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Title: Characterization of the Effects and Mechanisms of Prostaglandin E2 (PGE2) in Central Sensitization of the Cough Reflex
Authors: Al-Shaimaa Al-Kandery 
Supervisor: Prof. Ahmed El-Hashim
Degree Awarded: Master's Degree in: Pharmaceutical Sciences
Keywords: Cough, Central Sensitization, Prostaglandin E2, EP Receptors, TRPV1, TRPA1
Issue Date: 2019
Publisher:  Kuwait university - college of graduate studies
Abstract: Cough is one of the most common clinical problems, yet it is poorly understood, difficult to treat and is considered a major cause of impairment in quality of life. Furthermore, despite its clinical significance, current anti-tussive therapies remain unsatisfactory. Cough hypersensitivity is a main characteristic feature associated with several types of cough, including chronic cough. Several inflammatory mediators such as nerve growth factor (NGF) and bradykinin (BK) have been demonstrated to have important roles in the sensitization of the cough reflex. The inflammatory mediator, prostaglandin E2 (PGE2), has also been reported to cause irritation of upper airways, induce cough and sensitize the cough reflex both in preclinical and clinical studies. These effects are thought to be linked to activation of prostaglandin E2 receptors (EP) on airway sensory nerves which are currently subdivided into EP1,2,3 and 4. However, whether PGE2 can sensitize the cough reflex via a central mode of action has not been addressed yet. In this study, using a conscious guinea pig model of cough, I investigated (1) whether PGE2 was involved in the central sensitization of the cough reflex and if so, (2) which EP receptor/s may mediate this effect and (3) whether TRPV1/TRPA1 channels are downstream effectors of EP receptor activation. Drugs were administered centrally by the intracerebroventricular (i.c.v.) route, one week following stereotaxic surgery. Using a whole-body plethysmograph set-up, guinea pigs were exposed to aerosolized citric acid (0.2 M) to induce cough, which was recorded using an automated cough analyzer. PGE2, dose-dependently enhanced the citric acid-induced cough. A similar effect was seen with the non-selective EP1/EP3 agonist, sulprostone. Pretreatment with EP1 antagonist, ONO-8130, did not affect the sulprostone-induced cough sensitization, whilst the EP3 receptor antagonist, L-798,106 dose-dependently inhibited this effect. Treatment with either the EP2 receptor agonist, butaprost or the EP4 agonist, L-902,688, had no effect on the citric acid-induced cough. Furthermore, pretreatment with either the TRPV1 antagonist, JNJ-17203212 or the TRPA1 antagonist, HC-030031, alone or in combination, did not alter the PGE2-enhanced citric acid-induced cough. In conclusion, my study shows that PGE2 sensitizes the cough reflex via activation of central EP3 receptors but independently of TRPV1/TRPA1 channels activation. This study shows that PGE2 plays an important role in the sensitization of cough reflex, via a central mode of action, and suggests that central EP3 receptors may represent a novel antitussive molecular target.
Appears in Programs:1100 Pharmaceutical Sciences

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