The Experts below are selected from a list of 633 Experts worldwide ranked by ideXlab platform
Maria G. Belvisi - One of the best experts on this subject based on the ideXlab platform.
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tiotropium modulates transient receptor potential v1 trpv1 in Airway Sensory Nerves a beneficial off target effect
The Journal of Allergy and Clinical Immunology, 2014Co-Authors: Mark A Birrell, Kristof Raemdonck, Sarah A Maher, John J Adcock, Michael A Wortley, Eric Dubuis, Sara J Bonvini, Megan S Grace, Maria G. BelvisiAbstract:Background Recent studies have suggested that the long-acting muscarinic receptor antagonist tiotropium, a drug widely prescribed for its bronchodilator activity in patients with chronic obstructive pulmonary disease and asthma, improves symptoms and attenuates cough in preclinical and clinical tussive agent challenge studies. The mechanism by which tiotropium modifies tussive responses is not clear, but an inhibition of vagal tone and a consequent reduction in mucus production from submucosal glands and bronchodilation have been proposed. Objective The aim of this study was to investigate whether tiotropium can directly modulate Airway Sensory Nerve activity and thereby the cough reflex. Methods We used a conscious cough model in guinea pigs, isolated vagal Sensory Nerve and isolated Airway neuron tissue– and cell-based assays, and in vivo single-fiber recording electrophysiologic techniques. Results Inhaled tiotropium blocked cough and single C-fiber firing in the guinea pig to the transient receptor potential (TRP) V1 agonist capsaicin, a clinically relevant tussive stimulant. Tiotropium and ipratropium, a structurally similar muscarinic antagonist, inhibited capsaicin responses in isolated guinea pig vagal tissue, but glycopyrrolate and atropine did not. Tiotropium failed to modulate other TRP channel–mediated responses. Complementary data were generated in Airway-specific primary ganglion neurons, demonstrating that tiotropium inhibited capsaicin-induced, but not TRPA1-induced, calcium movement and voltage changes. Conclusion For the first time, we have shown that tiotropium inhibits neuronal TRPV1-mediated effects through a mechanism unrelated to its anticholinergic activity. We speculate that some of the clinical benefit associated with taking tiotropium (eg, in symptom control) could be explained through this proposed mechanism of action.
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theobromine inhibits Sensory Nerve activation and cough
The FASEB Journal, 2005Co-Authors: Omar S Usmani, Mark A Birrell, Maria G. Belvisi, Hema J Patel, Natascia Crispino, Marta Korbonits, Dezső Korbonits, Peter J BarnesAbstract:SPECIFIC AIMSCough is a condition that affects the vast majority of people at some point in their lives and is the most common complaint for which medical attention is sought. Currently, no effective treatment exists. The aim of this study was to investigate the utility of a novel antitussive called theobromine, a methylxanthine derivative present in cocoa and chocolate, on cough and Airway Sensory Nerve function in humans.PRINCIPAL FINDINGS1. Theobromine as a potential antitussiveSeveral synthetic antitussives are characterized by the presence of a 1,2,4-oxadiazole ring in their chemical structure. With the renaissance of the methylxanthine theophylline to treat asthma in the 1970s, a series of novel compounds with an oxadiazolylalkyl substituent at the N7 atom on the basic xanthine skeleton was synthesized and investigated as potential antiasthmatic and antitussive agents.With two of these compounds selected for preclinical testing, 3,7-dihydro-3-methyl-7-/(5-methyl-1,2,4-oxadiazol-3yl)methyl/-1H-purine...
Thomas E Taylorclark - One of the best experts on this subject based on the ideXlab platform.
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Sensory Nerve terminal mitochondrial dysfunction induces hyperexcitability in Airway nociceptors via protein kinase c
Molecular Pharmacology, 2014Co-Authors: Stephen H Hadley, Parmvir K Bahia, Thomas E TaylorclarkAbstract:Airway Sensory Nerve excitability is a key determinant of respiratory disease-associated reflexes and sensations such as cough and dyspnea. Inflammatory signaling modulates mitochondrial function and produces reactive oxygen species (ROS). Peripheral terminals of Sensory Nerves are densely packed with mitochondria; thus, we hypothesized that mitochondrial modulation would alter neuronal excitability. We recorded action potential firing from the terminals of individual bronchopulmonary C-fibers using a mouse ex vivo lung-vagal ganglia preparation. C-fibers were characterized as nociceptors or non-nociceptors based upon conduction velocity and response to transient receptor potential (TRP) channel agonists. Antimycin A (mitochondrial complex III Qi site inhibitor) had no effect on the excitability of non-nociceptors. However, antimycin A increased excitability in nociceptive C-fibers, decreasing the mechanical threshold by 50% and increasing the action potential firing elicited by a P2X2/3 agonist to 270% of control. Antimycin A–induced nociceptor hyperexcitability was independent of TRP ankyrin 1 or TRP vanilloid 1 channels. Blocking mitochondrial ATP production with oligomycin or myxothiazol had no effect on excitability. Antimycin A–induced hyperexcitability was dependent on mitochondrial ROS and was blocked by intracellular antioxidants. ROS are known to activate protein kinase C (PKC). Antimycin A–induced hyperexcitability was inhibited by the PKC inhibitor bisindolylmaleimide (BIM) I, but not by its inactive analog BIM V. In dissociated vagal neurons, antimycin A caused ROS-dependent PKC translocation to the membrane. Finally, H2O2 also induced PKC-dependent nociceptive C-fiber hyperexcitability and PKC translocation. In conclusion, ROS evoked by mitochondrial dysfunction caused nociceptor hyperexcitability via the translocation and activation of PKC.
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Sensory Nerve terminal mitochondrial dysfunction activates Airway Sensory Nerves via transient receptor potential trp channels
Molecular Pharmacology, 2013Co-Authors: Lika Nesuashvili, Stephen H Hadley, Parmvir K Bahia, Thomas E TaylorclarkAbstract:Mitochondrial dysfunction and subsequent oxidative stress has been reported for a variety of cell types in inflammatory diseases. Given the abundance of mitochondria at the peripheral terminals of Sensory Nerves and the sensitivity of transient receptor potential (TRP) ankyrin 1 (A1) and TRP vanilloid 1 (V1) to reactive oxygen species (ROS) and their downstream products of lipid peroxidation, we investigated the effect of Nerve terminal mitochondrial dysfunction on Airway Sensory Nerve excitability. Here we show that mitochondrial dysfunction evoked by acute treatment with antimycin A (mitochondrial complex III Qi site inhibitor) preferentially activated TRPA1-expressing “nociceptor-like” mouse bronchopulmonary C-fibers. Action potential discharge was reduced by the TRPA1 antagonist HC-030031. Inhibition of TRPV1 further reduced C-fiber activation. In mouse dissociated vagal neurons, antimycin A induced Ca2+ influx that was significantly reduced by pharmacological inhibition or genetic knockout of either TRPA1 or TRPV1. Inhibition of both TRPA1 and TRPV1 was required to abolish antimycin A-induced Ca2+ influx in vagal neurons. Using an HEK293 cell expression system, antimycin A induced concentration-dependent activation of both hTRPA1 and hTRPV1 but failed to activate nontransfected cells. Myxothiazol (complex III Qo site inhibitor) inhibited antimycin A-induced TRPA1 activation, as did the reducing agent dithiothreitol. Scavenging of both superoxide and hydrogen peroxide inhibited TRPA1 activation following mitochondrial modulation. In conclusion, we present evidence that acute mitochondrial dysfunction activates Airway Sensory Nerves preferentially via TRPA1 through the actions of mitochondrially-derived ROS. This represents a novel mechanism by which inflammation may be transduced into nociceptive electrical signaling.
Mark A Birrell - One of the best experts on this subject based on the ideXlab platform.
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tiotropium modulates transient receptor potential v1 trpv1 in Airway Sensory Nerves a beneficial off target effect
The Journal of Allergy and Clinical Immunology, 2014Co-Authors: Mark A Birrell, Kristof Raemdonck, Sarah A Maher, John J Adcock, Michael A Wortley, Eric Dubuis, Sara J Bonvini, Megan S Grace, Maria G. BelvisiAbstract:Background Recent studies have suggested that the long-acting muscarinic receptor antagonist tiotropium, a drug widely prescribed for its bronchodilator activity in patients with chronic obstructive pulmonary disease and asthma, improves symptoms and attenuates cough in preclinical and clinical tussive agent challenge studies. The mechanism by which tiotropium modifies tussive responses is not clear, but an inhibition of vagal tone and a consequent reduction in mucus production from submucosal glands and bronchodilation have been proposed. Objective The aim of this study was to investigate whether tiotropium can directly modulate Airway Sensory Nerve activity and thereby the cough reflex. Methods We used a conscious cough model in guinea pigs, isolated vagal Sensory Nerve and isolated Airway neuron tissue– and cell-based assays, and in vivo single-fiber recording electrophysiologic techniques. Results Inhaled tiotropium blocked cough and single C-fiber firing in the guinea pig to the transient receptor potential (TRP) V1 agonist capsaicin, a clinically relevant tussive stimulant. Tiotropium and ipratropium, a structurally similar muscarinic antagonist, inhibited capsaicin responses in isolated guinea pig vagal tissue, but glycopyrrolate and atropine did not. Tiotropium failed to modulate other TRP channel–mediated responses. Complementary data were generated in Airway-specific primary ganglion neurons, demonstrating that tiotropium inhibited capsaicin-induced, but not TRPA1-induced, calcium movement and voltage changes. Conclusion For the first time, we have shown that tiotropium inhibits neuronal TRPV1-mediated effects through a mechanism unrelated to its anticholinergic activity. We speculate that some of the clinical benefit associated with taking tiotropium (eg, in symptom control) could be explained through this proposed mechanism of action.
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theobromine inhibits Sensory Nerve activation and cough
The FASEB Journal, 2005Co-Authors: Omar S Usmani, Mark A Birrell, Maria G. Belvisi, Hema J Patel, Natascia Crispino, Marta Korbonits, Dezső Korbonits, Peter J BarnesAbstract:SPECIFIC AIMSCough is a condition that affects the vast majority of people at some point in their lives and is the most common complaint for which medical attention is sought. Currently, no effective treatment exists. The aim of this study was to investigate the utility of a novel antitussive called theobromine, a methylxanthine derivative present in cocoa and chocolate, on cough and Airway Sensory Nerve function in humans.PRINCIPAL FINDINGS1. Theobromine as a potential antitussiveSeveral synthetic antitussives are characterized by the presence of a 1,2,4-oxadiazole ring in their chemical structure. With the renaissance of the methylxanthine theophylline to treat asthma in the 1970s, a series of novel compounds with an oxadiazolylalkyl substituent at the N7 atom on the basic xanthine skeleton was synthesized and investigated as potential antiasthmatic and antitussive agents.With two of these compounds selected for preclinical testing, 3,7-dihydro-3-methyl-7-/(5-methyl-1,2,4-oxadiazol-3yl)methyl/-1H-purine...
Sara J Bonvini - One of the best experts on this subject based on the ideXlab platform.
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trpm3 a regulator of Airway Sensory Nerves and respiratory reflexes
European Respiratory Journal, 2016Co-Authors: Sara J Bonvini, Sarah A Maher, John J Adcock, Michael A Wortley, Eric Dubuis, Maham Arshad, Kassandra Kosmidou, Fisnik Shala, Joris Vriens, Thomas VoetsAbstract:In chronic lung diseases, activation of Airway Sensory Nerves initiate respiratory reflexes including cough for which there is currently no safe and effective treatment. Ion channels on Sensory afferents can activate these reflexes and as such are attractive therapeutic targets. The ion channel TRPM3 is a sensor of noxious heat (Vriens J. et al. Neuron.2011:70.482-494), is activated by hypoosmolarity and is expressed in somatoSensory neurons from dorsal root and trigeminal ganglia. We aimed to characterise the role of TRPM3 in Airway Sensory Nerve activation and the cough reflex. Single cell PCR demonstrated that TRPM3 was expressed in Airway specific neurons from guinea pig (GP) nodose and jugular ganglia. Functional experiments using selective pharmacological tools indicated that the TRPM3 agonist CIM0216 evoked [Ca 2+ ] i flux in isolated Airway neurons, and also depolarisation of mouse, GP and human vagus Nerves in an in vitro preparation. Depolarisation by CIM0216 and hypoosmolar solution was inhibited by two selective TRPM3 antagonists and in Trpm3 -/- mice. Preliminary results demonstrate action potential firing by CIM0216 of C-fibres in the anaesthetised GP. These data suggest that TRPM3 is expressed in Airway Sensory neurons and that activators of TRPM3 cause functionally relevant activation of Airway Nerves. Recent data using preclinical models and clinical challenge studies has demonstrated differing profiles of cough responses across diseases, supporting the concept of disease-specific neurophenotypes and underlining the need to understand Airway neurobiology (Belvisi MG. et al .AJRCCM.2016). The discovery of TRPM3 as a regulator of Airway reflexes suggests it may be a novel target for antitussive therapy.
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tiotropium modulates transient receptor potential v1 trpv1 in Airway Sensory Nerves a beneficial off target effect
The Journal of Allergy and Clinical Immunology, 2014Co-Authors: Mark A Birrell, Kristof Raemdonck, Sarah A Maher, John J Adcock, Michael A Wortley, Eric Dubuis, Sara J Bonvini, Megan S Grace, Maria G. BelvisiAbstract:Background Recent studies have suggested that the long-acting muscarinic receptor antagonist tiotropium, a drug widely prescribed for its bronchodilator activity in patients with chronic obstructive pulmonary disease and asthma, improves symptoms and attenuates cough in preclinical and clinical tussive agent challenge studies. The mechanism by which tiotropium modifies tussive responses is not clear, but an inhibition of vagal tone and a consequent reduction in mucus production from submucosal glands and bronchodilation have been proposed. Objective The aim of this study was to investigate whether tiotropium can directly modulate Airway Sensory Nerve activity and thereby the cough reflex. Methods We used a conscious cough model in guinea pigs, isolated vagal Sensory Nerve and isolated Airway neuron tissue– and cell-based assays, and in vivo single-fiber recording electrophysiologic techniques. Results Inhaled tiotropium blocked cough and single C-fiber firing in the guinea pig to the transient receptor potential (TRP) V1 agonist capsaicin, a clinically relevant tussive stimulant. Tiotropium and ipratropium, a structurally similar muscarinic antagonist, inhibited capsaicin responses in isolated guinea pig vagal tissue, but glycopyrrolate and atropine did not. Tiotropium failed to modulate other TRP channel–mediated responses. Complementary data were generated in Airway-specific primary ganglion neurons, demonstrating that tiotropium inhibited capsaicin-induced, but not TRPA1-induced, calcium movement and voltage changes. Conclusion For the first time, we have shown that tiotropium inhibits neuronal TRPV1-mediated effects through a mechanism unrelated to its anticholinergic activity. We speculate that some of the clinical benefit associated with taking tiotropium (eg, in symptom control) could be explained through this proposed mechanism of action.
John J Adcock - One of the best experts on this subject based on the ideXlab platform.
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trpm3 a regulator of Airway Sensory Nerves and respiratory reflexes
European Respiratory Journal, 2016Co-Authors: Sara J Bonvini, Sarah A Maher, John J Adcock, Michael A Wortley, Eric Dubuis, Maham Arshad, Kassandra Kosmidou, Fisnik Shala, Joris Vriens, Thomas VoetsAbstract:In chronic lung diseases, activation of Airway Sensory Nerves initiate respiratory reflexes including cough for which there is currently no safe and effective treatment. Ion channels on Sensory afferents can activate these reflexes and as such are attractive therapeutic targets. The ion channel TRPM3 is a sensor of noxious heat (Vriens J. et al. Neuron.2011:70.482-494), is activated by hypoosmolarity and is expressed in somatoSensory neurons from dorsal root and trigeminal ganglia. We aimed to characterise the role of TRPM3 in Airway Sensory Nerve activation and the cough reflex. Single cell PCR demonstrated that TRPM3 was expressed in Airway specific neurons from guinea pig (GP) nodose and jugular ganglia. Functional experiments using selective pharmacological tools indicated that the TRPM3 agonist CIM0216 evoked [Ca 2+ ] i flux in isolated Airway neurons, and also depolarisation of mouse, GP and human vagus Nerves in an in vitro preparation. Depolarisation by CIM0216 and hypoosmolar solution was inhibited by two selective TRPM3 antagonists and in Trpm3 -/- mice. Preliminary results demonstrate action potential firing by CIM0216 of C-fibres in the anaesthetised GP. These data suggest that TRPM3 is expressed in Airway Sensory neurons and that activators of TRPM3 cause functionally relevant activation of Airway Nerves. Recent data using preclinical models and clinical challenge studies has demonstrated differing profiles of cough responses across diseases, supporting the concept of disease-specific neurophenotypes and underlining the need to understand Airway neurobiology (Belvisi MG. et al .AJRCCM.2016). The discovery of TRPM3 as a regulator of Airway reflexes suggests it may be a novel target for antitussive therapy.
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tiotropium modulates transient receptor potential v1 trpv1 in Airway Sensory Nerves a beneficial off target effect
The Journal of Allergy and Clinical Immunology, 2014Co-Authors: Mark A Birrell, Kristof Raemdonck, Sarah A Maher, John J Adcock, Michael A Wortley, Eric Dubuis, Sara J Bonvini, Megan S Grace, Maria G. BelvisiAbstract:Background Recent studies have suggested that the long-acting muscarinic receptor antagonist tiotropium, a drug widely prescribed for its bronchodilator activity in patients with chronic obstructive pulmonary disease and asthma, improves symptoms and attenuates cough in preclinical and clinical tussive agent challenge studies. The mechanism by which tiotropium modifies tussive responses is not clear, but an inhibition of vagal tone and a consequent reduction in mucus production from submucosal glands and bronchodilation have been proposed. Objective The aim of this study was to investigate whether tiotropium can directly modulate Airway Sensory Nerve activity and thereby the cough reflex. Methods We used a conscious cough model in guinea pigs, isolated vagal Sensory Nerve and isolated Airway neuron tissue– and cell-based assays, and in vivo single-fiber recording electrophysiologic techniques. Results Inhaled tiotropium blocked cough and single C-fiber firing in the guinea pig to the transient receptor potential (TRP) V1 agonist capsaicin, a clinically relevant tussive stimulant. Tiotropium and ipratropium, a structurally similar muscarinic antagonist, inhibited capsaicin responses in isolated guinea pig vagal tissue, but glycopyrrolate and atropine did not. Tiotropium failed to modulate other TRP channel–mediated responses. Complementary data were generated in Airway-specific primary ganglion neurons, demonstrating that tiotropium inhibited capsaicin-induced, but not TRPA1-induced, calcium movement and voltage changes. Conclusion For the first time, we have shown that tiotropium inhibits neuronal TRPV1-mediated effects through a mechanism unrelated to its anticholinergic activity. We speculate that some of the clinical benefit associated with taking tiotropium (eg, in symptom control) could be explained through this proposed mechanism of action.