Abstract
Liver ischemia–reperfusion injury (LIRI) influences different body cells. Little is known about the effect of LIRI on the activity of neurons. Response of neurons to: (1) single ligation of hepatic artery (LIRIa) for 30 min and (2) combined ligation of portal triade (common hepatic artery, portal vein, common bile duct, LIRIb) for 15 min was investigated in Wistar rats. Ninety minutes, 5 h, and 24 h after liver reperfusion, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), interleukin 1α (IL-1α), and tumor necrosis factor α (TNFα) serum levels were analyzed and Fos-immunolabeled cells counted in subfornical organ (SFO), suprachiasmatic (SCH), paraventricular (PVN), supraoptic (SON), arcuate (ARC), and ventromedial (VMN) hypothalamic nuclei, locus coeruleus (LC), nucleus of the solitary tract (NTS), and A1/C1 catecholaminergic cell groups. LIRIb increased ALT serum level after 90 min and 24 h while AST activity only after 24 h in all experimental groups. IL-1α serum level was increased only after 90 min of LIRIb while TNFα level did not change. Ninety minutes after surgeries more Fos-immunostained cells occurred in both LIRIs than sham-operated animals in all structures studied. More distinct Fos expression occurred after LIRIb than LIRIa in SON, PVN, VMN, and NTS. Five hours after both LIRIs, Fos increased in the parabrachial nucleus (PBN) and NTS. Twenty-four hours after both LIRIs Fos incidence decreased in all groups. Although the present data indicate that increased neuronal activity after both LIRIs is mainly a consequence of the liver damage itself partial impact of non-specific factors can not be excluded. However, the anatomical distribution of Fos occurrence detected after LIRIs gives great opportunity to perform a targeted phenotypic identification of the activated neurons by LIRIs in the subsequent experiments.
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References
Bailey SM, Reinke LA (2000) Effect of low flow ischemia–reperfusion injury on liver function. Life Sci 66:1033–1044. doi:10.1016/S0024-3205(99)00668-2
Becskei C, Lutz TA, Riediger T (2008) Glucose reverses fasting-induced activation in the arcuate nucleus of mice. Neuroreport 19:105–109
Bellavance LL, Beitz AJ (1996) Altered c-fos expression in the parabrachial nucleus in a rodent model of CFA-induced peripheral inflammation. J Comp Neurol 366:431–447. doi:10.1002/(SICI)1096-9861(19960311)366:3<431::AID-CNE5>3.0.CO;2-5
Berthoud HR (2004) Anatomy and function of sensory hepatic nerves. Anat Rec A Discov Mol Cell Evol Biol 280:827–835. doi:10.1002/ar.a.20088
Berthoud HR, Kressel M, Neuhuber WL (1992) An anterograde tracing study of the vagal innervation of rat liver, portal vein and biliary system. Anat Embryol (Berl) 186:431–442. doi:10.1007/BF00185458
Blair ML, Jaworski RL, Want A, Piekut DT (2001) Parabrachial nucleus modulates cardiovascular responses to blood loss. Am J Physiol Regul Integr Comp Physiol 280:R1141–R1148
Bonaz B, Taché Y (1997) Corticotropin-releasing factor and systemic capsaicin-sensitive afferents are involved in abdominal surgery-induced Fos expression in the paraventricular nucleus of the hypothalamus. Brain Res 748:12–20. doi:10.1016/S0006-8993(96)01281-4
Buller KM, Allen T, Wilson LD, Munro F, Day TA (2004) A critical role for the parabrachial nucleus in generating central nervous system responses elicited by a systemic immune challenge. J Neuroimmunol 152:20–32. doi:10.1016/j.jneuroim.2004.03.013
Cailotto C, La Fleur SE, Van Heijningen C, Wortel J, Kalsbeek A, Feenstra M, Pévet P, Buijs RM (2005) The suprachiasmatic nucleus controls the daily variation of plasma glucose via the autonomic output to the liver: are the clock genes involved? Eur J NeuroSci 22:2531–2540. doi:10.1111/j.1460-9568.2005.04439.x
Carrasco M, Portillo F, Larsen PJ, Vallo JJ (2001) Insulin and glucose administration stimulates Fos expression in neurones of the paraventricular nucleus that project to autonomic preganglionic structures. J Neuroendocrinol 13:339–346. doi:10.1046/j.1365-2826.2001.00631.x
Centurion SA, Centurion LM, Souza ME, Gomes MC, Sankarankutty AK, Mente ED, Castro e Silva O (2007) Effects of ischemic liver preconditioning on hepatic ischemia/reperfusion injury in the rat. Transplant Proc 39:361–364. doi:10.1016/j.transproceed.2007.01.011
Chávez-Cartaya RE, Ramirez-Romero P, Calne RY, Jamieson NV (1994) Laser-Doppler flowmetry in the study of in vivo liver ischemia and reperfusion in the rat. J Surg Res 56:473–477. doi:10.1006/jsre.1994.1075
Dong YX, Xiong KH, Rao ZR (1997) Medullary catecholaminergic neurons projecting to lateral hypothalamic area and expressing Fos after chemical stimulation of the stomach in the rat. J Hirnforsch 38:3–7
Ek M, Kurosawa M, Lundeberg T, Ericsson A (1998) Activation of vagal afferents after intravenous injection of interleukin-1beta: role of endogenous prostaglandins. J Neurosci 18:9471–9479
Eum HA, Cha YN, Lee SM (2007) Necrosis and apoptosis: sequence of liver damage following reperfusion after 60 min ischemia in rats. Biochem Biophys Res Commun 358:500–505. doi:10.1016/j.bbrc.2007.04.153
Frangogiannis NG (2007) Chemokines in ischemia and reperfusion. Thromb Haemost 97:738–747
Girn HR, Ahilathirunayagam S, Mavor AI, Homer-Vanniasinkam S (2007) Reperfusion syndrome: cellular mechanisms of microvascular dysfunction and potential therapeutic strategies. Vasc Endovascular Surg 41:277–293. doi:10.1177/1538574407304510
Golling M, Jahnke C, Fonouni H, Ahmadi R, Urbaschek R, Breitkreutz R, Schemmer P, Kraus TW, Gebhard MM, Büchler MW, Mehrabi A (2007) Distinct effects of surgical denervation on hepatic perfusion, bowel ischemia, and oxidative stress in brain dead and living donor porcine models. Liver Transpl 13:607–617. doi:10.1002/lt.21069
Gourcerol G, Gallas S, Mounien L, Leblanc I, Bizet P, Boutelet I, Leroi AM, Ducrotte P, Vaudry H, Jegou S (2007) Gastric electrical stimulation modulates hypothalamic corticotropin-releasing factor-producing neurons during post-operative ileus in rat. Neuroscience 148:775–781. doi:10.1016/j.neuroscience.2007.07.001
Grindstaff RJ, Grindstaff RR, Sullivan MJ, Cunningham JT (2000) Role of the locus coeruleus in baroreceptor regulation of supraoptic vasopressin neurons in the rat. Am J Physiol Regul Integr Comp Physiol 279:R306–R319
Gu GB, Ju G (1995) The parabrachio-subfornical organ projection in the rat. Brain Res Bull 38:41–47. doi:10.1016/0361-9230(95)00070-U
Herbert H, Moga MM, Saper CB (1990) Connections of the parabrachial nucleus with the nucleus of the solitary tract and the medullary reticular formation in the rat. J Comp Neurol 293:540–580. doi:10.1002/cne.902930404
Ishii S, Abe T, Saito T, Tsuchiya T, Kanno H, Miyazawa M, Suzuki M, Motoki R, Gotoh M (2001) Effect of preconditioning on ischemia/reperfusion injury of hepatocytes determined by early gene transcription. J Hepatobiliary Pancreat Surg 8:461–486. doi:10.1007/s005340100010
Jaeschke H, Bautista AP, Spolarics Z, Spitzer JJ (1992) Superoxide generation by neutrophils and Kupffer cells during in vivo reperfusion after hepatic ischemia in rats. J Leukoc Biol 52:377–382
Kobashi M, Adachi A (1986) Projection of nucleus tractus solitarius units influenced by hepatoportal afferent signal to parabrachial nucleus. J Auton Nerv Syst 16:153–158. doi:10.1016/0165-1838(86)90006-8
Kondo T, Todoroki T, Hirano T, Schildberg FW, Messmer K (1998) Impact of ischemia–reperfusion injury on dimensional changes of hepatic microvessels. Res Exp Med (Berl) 198:63–72. doi:10.1007/s004330050090
Krukoff TL, MacTavish D, Harris KH, Jhamandas JH (1995) Changes in blood volume and pressure induce c-fos expression in brainstem neurons that project to the paraventricular nucleus of the hypothalamus. Brain Res Mol Brain Res 34:99–108. doi:10.1016/0169-328X(95)00142-F
Magni F, Carobi C (1983) The afferent and preganglionic parasympathetic innervation of the rat liver, demonstrated by the retrograde transport of horseradish peroxidase. J Auton Nerv Syst 8:237–260. doi:10.1016/0165-1838(83)90108-X
Martins PN, Neuhaus P (2007) Surgical anatomy of the liver, hepatic vasculature and bile ducts in the rat. Liver Int 27:384–392. doi:10.1111/j.1478-3231.2006.01414.x
McCurry KR, Campbell DA Jr, Scales WE, Warren JS, Remick DG (1993) Tumor necrosis factor, interleukin 6, and the acute phase response following hepatic ischemia/reperfusion. J Surg Res 55:49–54. doi:10.1006/jsre.1993.1107
Mikkelsen JD, Vrang N, Mrosovsky N (1998) Expression of Fos in the circadian system following nonphotic stimulation. Brain Res Bull 47:367–376. doi:10.1016/S0361-9230(98)00121-X
Miura M, Okada J, Takayama K, Jingu H (1996) Barosensitive and chemosensitive neurons in the rat medulla: a double labeling study with c-Fos/glutamate, GAD, PNMT and calbindin. J Auton Nerv Syst 61:17–25
Morita H, Yamashita Y, Nishida Y, Tokuda M, Hatase O, Hosomi H (1997) Fos induction in rat brain neurons after stimulation of the hepatoportal Na-sensitive mechanism. Am J Physiol 272:R913–R923
Nathwani RA, Pais S, Reynolds TB, Kaplowitz N (2005) Serum alanine aminotransferase in skeletal muscle diseases. Hepatology 41:380–382. doi:10.1002/hep.20548
Niijima A (1996) The afferent discharges from sensors for interleukin 1 beta in the hepatoportal system in the anesthetized rat. J Auton Nerv Syst 61:287–291. doi:10.1016/S0165-1838(96)00098-7
Nishida T, Ueshima S, Kazuo H, Ito T, Seiyama A, Matsuda H (2000) Vagus nerve in involved in lack of blood reflow into sinusoid after rat hepatic ichcemia. Am J Physiol Heart Circ Physiol 278:H1565–H1570
Ozer J, Ratner M, Shaw M, Bailey W, Schomaker S (2008) The current state of serum biomarkers of hepatotoxicity. Toxicology 245:194–205. doi:10.1016/j.tox.2007.11.021
Palkovits M (1999) Interconnections between the neuroendocrine hypothalamus and the central autonomic system. Front Neuroendocrinol 20:270–295. doi:10.1006/frne.1999.0186
Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. Academic Press, New York
Pirnik Z, Mravec B, Kiss A (2004) Fos protein expression in mouse hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei upon osmotic stimulus: colocalization with vasopressin, oxytocin, and tyrosine hydroxylase. Neurochem Int 45:597–607. doi:10.1016/j.neuint.2004.04.003
Ricardo JA, Koh ET (1978) Anatomical evidence of direct projections from the nucleus of the solitary tract to the hypothalamus, amygdala, and other forebrain structures in the rat. Brain Res 153:1–26. doi:10.1016/0006-8993(78)91125-3
Romani F, Vertemati M, Frangi M, Aseni P, Monti R, Codeghini A, Belli L (1988) Effect of superoxide dismutase on liver ischemia–reperfusion injury in the rat: a biochemical monitoring. Eur Surg Res 20:335–340. doi:10.1159/000128783
Shirasugi N, Wakabayashi G, Shimazu M, Oshima A, Shito M, Kawachi S, Karahashi T, Kumamoto Y, Yoshida M, Kitajima M (1997) Up-regulation of oxygen-derived free radicals by interleukin-1 in hepatic ischemia/reperfusion injury. Transplantation 64:1398–1403. doi:10.1097/00007890-199711270-00004
Shito M, Wakabayashi G, Ueda M, Shimazu M, Shirasugi N, Endo M, Mukai M, Kitajima M (1997) Interleukin 1 receptor blockade reduces tumor necrosis factor production, tissue injury, and mortality after hepatic ischemia–reperfusion in the rat. Transplantation 63:143–148. doi:10.1097/00007890-199701150-00026
Smith DW, Sibbald JR, Khanna S, Day TA (1995) Rat vasopressin cell responses to simulated hemorrhage: stimulus-dependent role for A1 noradrenergic neurons. Am J Physiol 268:R1336–R1342
Song D, Liu H, Sharkey KA, Lee SS (2002) Hyperdynamic circulation in portal-hypertensive rats is dependent on central c-fos gene expression. Hepatology 35:159–166. doi:10.1053/jhep.2002.30417
Souza ME, Castro-e-Silva O Jr, Picinato MA, Franco CF, Mazzetto SA, Ceneviva R, Roselino JE (1990) Serum transaminase levels in the acute phase of chronic extrahepatic cholestasis. Braz J Med Biol Res 23:995–997
Spiegel HU, Bahde R (2006) Experimental models of temporary normothermic liver ischemia. J Invest Surg 19:113–123. doi:10.1080/08941930600569704
Steiner PE, Martinez JB (1961) Effects on the rat liver of bile duct, portal vein and hepatic artery ligations. Am J Pathol 39:257–289
Sumal KK, Blessing WW, Joh TH, Reis DJ, Pickel VM (1983) Synaptic interaction of vagal afferents and catecholaminergic neurons in the rat nucleus tractus solitarius. Brain Res 277:31–40. doi:10.1016/0006-8993(83)90904-6
Suzuki S, Toledo-Pereyra LH (1994) Interleukin 1 and tumor necrosis factor production as the initial stimulants of liver ischemia and reperfusion injury. J Surg Res 57:253–258. doi:10.1006/jsre.1994.1140
Szabo AJ, Iguchi A, Burleson PD, Szabo O (1983) Vagotomy or atropine blocks hypoglycemic effect of insulin injected into ventromedial hypothalamic nucleus. Am J Physiol 244:E467–E471
Takahashi A, Ishimaru H, Ikarashi Y, Kishi E, Maruyama Y (1997) Effects of ventromedial hypothalamus stimulation on glycogenolysis in rat liver using in vivo microdialysis. Metabolism 46:897–901. doi:10.1016/S0026-0495(97)90076-7
Teoh NC, Farrell GC (2003) Hepatic ischemia reperfusion injury: pathogenic mechanisms and basis for hepatoprotection. J Gastroenterol Hepatol 18:891–902. doi:10.1046/j.1440-1746.2003.03056.x
Ter Horst GJ, de Boer P, Luiten PG, van Willigen JD (1989) Ascending projections from the solitary tract nucleus to the hypothalamus. A Phaseolus vulgaris lectin tracing study in the rat. Neuroscience 31:785–797. doi:10.1016/0306-4522(89)90441-7
Torii K, Niijima A (2001) Effect of lysine on afferent activity of the hepatic branch of the vagus nerve in normal and L-lysine-deficient rats. Physiol Behav 72:685–690. doi:10.1016/S0031-9384(01)00426-7
Uyama N, Geerts A, Reynaert H (2004) Neural connections between the hypothalamus and the liver. Anat Rec A Discov Mol Cell Evol Biol 280:808–820. doi:10.1002/ar.a.20086
Wanner GA, Ertel W, Müller P, Höfer Y, Leiderer R, Menger MD, Messmer K (1996) Liver ischemia and reperfusion induces a systemic inflammatory response through Kupffer cell activation. Shock 5:34–40. doi:10.1097/00024382-199601000-00008
Weiss S, Kotsch K, Francuski M, Reutzel-Selke A, Mantouvalou L, Klemz R, Kuecuek O, Jonas S, Wesslau C, Ulrich F, Pascher A, Volk HD, Tullius SG, Neuhaus P, Pratschke J (2007) Brain death activates donor organs and is associated with a worse I/R injury after liver transplantation. Am J Transplant 7:1584–1593. doi:10.1111/j.1600-6143.2007.01799.x
Woldbye DP, Greisen MH, Bolwig TG, Larsen PJ, Mikkelsen JD (1996) Prolonged induction of c-fos in neuropeptide Y- and somatostatin-immunoreactive neurons of the rat dentate gyrus after electroconvulsive stimulation. Brain Res 720:111–119. doi:10.1016/0006-8993(96)00158-8
Xiao JS, Cai FG, Niu Y, Zhang Y, Xu XL, Ye QF (2005) Preconditioning effects on expression of proto-oncogenes c-fos and c-jun after hepatic ischemia/reperfusion in rats. Hepatobiliary Pancreat Dis Int 4:197–202
Yoshimatsu H, Niijima A, Oomura Y, Katafuchi T (1988) Lateral and ventromedial hypothalamic influences on hepatic autonomic nerve activity in the rat. Brain Res Bull 21:239–244. doi:10.1016/0361-9230(88)90237-7
Zittel TT, De Giorgio R, Brecha NC, Sternini C, Raybould HE (1993) Abdominal surgery induces c-fos expression in the nucleus of the solitary tract in the rat. Neurosci Lett 159:79–82. doi:10.1016/0304-3940(93)90803-S
Acknowledgments
The authors wish to thank to Institute of Laboratory Diagnostic (Alpha medical, Bratislava, SR) for determination of ALT and AST serum activities. Fos antiserum (No. 94012) was provided by Dr. Jens Mikkelsen (NeuroSearch A/S Ballerup, Denmark). This work was supported by grant of the Ministry of Health of the Slovak Republic under the project MZ 2006/19-SAV-01 entitled “Stimulation of the vagus nerve as a new method for prevention of ischemia–reperfusion injury of transplanted organs” and VEGA grant 1/4312/07.
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Pirnik, Z., Bundzikova, J., Francisty, T. et al. Effect of Liver Ischemia–Reperfusion Injury on the Activity of Neurons in the Rat Brain. Cell Mol Neurobiol 29, 951–960 (2009). https://doi.org/10.1007/s10571-009-9381-7
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DOI: https://doi.org/10.1007/s10571-009-9381-7