Investigation Into the mechanism of action of disodium cromoglycate in pre-clinical models of asthma
File(s)
Author(s)
Chen, Xue
Type
Thesis
Abstract
Asthma is a disease with increasing global prevalence and patients typically suffer from symptoms
such as wheezing, breathlessness, chest tightness and cough. Although in most cases asthma can be well controlled with current treatments, there remains an unmet need as patients do not always comply with therapies, and some remain unresponsive to treatment. In allergic asthma, exposure to allergen can lead to episodes of bronchoconstriction known as the late asthmatic response (LAR), a characteristic feature of asthma which has been shown to involve the activation of airway sensory nerves in a preclinical model. In asthmatics, DiSodium Cromoglycate (DSCG) is known to modulate the LAR but its use is limited because of its short duration of action seen evidenced by its pharmacokinetic profile. Although a safe and effective drug, the mechanism of action of DSCG remains unclear. The aim of this thesis is to investigate the mechanism with the possibility to develop a novel therapy with an improved PK profile and thus be a more useful treatment.
Using a pre-clinical Brown Norway (BN) rat model of the LAR, it was established that both DSCG and a TRPA1 inhibitor can attenuate the LAR, suggesting an association between DSCG and TRPA1 on airway sensory nerves. This was confirmed by using an in vitro model of vagal sensory nerve activation, an in vitro model of airway specific neuron activation, in vivo sensory nerve recordings and an in vivo cough model, which all showed that DSCG can attenuate TRPA1 induced activation of airway sensory nerves.
While investigating the mechanism by which DSCG inhibits airway sensory nerves, two distinct mechanisms were uncovered which depended on how the channel was opened. The first was that DSCG inhibited TRPA1 activity on airway sensory nerves through agonising GPR35 receptors. Selective GPR35 agonists demonstrated a similar inhibitory effect as DSCG, and this was reversed with GPR35 antagonists. Investigations showed that GPR35 was only responsible for some of the activity of DSCG on sensory nerves (i.e. with acrolein as the trigger); some DSCG modulated TRPA1 triggers were independent of GPR35 (i.e. PGE2). The second mechanism appeared to be via the blockade of TRPV2 channel/signalling and subsequent reduction of NADPH oxidase activity.
The work within my thesis has therefore uncovered the important role of GPR35, TRPV2 and NADPH oxidase activity in the mechanism of action of DSCG by using pre-clinical models. These findings help to explain the beneficial effects observed in the clinic and also highlight novel targets for drug discovery.
such as wheezing, breathlessness, chest tightness and cough. Although in most cases asthma can be well controlled with current treatments, there remains an unmet need as patients do not always comply with therapies, and some remain unresponsive to treatment. In allergic asthma, exposure to allergen can lead to episodes of bronchoconstriction known as the late asthmatic response (LAR), a characteristic feature of asthma which has been shown to involve the activation of airway sensory nerves in a preclinical model. In asthmatics, DiSodium Cromoglycate (DSCG) is known to modulate the LAR but its use is limited because of its short duration of action seen evidenced by its pharmacokinetic profile. Although a safe and effective drug, the mechanism of action of DSCG remains unclear. The aim of this thesis is to investigate the mechanism with the possibility to develop a novel therapy with an improved PK profile and thus be a more useful treatment.
Using a pre-clinical Brown Norway (BN) rat model of the LAR, it was established that both DSCG and a TRPA1 inhibitor can attenuate the LAR, suggesting an association between DSCG and TRPA1 on airway sensory nerves. This was confirmed by using an in vitro model of vagal sensory nerve activation, an in vitro model of airway specific neuron activation, in vivo sensory nerve recordings and an in vivo cough model, which all showed that DSCG can attenuate TRPA1 induced activation of airway sensory nerves.
While investigating the mechanism by which DSCG inhibits airway sensory nerves, two distinct mechanisms were uncovered which depended on how the channel was opened. The first was that DSCG inhibited TRPA1 activity on airway sensory nerves through agonising GPR35 receptors. Selective GPR35 agonists demonstrated a similar inhibitory effect as DSCG, and this was reversed with GPR35 antagonists. Investigations showed that GPR35 was only responsible for some of the activity of DSCG on sensory nerves (i.e. with acrolein as the trigger); some DSCG modulated TRPA1 triggers were independent of GPR35 (i.e. PGE2). The second mechanism appeared to be via the blockade of TRPV2 channel/signalling and subsequent reduction of NADPH oxidase activity.
The work within my thesis has therefore uncovered the important role of GPR35, TRPV2 and NADPH oxidase activity in the mechanism of action of DSCG by using pre-clinical models. These findings help to explain the beneficial effects observed in the clinic and also highlight novel targets for drug discovery.
Version
Open Access
Date Issued
2020-09
Date Awarded
2021-01
Copyright Statement
Creative Commons Attribution NonCommercial NoDerivatives Licence
Advisor
Belvisi, Maria
Birrell, Mark
Edel, Joshua
Publisher Department
NHLI and Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)