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Antithrombin reduces ischemia/reperfusion-induced liver injury in mice by enhancing the activation of sensory neurons through protein kinase A activation

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 wildtype mice (CGRP+/+) and congenital α CGRP-deficient mice (CGRP-/-). We further investigated whether AT affects CGRP release from dorsal root ganglion neurons (DRG) isolated from CGRP+/+. Based on results obtained in the present study, we attempted to determine whether the anti-inflammatory activity of AT in vivo is dependent mainly on sensory neuron activation. AT enhanced I/R-induced increases in hepatic tissue levels of CGRP and 6-keto-PGF a stable metabolite of PGI2, in CGRP+/+, while 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+/+, while it showed neither of these therapeutic effects in CGRP-/-. AT increased CGRP release from cultured DRGs only in the presence of anandamide, and the AT-induced increase in CGRP release was not observed in the presence of KT5720, an inhibitor of protein kinase A (PKA). AT markedly increased intracellular levels of cAMP in the presence of anandamide. In conclusion, 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.

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Harada, N., Okajima, K., Kuhihara, H. et al. Antithrombin reduces ischemia/reperfusion-induced liver injury in mice by enhancing the activation of sensory neurons through protein kinase A activation. Crit Care 10, P159 (2006). https://doi.org/10.1186/cc4506

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Keywords

  • Dorsal Root Ganglion
  • Liver Injury
  • Sensory Neuron
  • Dorsal Root Ganglion Neuron
  • Antithrombin