In this review, we provide an overview of the US Food and Drug Administration (FDA)-approved clinical uses of vagus nerve stimulation (VNS) as well as information about the ongoing studies and preclinical research to expand the use of VNS to additional applications. VNS is currently FDA approved for therapeutic use in patients aged >12 years with drug-resistant epilepsy and depression. Recent studies of VNS in in vivo systems have shown that it has anti-inflammatory properties which has led to more preclinical research aimed at expanding VNS treatment across a wider range of inflammatory disorders. Although the signaling pathway and mechanism by which VNS affects inflammation remain unknown, VNS has shown promising results in treating chronic inflammatory disorders such as sepsis, lung injury, rheumatoid arthritis (RA), and diabetes. It is also being used to control pain in fibromyalgia and migraines. This new preclinical research shows that VNS bears the promise of being applied to a wider range of therapeutic applications.

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BackgroundVagus Nerve Stimulation (VNS) is an FDA-approved method delivering electrical impulses for treatment of depression and epilepsy in adults. The vagus nerve innervates the majority of visceral organs and cervix, but potential impacts of VNS on the progress of pregnancy and the fetus are not well studied.MethodsWe tested the hypothesis that VNS in pregnant dams does not induce inflammatory changes in the cardiorespiratory control regions of the pups’ brainstem, potentially impacting the morbidity and mortality of offspring. Pregnant dams were implanted with stimulators providing intermittent low or high frequency electrical stimulation of the sub-diaphragmatic esophageal segment of the vagus nerve for 6–7 days until delivery. After birth, we collected pup brainstems that included cardio-respiratory control regions and counted the cells labeled for pro-inflammatory cytokines (IL-1β, IL-6, TNFα) and HMGB1.ResultsNeither pup viability nor number of cells labeled for pro-inflammatory cytokines in nTS nor XII was impaired by VNS. We provide evidence suggesting that chronic VNS of pregnant mothers does not impede the progress or outcome of pregnancy.ConclusionsVNS does not cause preterm birth, affect well-being of progeny, or impact central inflammatory processes that are critical for normal cardiovascular and respiratory function in newborns.

Traumatic brain injury (TBI) is a leading cause of mortality/morbidity and is associated with chronic neuroinflammation. Melanocortin receptor (MCR) agonists (e.g., ACTH or adrenocorticotropic hormone) that target MC3R/4R ameliorate inflammation and provide a novel therapeutic approach. Following TBI, quiescent microglia become activated resulting in anti and pro‐inflammatory responses and morphological changes. We examined the effect of Cosyntropin (synthetic ACTH) administration on microglial activation through quantification of microglia morphology in a rodent TBI model. We hypothesized that Cosyntropin administration would reduce injury‐induced microglia morphological changes following experimental TBI in rats. We used CCI in adult Sprague‐Dawley rats, randomized to 4 groups: sham‐vehicle (N = 2), sham‐Cosyntropin (N = 2), CCI‐vehicle (N = 4), and CCI‐Cosyntropin (N = 4). Subcutaneous injections of Cosyntropin (120U/kg/day; West Therapeutic Development; Grayslake, IL) were given 30 minutes after CCI and every 12 hours for 7 days thereafter. Microglia activation was quantified based on morphology. Sectioned brains were immunostained (Iba1) and visualized with diaminobenzidine. Image processing and quantification were conducted with FIJI and FracLac for ImageJ resulting in 15 morphological values/cell. Parameters included cell area, fractal dimension, circularity, and cell perimeter and density. CCI animals exhibited increased microglia in the lesion site with no difference in cell count between vehicle and treated. Microglia from CCI animals exhibited no change in cell area, decreased cell perimeter and increased density and circularity compared to sham animals. Cosyntropin treatment altered CCI‐induced microglia changes in cell area, cell perimeter, and cell density. Cosyntropin‐treated CCI animals showed reduced morphological changes in microglia suggesting a reduced activation state. Decreased activation may decrease long‐term deleterious neuroinflammatory effects and may be mediated by Cosyntropin effects on melanocortin receptor signaling.Support or Funding InformationSupported in part by the Pediatric Epilepsy Research Foundation. Cosyntropin was supplied by West Therapeutic Development (Grayslake, IL).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

B cell precursor acute lymphoblastic leukemia (B-ALL) is the most common childhood malignancy. A subset of children with B-ALL are at high risk for relapse and death. Gene expression profiles in these high-risk B-ALLs is similar to that of Philadelphia chromosome positive ALL. Approximately half of these Ph-like B-ALL are characterized by genetic alterations that result in overexpression of CRLF2. CRLF2, together with the IL-7 receptor α chain, forms a receptor complex for the cytokine, TSLP. When TSLP binds, the receptor initiates downstream JAK2/STAT5 and PI3/AKT/mTOR pathway activation. The activating JAK mutations found in some CRLF2 B-ALL led to speculation that TSLP stimulation is not a factor in this disease. However, we find that TSLP increases phosphorylation of STAT5, AKT and S6 (downstream of mTOR) in CRLF2 B-ALL cells, including those with JAK defects. Activation of these pathways has been associated with oncogenesis and chemoresistance and their downstream targets include members of the Bcl2 family. The Bcl2 family pro-survival molecule Bcl-XL is a down stream target of STAT5 in Ph+ B-ALL. Mcl-1, another BCL2 family pro-survival molecule is known to be upregulated by mTOR activation via post-translational mechanisms in B cell lymphoma. We hypothesized that TSLP-induced JAK2/STAT5 and PI3/AKT/mTOR pathway activation contribute to chemoresistance in high risk CRLF2 B-ALL by upregulating the expression of Bcl-XL and Mcl-1. To test this hypothesis we cultured human CRLF2 B-ALL cell lines (MUTZ5 and CALL4) with and without TSLP and evaluated expression of the Bcl2 family pro-survival proteins, Bcl-XL, Mcl-1, and Bcl2. We found that TSLP induced significant increases in Bcl-XL and Mcl-1 proteins, but not Bcl2 in CRLF2 B-ALL cells. These cell lines have activating Jak mutations and thus reflect the ability of TSLP to increase expression of the Bcl2 family proteins in cases where activating JAK mutations are present. Next we evaluated the effect of Mcl-1 inhibitor on MUTZ5 and CALL4 cells. Preliminary data from these experiments show that cell counts in cultures treated with Mcl-1 inhibitor are reduce by >90% and this reduction is maintained in the presence of TSLP. These data provide evidence that TSLP-induced CRLF2 signals increase expression of Bcl2 pro-survival proteins, even in CRLF2 B-ALL cells with activating JAK mutations. These data also suggest that Mcl-1 inhibitors could be an effective treatment for this disease. Ongoing studies will evaluate the effect of TSLP and Mcl-1 inhibitors in primary CRLF2 B-ALL samples. Citation Format: Cornelia Stoian, Muhammad Omair Kamal, Olivia Francis, Rhaya Johnson, Simone Montgomery, Jacqueline Coats, Hannah Choi, Shania Aponte-Paris, Micheal Reed, Shanalee Martinez, Karina Mayagoitia, Evgeny Chirshev, Chunhua Song, Sinisa Dovat, Kimberly J. Payne. TSLP regulates expression of Bcl2 family proteins in Ph-like ALL with CRLF2 alterations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2444.