title: Inhibiting TRPA1 ion channel reduces loss of cutaneous nerve fiber function in diabetic animals: sustained activation of the TRPA1 channel contributes to the pathogenesis of peripheral diabetic neuropathy.
abstract: Peripheral diabetic neuropathy (PDN) is a devastating complication of diabetes mellitus (DM). Here we test the hypothesis that the transient receptor potential ankyrin 1 (TRPA1) ion channel on primary afferent nerve fibers is involved in the pathogenesis of PDN, due to sustained activation by reactive compounds generated in DM. DM was induced by streptozotocin in rats that were treated daily for 28 days with a TRPA1 channel antagonist (Chembridge-5861528) or vehicle. Laser Doppler flow method was used for assessing axon reflex induced by intraplantar injection of a TRPA1 channel agonist (cinnamaldehyde) and immunohistochemistry to assess substance P-like innervation of the skin. In vitro calcium imaging and patch clamp were used to assess whether endogenous TRPA1 agonists (4-hydroxynonenal and methylglyoxal) generated in DM induce sustained activation of the TRPA1 channel. Axon reflex induced by a TRPA1 channel agonist in the plantar skin was suppressed and the number of substance P-like immunoreactive nerve fibers was decreased 4 weeks after induction of DM. Prolonged treatment with Chembridge-5861528 reduced the DM-induced attenuation of the cutaneous axon reflex and loss of substance P-like immunoreactive nerve fibers. Moreover, in vitro calcium imaging and patch clamp results indicated that reactive compounds generated in DM (4-hydroxynonenal and methylglyoxal) produced sustained activations of the TRPA1 channel, a prerequisite for adverse long-term effects. The results indicate that the TRPA1 channel exerts an important role in the pathogenesis of PDN. Blocking the TRPA1 channel provides a selective disease-modifying treatment of PDN.
authors: Orion Corporation, OrionPharma, Finland.
authors: Ari
authors: A
authors: Koivisto
authors: Mika
authors: M
authors: Hukkanen
authors: Marja
authors: M
authors: Saarnilehto
authors: Hugh
authors: H
authors: Chapman
authors: Katja
authors: K
authors: Kuokkanen
authors: Hong
authors: H
authors: Wei
authors: Hanna
authors: H
authors: Viisanen
authors: Karl E
authors: KE
authors: Akerman
authors: Ken
authors: K
authors: Lindstedt
authors: Antti
authors: A
authors: Pertovaara
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008564:Membrane Potentials; D009412:Nerve Fibers / Q000187:drug effects* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009431:Neural Conduction / Q000187:drug effects; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D012018:Reflex / Q000187:drug effects; D018689:Sensory System Agents / Q000494:pharmacology*; D012867:Skin / Q000294:innervation*; D013373:Substance P / Q000378:metabolism; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D009419:Nerve Tissue Proteins; D018689:Sensory System Agents; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050052:TRPC Cation Channels; D050051:Transient Receptor Potential Channels; C480976:Trpa1 protein, rat; D013373:Substance P