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Transient receptor potential ankyrin 1 (TRPA1) ion channel in the pathophysiology of peripheral diabetic neuropathy.
Scand J Pain. 2013 Jul 01; 4(3):129-136.SJ

Abstract

Background Transient receptor potential ankyrin 1 (TRPA1) is a non-selective cation channel permeable to calcium that is expressed on pain-mediating primary afferent nerve fibers. Here we review recent experimental evidence supporting the hypothesis that activation of the TRPA1 channel by reactive compounds generated in diabetes mellitus, such as 4-hydroxynonenal and methylglyoxal, exerts an important role in the pathophysiology of peripheral diabetic neuropathy (PDN). The hypothesis includes development of the early diabetic pain hypersensitivity and the later loss of cutaneous nerve endings of pain fibers and their dysfunction, which are hallmarks of peripheral diabetic neuropathy (PDN). Methods The evidence for a role of the TRPA1 channel in PDN consists of in vitro patch clamp and calcium imaging data and assessments of pain behavior, axon reflex measurements, and immunohistochemical analyses of cutaneous innervation in an experimental animal model of diabetes. The experiments were combined with blocking the TRPA1 channel with selective antagonists Chembridge-5861528 or A-967079. Results In vitro studies indicate that under physiological concentration of Ca2+, methylglyoxal and 4-hydroxynonenal produce sustained activation of the TRPA1 channel and sustained inflow of calcium. In vivo studies indicate that diabetic pain hypersensitivity is maintained by the TRPA1 channel as indicated by the antihypersensitivity effect induced by acute blocking of the TRPA1 channel. Moreover, TRPA1 channel is involved in the development of diabetic hypersensitivity as indicated by prevention of the development of pain hypersensitivity in diabetic animals treated daily with Chembridge-5861528. The diabetes-induced loss of substance P-like cutaneous innervation and that of the TRPA1 channel-mediated cutaneous axon reflex function during the later phase of diabetes were also prevented or delayed by prolonged blocking of the TRPA1 channel. No motor impairment or other obvious side-effects were observed following block of the TRPA1 channel. Conclusions Together the in vitro and in vivo results indicate that reactive compounds generated in diabetes exert, through action on the TRPA1 channel, an important role in the pathophysiology of PDN. Sustained activation of the TRPA1 channel is a plausible mechanism that contributes to the early diabetic pain hypersensitivity and the later loss of cutaneous pain fiber endings and their dysfunction with prolonged diabetes. Implications Blocking the TRPA1 channel with a selective antagonist provides a promising disease-modifying treatment for PDN, with only minor, if any, side-effects.

Authors+Show Affiliations

Orion Corporation, OrionPharma, Turku, Finland.Institute of Biomedicine/Physiology, University of Helsinki, Helsinki, Finland.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29913916

Citation

Koivisto, Ari, and Antti Pertovaara. "Transient Receptor Potential Ankyrin 1 (TRPA1) Ion Channel in the Pathophysiology of Peripheral Diabetic Neuropathy." Scandinavian Journal of Pain, vol. 4, no. 3, 2013, pp. 129-136.
Koivisto A, Pertovaara A. Transient receptor potential ankyrin 1 (TRPA1) ion channel in the pathophysiology of peripheral diabetic neuropathy. Scand J Pain. 2013;4(3):129-136.
Koivisto, A., & Pertovaara, A. (2013). Transient receptor potential ankyrin 1 (TRPA1) ion channel in the pathophysiology of peripheral diabetic neuropathy. Scandinavian Journal of Pain, 4(3), 129-136. https://doi.org/10.1016/j.sjpain.2012.11.001
Koivisto A, Pertovaara A. Transient Receptor Potential Ankyrin 1 (TRPA1) Ion Channel in the Pathophysiology of Peripheral Diabetic Neuropathy. Scand J Pain. 2013 Jul 1;4(3):129-136. PubMed PMID: 29913916.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Transient receptor potential ankyrin 1 (TRPA1) ion channel in the pathophysiology of peripheral diabetic neuropathy. AU - Koivisto,Ari, AU - Pertovaara,Antti, Y1 - 2013/07/01/ PY - 2012/10/09/received PY - 2012/11/04/accepted PY - 2018/6/20/entrez PY - 2018/6/20/pubmed PY - 2018/6/20/medline KW - Axon reflex KW - Cutaneous nerve fiber density KW - Diabetic neuropathy KW - Methylglyoxal KW - Pain hypersensitivity KW - TRPA1 SP - 129 EP - 136 JF - Scandinavian journal of pain JO - Scand J Pain VL - 4 IS - 3 N2 - Background Transient receptor potential ankyrin 1 (TRPA1) is a non-selective cation channel permeable to calcium that is expressed on pain-mediating primary afferent nerve fibers. Here we review recent experimental evidence supporting the hypothesis that activation of the TRPA1 channel by reactive compounds generated in diabetes mellitus, such as 4-hydroxynonenal and methylglyoxal, exerts an important role in the pathophysiology of peripheral diabetic neuropathy (PDN). The hypothesis includes development of the early diabetic pain hypersensitivity and the later loss of cutaneous nerve endings of pain fibers and their dysfunction, which are hallmarks of peripheral diabetic neuropathy (PDN). Methods The evidence for a role of the TRPA1 channel in PDN consists of in vitro patch clamp and calcium imaging data and assessments of pain behavior, axon reflex measurements, and immunohistochemical analyses of cutaneous innervation in an experimental animal model of diabetes. The experiments were combined with blocking the TRPA1 channel with selective antagonists Chembridge-5861528 or A-967079. Results In vitro studies indicate that under physiological concentration of Ca2+, methylglyoxal and 4-hydroxynonenal produce sustained activation of the TRPA1 channel and sustained inflow of calcium. In vivo studies indicate that diabetic pain hypersensitivity is maintained by the TRPA1 channel as indicated by the antihypersensitivity effect induced by acute blocking of the TRPA1 channel. Moreover, TRPA1 channel is involved in the development of diabetic hypersensitivity as indicated by prevention of the development of pain hypersensitivity in diabetic animals treated daily with Chembridge-5861528. The diabetes-induced loss of substance P-like cutaneous innervation and that of the TRPA1 channel-mediated cutaneous axon reflex function during the later phase of diabetes were also prevented or delayed by prolonged blocking of the TRPA1 channel. No motor impairment or other obvious side-effects were observed following block of the TRPA1 channel. Conclusions Together the in vitro and in vivo results indicate that reactive compounds generated in diabetes exert, through action on the TRPA1 channel, an important role in the pathophysiology of PDN. Sustained activation of the TRPA1 channel is a plausible mechanism that contributes to the early diabetic pain hypersensitivity and the later loss of cutaneous pain fiber endings and their dysfunction with prolonged diabetes. Implications Blocking the TRPA1 channel with a selective antagonist provides a promising disease-modifying treatment for PDN, with only minor, if any, side-effects. SN - 1877-8879 UR - https://www.unboundmedicine.com/medline/citation/29913916/Transient_receptor_potential_ankyrin_1__TRPA1__ion_channel_in_the_pathophysiology_of_peripheral_diabetic_neuropathy_ L2 - https://www.degruyter.com/document/doi/10.1016/j.sjpain.2012.11.001 DB - PRIME DP - Unbound Medicine ER -
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