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Title: Investigations into the Sensitizing Effects of Bradykinin on Central Cough Pathways and its Signaling Mechanisms
Authors: Fajer Al-Shamlan 
Supervisor: Prof. Ahmed El-Hashim
Keywords: Investigations : Signaling Mechanisms
Issue Date: 2018
Publisher:  Kuwait university - college of graduate studies
Abstract: Chronic cough is a poorly understood and managed clinical problem with a high prevalence rate. Thus, current anti-tussive therapies are relatively ineffective. Recently the sensitization of cough reflex has been identified as an important mechanism in chronic cough, with the term cough hypersensitivity syndrome (CHS) coined to describe this phenomenon. Many mediators such as nerve growth factor and substance P can sensitize the cough reflex. Bradykinin (BK), a well-established inflammatory mediator of both acute and chronic pain, has also been reported to both induce cough and sensitize the cough reflex in preclinical animal models and humans, possibly due to its action on airway sensory nerves. In this study, using a stereotaxic set-up, I investigated whether BK can exert a central action to sensitize the cough reflex and the airway response, and if so, by what molecular mechanisms. In all experiments, BK and other inhibitors were administered by intracerebroventricular (i.c.v.) route after which low dose citric acid was administered by aerosolization to induce cough and airway obstruction. BK treatment significantly enhanced the citric acid-induced cough and airway obstruction; this was reversed following treatment with a B2 receptor antagonist, transient receptor potential vanilloid 1 (TRPV1) antagonist, transient receptor potential ankyrin 1 (TRPA1) antagonist, cyclooxygenase (COX) inhibitor, and the 12-LOX but not the 15-LOX inhibitor. Furthermore, my data showed that combined blockade of either TRPV1/TPRA1 or COX/12LOX produced greater inhibition of BK enhanced cough and airway obstruction. In conclusion, my study has demonstrated the important role that central BK receptors play in the enhancement of the cough reflex and airway response and identified the downstream signaling molecules involved. These findings highlight the critical function that CNS plays in the sensitization of cough and enhanced airway response, underscore the important role that central TRPV1 and TPRA1 channels and the products of central COX and 12-LOX play in this regard, and also suggest that combined targeting of TRPV1/TPRA1 and/or COX/12-LOX may have particular therapeutic benefit.
Appears in Programs:1100 Pharmaceutical Sciences

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