Small molecule dual-inhibitors of TRPV4 and TRPA1 for attenuation of inflammation and pain.
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2016-06-01
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TRPV4 ion channels represent osmo-mechano-TRP channels with pleiotropic function and wide-spread expression. One of the critical functions of TRPV4 in this spectrum is its involvement in pain and inflammation. However, few small-molecule inhibitors of TRPV4 are available. Here we developed TRPV4-inhibitory molecules based on modifications of a known TRPV4-selective tool-compound, GSK205. We not only increased TRPV4-inhibitory potency, but surprisingly also generated two compounds that potently co-inhibit TRPA1, known to function as chemical sensor of noxious and irritant signaling. We demonstrate TRPV4 inhibition by these compounds in primary cells with known TRPV4 expression - articular chondrocytes and astrocytes. Importantly, our novel compounds attenuate pain behavior in a trigeminal irritant pain model that is known to rely on TRPV4 and TRPA1. Furthermore, our novel dual-channel blocker inhibited inflammation and pain-associated behavior in a model of acute pancreatitis - known to also rely on TRPV4 and TRPA1. Our results illustrate proof of a novel concept inherent in our prototype compounds of a drug that targets two functionally-related TRP channels, and thus can be used to combat isoforms of pain and inflammation in-vivo that involve more than one TRP channel. This approach could provide a novel paradigm for treating other relevant health conditions.
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Kanju, P, Y Chen, W Lee, M Yeo, SH Lee, J Romac, R Shahid, P Fan, et al. (2016). Small molecule dual-inhibitors of TRPV4 and TRPA1 for attenuation of inflammation and pain. Sci Rep, 6. p. 26894. 10.1038/srep26894 Retrieved from https://hdl.handle.net/10161/12075.
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Scholars@Duke
Yong Chen
Dr. Yong Chen is an Associate Professor of Neurology at the Duke University School of Medicine. He is also affiliated with Duke Anesthesiology-Center for Translational Pain Medicine (CTPM) and Duke-Pathology.
The Chen lab mainly studies sensory neurobiology of pain and itch, with a focus on TRP ion channels and neural circuits. The main objective of our lab is to identify molecular and cellular mechanisms underlying chronic pain and chronic-disease associated itch, using a combination of animal behavioral, genetic, molecular and cellular, advanced imaging, viral, and optogenetic approaches. There are three major research areas in the lab: craniofacial pain, arthritis pain and joint function, and systemic-disease associated itch.
Sidney Arthur Simon
Dr. Simon's laboratory studies the interaction of chemical stimuli with cultured and intact trigeminal ganglion neurons and taste receptor cells both in culture, in anesthetized and in awake behaving animals. We investigate how chemicals that are either bitter and/or irritating ( e.g., nicotine, capsaicin, colloidal particles) interact with particular types of receptors (e.g. nicotinic acetylcholine receptors or vanilloid receptors) to produce a bitter, irritating or painful sensation. We also investigate how these compounds evoke responses in various cortical regions such as the ventral tegmental area, orbitofrontal cortex and gustatory cortex. Our overall goal is to obtain a understanding of the events from the molecular to the behavioral levels that underlie gustatory and irritating sensations produced by chemical stimuli. We collaborate with the Nicolelis and Reinhart laboratories.
Another focus of Dr. Simon's laboratory is to investigate the physical chemical interactions that occur when peptides interact with membranes. To date we have focused on leader sequences. This work is in collaboration with the laboratory of Dr. Tom Mcintosh in the Cell Biology Department.
Ivan Spasojevic
Robert Anthony Mook
Rodger Alan Liddle
Our laboratory has two major research interests:
Enteroendocrine Cell Biology
Enteroendocrine cells (EECs) are sensory cells of the gut that send signals throughout the body. They have the ability to sense food and nutrients in the lumen of the intestine and secrete hormones into the blood. Our laboratory has had a longstanding interest in two types of EECs that regulate satiety and signal the brain to stop eating. Cholecystokinin (CCK) is secreted from EECs of the upper small intestine and regulates the ingestion and digestion of food through effects on the stomach, gallbladder, pancreas and brain. Peptide YY (PYY) is secreted from EECs of the small intestine and colon and regulates satiety. We recently demonstrated that CCK and PYY cells not only secrete hormones but are directly connected to nerves through unique cellular processes called ‘neuropods’. Our laboratory is devoted to understanding EECs signaling and its role in disease.
Pancreatitis
Pancreatitis is an inflammatory disease of the pancreas compounded by intrapancreaatic activation of digestive enzymes. Our laboratory is studying the influence of nerves on the development of pancreatitis. Neurogenic inflammation results from the release of bioactive substances from sensory neurons in the pancreas causing vasodilatation, edema, and inflammatory cell infiltration producing tissue necrosis. Our goal is to identify the agents that activate sensory neurons, characterize the receptors on sensory nerves that mediate these actions, and determine the effects of neural stimulation on pancreatic injury with the long-term objective of developing strategies to reduce neurogenic inflammation to treat pancreatitis.
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