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Please use this identifier to cite or link to this item: http://hdl.handle.net/123456789/14414

Title: Coadministration of stigmasterol and dexamethasone modulates steroid resistant asthma
Authors: Hohoayi, Abigail
Ainooson, George Kwaw
Keywords: Coadministration
Issue Date: 16-Jul-2021
Abstract: Airway inflammation in asthma is managed with anti-inflammatory steroids such as dexamethasone. However, about 20% of asthmatics do not respond to this therapy and are classified as steroid resistant. One important cause of steroid resistance in asthma is the accumulation of lipopolysaccharide (LPS), an endotoxin from Gram negative bacteria, in the airway of asthmatics. Mechanistically, LPS induces steroid resistance in asthma by stimulating neutrophilia, burst in oxidative and nitrative stress, degradation of the gene transcription repressor (histone deacetylase 2 [HDAC2]), leading to downstream increase in the expression of proinflammatory cytokines such as Interleukin 17 (IL-17). These molecular changes result in severe asthma attack evident by dyspnea and convulsion in experimental animals. Currently, no effective therapy is available for steroid resistant asthma. This has led to the search for novel therapeutic agents from different sources including natural products. One of such natural products is stigmasterol, the subject of this investigation, which is a plant sterol with potent anti-inflammatory and airway modulatory properties. This work therefore evaluated the effect of stigmasterol alone and in combination with the anti-inflammatory glucocorticoid, dexamethasone in LPS-ovalbumin-induced steroid resistant asthma in Guinea pigs. To do this, the effect of drugs on disease severity was assessed by assessing the time to and duration of convulsion in addition to pathological examination of lung tissue. Additionally, the possible molecular mechanism of drug action was assessed by measuring neutrophil levels, oxidative and nitrative stress, HDAC2 and IL-17 levels. As expected, dexamethasone did not significantly inhibit disease severity or the associated molecular events. Similarly stigmasterol alone did not effectively inhibit disease severity, although it caused some changes in molecular events. However, coadministration of stigmasterol and dexamethasone caused significant inhibition of disease severity by protecting against convulsion and destruction of lung tissue. This protection was associated with significant inhibition of the neutrophilia, oxidative and nitrative stress, decrease in HDAC2 and increase in IL-17 levels that is usually associated with steroid resistant asthma. This shows that although stigmasterol and dexamethasone individually do not protect against steroid resistant asthma, their coadministration results in significant inhibition of disease severity and the associated molecular events that lead to steroid resistant asthma.
Description: A thesis submitted to the Department of Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, College of Health Sciences in partial fulfillment of the requirements for the Degree of Master of Philosophy in Pharmacology. June, 2019
URI: http://hdl.handle.net/123456789/14414
Appears in Collections:College of Health Sciences

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