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Deutsches Institut für Urbanistik
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Naoaki Harada, Kenji Okajima, Mitsuhiro Uchiba, Hiroki Kurihara, Naomi Nakagata

Antithrombin reduces reperfusion-induced liver injury in mice by enhancing sensory neuron activation

Keywords: Antithrombin, Capsaicin-sensitive sensory neurons, calcitonin gene-related peptide, liver injury, protein kinase A

We recently demonstrated that antithrombin (AT) reduces ischemia/reperfusion (I/R)-induced liver injury in rats by increasing hepatic tissue levels of calcitonin gene-related peptide (CGRP), a neuropeptide released from the sensory nerve endings. In the present study, we examined the effect of AT on I/R-induced liver injury in wild type mice (CGRP+/+) and congenitally CGRP-deficient mice (CGRP/). We also investigated any effects of AT on CGRP release from dorsal root ganglion neurons (DRG) isolated from CGRP+/+. Based on results obtained in the present study, we attempted to determine if the anti-inflammatory activity of AT in vivo is dependent mainly on sensory neuron activation. AT enhanced ischemia/reperfusion-induced increases in hepatic tissue levels of CGRP and 6-keto-PGF1, a stable metabolite of PGI2, in CGRP+/+, but it did not enhance these increases in CGRP/. AT inhibited reperfusion-induced increases in serum alanine aminotransferase levels by increasing hepatic tissue blood flow and by attenuating increases in hepatic levels of tumor necrosis factor and myeloperoxidase in CGRP+/+, although it showed neither of these therapeutic effects in CGRP/. AT increased CGRP release from cultured DRGs only in the presence of anandamide, and AT-induced increase in CGRP release was not observed in the presence KT5720, an inhibitor of protein kinase A (PKA). AT markedly increased intracellular levels of cAMP in the presence of anandamide. These results strongly suggest that AT might reduce I/R-induced liver injury by enhancing activation of the sensory neurons through activation of PKA in sensory neurons.

Thrombosis and Haemostasis, Schattauer

Print ISSN: 0340-6245
Volume: 95, 05/2006
Pages: 788 - 795

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