals subsequently develop physiological and psychiatric conditions that likely result from ongoing neuroinflammation and neuronal death. The present study was conducted to better understand the pathophysiological effects of cardiac arrest on neuronal cell death and inflammation, and their modulation by the cholinergic system. Using a well validated model of cardiac arrest, here we show that global cerebral ischemia increases microglial activation, proinflammatory cytokine mRNA expression (interleukin-1␤, interleukin-6, tumor necrosis factor-␣), and neuronal damage. Cardiac arrest also induces alterations in numerous cellular components of central cholinergic signaling, including a reduction in choline acetyltransferase enzymatic activity and the number of choline acetyltransferasepositive neurons, as well as, reduced acetylcholinesterase and vesicular acetylcholine transporter mRNA. However, treatment with a selective agonist of the ␣7 nicotinic acetylcholine receptor, the primary receptor mediating the cholinergic anti-inflammatory pathway, significantly decreases the neuroinflammation and neuronal damage resulting from cardiac arrest. These data suggest that global cerebral ischemia results in significant declines in central cholinergic signaling, which may in turn diminish the capacity of the cholinergic anti-inflammatory pathway to control inflammation. Furthermore, we provide evidence that pharmacological activation of ␣7 nicotinic acetylcholine receptors provide significant protection against ischemia-related cell death and inflammation within a clinically relevant time frame.

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BackgroundAromatase Inhibitors (AIs) block physiological estrogen production in peripheral tissues and significantly improve overall survival rates of post-menopausal, hormone receptor-positive breast cancer patients by reducing tumor recurrences. However, half of patients taking these drugs develop aromatase inhibitor induced arthralgia (AIIA), which is characterized by severe pain and inflammation in various joints. Since AIIA leads to suspension of therapy in 20% of patients, reducing incidence may provide sustained AI treatment and enhanced long-term survival.ObjectivesIn order to establish a better understanding of the inflammatory mechanism and to create a platform that can be used to explore interventional strategies, our objective in this study was to design a novel animal model of AIIA.MethodsFemale BALB/C-Tg (NFκB-RE-luc)-Xen mice, which have a firefly luciferase cDNA reporter gene under the regulation of 3 κB responsive binding sites, were oophorectomized and treated with AI (letrozole) by daily subcutaneous injections. Control groups included oophorectomized mice receiving vehicle control injections and non-oophorectomized mice treated with AI. Bioluminescent imaging of hind limbs was performed after 3 weeks on the in vivo imaging system (IVIS) to measure NFκB activation. At 5 weeks, knee joints and surrounding tissue were imaged on the BioSpec 94/30 micro-MRI. Legs were collected for histopathological analysis and serum cytokine levels were measured at experimental endpoint.ResultsBioluminescent imaging showed significantly enhanced NFκB activation in the hind limbs compared to oophorectomized controls receiving vehicle treatment. Analysis of knee joints and legs by MRI imaging showed enhanced signal detection in the joint space and surrounding tissue following AI treatment. Surprisingly, enhanced MRI detection was also demonstrated in non-oophorectomized mice that were treated with AI. Histopathological analysis further demonstrated mild inflammation in the synovial tissue and joint damage in mice treated receiving AI both with and without oophorectomy. Moreover, tenosynovitis and inflammatory muscle tissue infiltrates were detected in AI-treated mice and serum cytokine levels of IL-2, IL-4, IL-6, and CXCL1 were significantly elevated.ConclusionsCollectively, these data establish a novel mouse model of AIIA and suggest that the pathogenesis of AI-induced inflammation is estrogen-independent. Future studies will be directed into the characterization of this inflammatory mechanism to provide insight into potential therapeutic strategies directed at mitigating this adverse inflammatory burden.References Henry NL, Giles JT, Ang D, et al. Prospective characterization of musculoskeletal symptoms in early stage breast cancer patients treated with aromatase inhibitors. Breast cancer research and treatment. 2008;111(2):365–372.Mao JJ, Stricker C, Bruner D, et al. Patterns and risk factors associated with aromatase inhibitor-related arthralgia among breast cancer survivors. Cancer. 2009;115(16):3631–3639. Ackn...

Background: Many breast cancer (BC) patients, particularly those who receive chemotherapy (chemo), experience affective symptoms and cognitive changes that can negatively impact their quality of life. Causal links between inflammatory mediators and the development of depressive-like behavior and cognitive defects, have been established in mouse models, including studies by our group showing increased microglial activation following chemo (A.C DeVries et al). Microglia are resident immune cells of the brain, which release proinflammatory cytokines when activated. Doxorubicin (DOX) induces microglial activation in the brain. Minocycline, a second generation tetracycline, has been shown to suppress inflammation by inhibiting microglial activation in CNS disease models. We hypothesize that (1) chemo activates microglia in the brains of women being treated for BC, which can precipitate or exacerbate depression, anxiety and cognitive deficits and (2) Minocycline administration during neoadjuvant or adjuvant chemo will prevent chemo-induced microglial activation and will reduce affective and cognitive symptom burden. Trial Design: This is a single center, Phase II, double blinded randomized study of minocycline (100 mg twice a day) vs placebo twice a day in women with BC receiving DOX-based or other chemo for BC. Pts will be randomized to either oral minocycline or placebo for up to a 1 week loading period plus chemo treatment period and an optional subsequent 2 week period. Eligibility Criteria: Women diagnosed with BC stages I-III initiating first line adjuvant or neoadjuvant chemo. Aims: (1) to evaluate symptoms related to anxiety and depression and cognitive changes during and after chemo completion (2) to evaluate markers of neuro inflammation as assessed by blood based inflammatory cytokines and central markers of inflammation and microglia activation using 1 F-Fludeoxyglucose and 11C-PK11195 positron emission tomography. Primary endpoints are changes in Center for Epidemiological Studies Depression Scale (CES-D) and State Trait Anxiety Index (STAI) from baseline to end of study after minocycline vs placebo intervention. Secondary endpoints are changes in cognitive function during chemo using validated cognitive testing including N-Back Test, Behavioural Rating Inventory of Executive Function (BRIEF) and the Multifactorial Memory Questionnaire Ability Scale (MMQ). Statistical Methods: Primary analysis for efficacy will be intention-to-treat. The main objective is to preliminarily evaluate the effect of minocycline on chemo-induced depressive symptoms in terms of changes in CES-D and STAI scores. Mixed models will be used to evaluate cognitive function changes. A sample size of 23 per group, will give 80% power to detect an effect size of 0.74 standard deviation (SD) difference between the 2 groups at significance level of 0.10 based on a 2 sided two-sample t-test. From our experience, attrition of less than 20% is expected for studies in this patient population in our center, and to account for this, we plan to recruit up to 60 patients. 16 of 46 evaluable pts have been accrued to date. Accrual started in January 2016. Funded by Pelotonia grant from The OSUCCC. Contact: Study PI: Maryam.lustberg@osumc.edu Citation Format: Boutrid H, Reinbolt R, Knopp M, Williams N, VanDeusen J, Sardesai S, Noonan A, Flora L, Gleich E, Pan X, Berger M, Vargo C, Wesolowski R, Ramaswamy B, DeVries AC, Lustberg M. Does minocycline mitigate chemotherapy induced neuroinflammation? A phase II randomized placebo controlled study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-05-03.