学術雑誌論文 Hypoxia-induced sensitisation of TRPA1 in painful dysesthesia evoked by transient hindlimb ischemia/reperfusion in mice

So, Kanako  ,  Tei, Yuna  ,  Zhao, Meng  ,  Miyake, Takahito  ,  Hiyama, Haruka  ,  Shirakawa, Hisashi  ,  Imai, Satoshi  ,  Mori, Yasuo  ,  Nakagawa, Takayuki  ,  Matsubara, Kazuo  ,  Kaneko, Shuji

62016-03-17 , Nature Publishing Group
ISSN:2045-2322
内容記述
「しびれ」による痛みのメカニズムを解明 -糖尿病や血流障害によるしびれ治療薬の開発に期待-. 京都大学プレスリリース. 2016-03-18.
Dysesthesia is an unpleasant abnormal sensation, which is often accompanied by peripheral neuropathy or vascular impairment. Here, we examined the roles of transient receptor potential ankyrin 1 (TRPA1) in dysesthesia-like behaviours elicited by transient hindlimb ischemia (15–60 min) by tightly compressing the hindlimb, and reperfusion by releasing the ligature. The paw-withdrawal responses to tactile stimulation were reduced during ischemia and lasted for a while after reperfusion. Hindlimb ischemia/reperfusion elicited spontaneous licking of the ischemic hindpaw that peaked within 10 min. The licking was inhibited by reactive oxygen species (ROS) scavengers, a TRPA1 antagonist, or TRPA1 deficiency, but not by TRPV1 deficiency. In human TRPA1-expressing cells as well as cultured mouse dorsal root ganglion neurons, the H[2]O[2]-evoked TRPA1 response was significantly increased by pretreatment with hypoxia (80 mmHg) for 30 min. This hypoxia-induced TRPA1 sensitisation to H[2]O[2] was inhibited by overexpressing a catalytically-inactive mutant of prolyl hydroxylase (PHD) 2 or in a TRPA1 proline mutant resistant to PHDs. Consistent with these results, a PHD inhibitor increased H[2]O[2]-evoked nocifensive behaviours through TRPA1 activation. Our results suggest that transient hindlimb ischemia/reperfusion-evoked spontaneous licking, i.e. painful dysesthesia, is caused by ROS-evoked activation of TRPA1 sensitised by hypoxia through inhibiting PHD-mediated hydroxylation of a proline residue in TRPA1.
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http://www.kyoto-u.ac.jp/ja/research/research_results/2015/160317_1.html

http://repository.kulib.kyoto-u.ac.jp/dspace/bitstream/2433/209707/1/srep23261.pdf

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