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ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 36 Issue 6
Jun.  2020
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Article Contents

Expression and significance of semaphorin 3A and its receptor NRP-1 in a rat model of chronic hepatic encephalopathy

DOI: 10.3969/j.issn.1001-5256.2020.06.029
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  • Published Date: 2020-06-20
  • Objective To investigate the changes in the expression of semaphorin 3 A( Sema3 A) and receptor neuropilins-1( NRP-1) in the prefrontal cortex and the hippocampal CA1,CA3,and DG regions in rats with hepatic encephalopathy( HE) and their possible significance. Methods A total of 40 Sprague-Dawley rats were randomly divided into control group and 1-,15-,and 30-day HE groups,with 10 rats in each group. Bile duct ligation and ammonium acetate by gavage were used to establish a rat model of chronic HE( type C).The behavioral and neurological changes were observed; ELISA was used to measure blood ammonia and related biochemical parameters; HE staining was used to observe morphological changes of the liver and brain tissue; real-time PCR was used to measure the mRNA expression of Sema3 A and NRP-1 in each brain region; immunohistochemistry and Western blot were used to measure the protein expression of Sema3 A and NRP-1 in the cerebral cortex and the hippocampal CA1,CA3,and DG regions. A one-way analysis of variance was used for comparison of continuous data between multiple groups,and the least significant difference t-test was used for further comparison between two groups. Results There were significant differences between the four groups in nerve reflex level,blood ammonia,and HE grade( F =76. 39,417. 07,and 71. 56,all P < 0. 001),and compared with the control group,the 1-,15-,and 30-day HE groups had significant increases in nerve reflex score,blood ammonia,and HE grade( all P < 0. 05). There were significant differences between the four groups in total bile acid,albumin,total bilirubin,aspartate aminotransferase,alanine aminotransferase,and alkaline phosphatase( F = 1022. 61,171. 56,685. 18,421. 01,675. 98,and 2405. 04,all P < 0. 001),and compared with the control group,the 1-,15-,and 30-day HE groups had a significant reduction in albumin( P < 0. 05) and significant increases in the other indices( all P < 0. 05). The pathological results showed that compared with the control group,the HE groups had varying degrees of degeneration,necrosis,and inflammatory cell infiltration in the liver,with the pathological signs of swelling,tortuous,and ruptured nerve axons in the prefrontal cortex and the hippocampal CA1,CA3,and DG regions. There were significant differences between the four groups in the mRNA expression of Sema3 A and NRP-1( Sema3 A: F = 273. 83,158. 84,103. 59,and 128. 90,all P < 0. 001; NRP-1: F = 88. 78,173. 02,156. 44,and 289. 09,all P<0. 001),and compared with the control group,the 1-,15-,and 30-day HE groups had significantly higher relative mRNA expression of Sema3 A and NRP-1 in the prefrontal cortex and the hippocampal CA1,CA3,and DG regions( all P < 0. 05). There were increases in the protein expression of Sema3 A and NRP-1 after modeling,and immunohistochemistry showed that the HE groups had positive staining of Sema3 A and NRP-1 in the prefrontal cortex and the hippocampal CA1,CA3,and DG regions. Western blot showed that there were significant differences between the four groups in the protein expression of Sema3 A and NRP-1 in the prefrontal cortex and the hippocampal CA1,CA3,and DG regions( Sema3 A: F = 835. 14,774. 16,282. 60,and 856. 29,all P < 0. 001; NRP-1 : F = 876. 59,472. 48,402. 36,and 207. 47,all P < 0. 001),and compared with the control group,the 1-,15-,and 30-day HE groups had significant increases in the protein expression of Sema3 A and NRP-1 in the prefrontal cortex and the hippocampal CA1,CA3,and DG regions( all P < 0. 05). Conclusion Sema3 A/NRP-1 is upregulated in the brain tissue of chronic HE rats and is involved in the pathophysiological process of nerve injury in HE.

     

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  • [1] VILSTRUP H,AMODIO P,BAJAJ J,et al. Hepatic encephalopathy in chronic liver disease:2014 practice guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver[J]. Hepatology,2014,60(2):715-735.
    [2] Chinese Society of Hepatology,Chinese Medical Association.Guidelines on the management of hepatic encephalopathy in cirrhosis[J]. J Clin Hepatol,2018,34(10):2076-2089.(in Chinese)中华医学会肝病学分会.肝硬化肝性脑病诊疗指南[J].临床肝胆病杂志,2018,34(10):2076-2089.
    [3] European Association for the Study of the Liver. EASL clinical practical guidelines on the management of acute(fulminant)liver failure[J]. J Hepatol,2017,66(5):1047-1081.
    [4] BRAISSANT O,RACKAYOVA V,PIERZCHALA K,et al. Longitudinal neurometabolic changes in the hippocampus of a rat model of chronic hepatic encephalopathy[J]. J Hepatol,2019,71(3):505-515.
    [5] TAPPER EB. Predicting overt hepatic encephalopathy for the population with cirrhosis[J]. Hepatology,2019,70(1):403-409.
    [6] LI XK,WANG S,LI ZG,et al. Updated key points of guidelines for the diagnosis and management of hepatic encephalopathy in cirrhosis(2018)[J]. J Clin Hepatol,2019,35(7):1485-1488.(in Chinese)李小科,王姗,李志国,等.2018年《肝硬化肝性脑病诊疗指南》更新要点解读[J].临床肝胆病杂志,2019,35(7):1485-1488.
    [7] HAUSSINGER D,SCHLIESS F. Pathogenetic mechanisms of hepatic encephalopathy[J]. Gut,2008,57(8):1156-1165.
    [8] MOLOFSKY AV,KELLEY KW,TSAI HH,et al. Astrocyte-encoded positional cues maintain sensorimotor circuit integrity[J]. Nature,2014,509(7499):189-194.
    [9] YANG M,WANG X,FAN Y,et al. Semaphorin 3A contributes to secondary blood-brain barrier damage after traumatic brain injury[J]. Front Cell Neurosci,2019,13:117.
    [10] BATTIN C,de SOUSA LINHARES A,PASTER W,et al. Neuropilin-1 acts as a receptor for complement split products[J]. Front Immunol,2019,10:2209.
    [11] LI S,KARRI D,SANCHEZ-ORTIZ E,et al. Sema3a-Nrp1signaling mediates fast-twitch myofiber specificity of Tw2(+)cells[J]. Dev Cell,2019,51(1):89-98. e84.
    [12] HE Y,YANG Y,WANG RL,et al. Expression changes and roles of Sema3A and Nrp1 in cultured rat cortical neurons after oxygen glucose deprivation[J]. Cel Mol Biol(Noisy-le-grand),2018,64(9):64-69.
    [13] SUN XP,WANG J,SHI Z,et al. Review and prospect of experiment methodology on animal behavior[J]. Chin J Comp Med,2018,28(3):1-7.(in Chinese)孙秀萍,王琼,石哲,等.动物行为实验方法学研究的回顾与展望[J].中国比较医学杂志,2018,28(3):1-7.
    [14] ZIMMERMANN C,FERENCI P,PIF C,et al. Hepaticencephalopathy in thioacetamide-induced acute liver failure in rats:Characterization of an improved model and study of aminoacid-ergic neurotransmission[J]. Hepatology,1989,9:594-601.
    [15] LI Z,SHI H. Research progress of animal models of hepatic encephalopathy[J]. Chin Hepatol,2016,21(3):222-224.(in Chinese)李政,石虹.肝性脑病动物模型的研究进展[J].肝脏,2016,21(3):222-224.
    [16] DHANDA S,GUPTA S,HALDER A,et al. Systemic inflammation without gliosis mediates cognitive deficits through impaired BDNF expression in bile duct ligation model of hepatic encephalopathy[J]. Brain Behav Immun,2018,70:214-232.
    [17] MONTOLIU C,URIOS A,FORN C,et al. Reduced white matter microstructural integrity correlates with cognitive deficits in minimal hepatic encephalopathy[J]. Gut,2014,63(6):1028-1030.
    [18] DING S,WANG X,ZHUGE W,et al. Dopamine induces glutamate accumulation in astrocytes to disrupt neuronal function leading to pathogenesis of minimal hepatic encephalopathy[J]. Neuroscience,2017,365:94-113.
    [19] RODRIGO R,CAULI O,GOMEZ-PINEDO U,et al. Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy[J]. Gastroenterology,2010,139(2):675-684.
    [20] NAKAMURA F,KUMETA K,HIDA T,et al. Amino-and carboxyl-terminal domains of Filamin-A interact with CRMP1 to mediate Sema3A signalling[J]. Nat Commun, 2014, 5:5325.
    [21] CHEN G,SIMA J,JIN M,et al. Semaphorin-3A guides radial migration of cortical neurons during development[J]. Nat Neurosci,2008,11(1):36-44.
    [22] BALASTIK M,ZHOU XZ,ALBERICH-JORDA M,et al. Prolyl isomerase Pin1 regulates axon guidance by stabilizing CRMP2A selectively in distal axons[J]. Cell Rep,2015,13(4):812-828.
    [23] GIOELLI N,MAIONE F,CAMILLO C,et al. A rationally designed NRP1-independent superagonist SEMA3A mutant is an effective anticancer agent[J]. Sci Transl Med,2018,10(442):1946-6234
    [24] van der KLAAUW AA,CROIZIER S,de OLIVEIRA ME,et al.Human Semaphorin 3 variants link melanocortin circuit development and energy balance[J]. Cell,2019,176(4):729-742. e18.
    [25] TAHAMTAN M,AGHAEI I,POOLADVAND V,et al. Characterization of the CA1 pyramidal neurons in rat model of hepatic cirrhosis:Insights into their electrophysiological properties[J].Metab Brain Dis,2017,32(3):881-889.
    [26] DEGLINCERTI A,LIU Y,COLAK D,et al. Coupled local translation and degradation regulate growth cone collapse[J]. Nat Commun,2015,6:6888.
    [27] NAKANISHI T,FUJITA Y,YAMASHITA T. Neuropilin-1-mediated pruning of corticospinal tract fibers is required for motorecovery after spinal cord injury[J]. Cell Death Dis,2019,10(2):67.
    [28] KANO M,HASHIMOTO K. Synapse elimination in the central nervous system[J]. Curr Opin Neurobiol,2009,19(2):154-161.
    [29] LECLERC M,VOILIN E,GROS G,et al. Regulation of antitumour CD8 T-cell immunity and checkpoint blockade immunotherapy by Neuropilin-1[J]. Nat Commun,2019,10(1):3345.
    [30] FANTIN A,LAMPROPOULOU A,SENATORE V,et al. VEGF165-induced vascular permeability requires NRP1 for ABL-mediated SRC family kinase activation[J]. J Exp Med,2017,214(4):1049-1064.
    [31] CICHOZ-LACH H,MICHALAK A. Current pathogenetic aspects of hepatic encephalopathy and noncirrhotic hyperammonemic encephalopathy[J]. World J Gastroenterol,2013,19(1):26-34.
    [32] DUMAN B,CAN K C,AGTAS-ERTAN E,et al. Risk factors for valproic acid induced hyperammonemia and its association with cognitive functions[J]. Gen Hosp Psychiatry,2019,59:67-72.
    [33] LU L,WU C,LU B J,et al. BabaoDan cures hepatic encephalopathy by decreasing ammonia levels and alleviating inflammation in rats[J]. J Ethnopharmacol,2020,249:112301.
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