Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

General Research Article

A Combination of Ulinastatin and Xuebijing Amplifies Neuroprotection after Transient Cerebral Ischemia via Attenuating Apoptosis Signal Pathways in Hippocampus

Author(s): Chi Ma, Dong-Feng Han, Hang Jin, Ying-Ying Cheng, Hai-Xia Hu* and Xu Wang*

Volume 24 , Issue 44 , 2018

Page: [5342 - 5347] Pages: 6

DOI: 10.2174/1381612825666190206224134

Price: $65


Background: Ulinastatin (UTI) plays the beneficial roles in modifying cerebral ischemic injury evoked by cardiac arrest (CA). XueBiJing (XBJ), comprised of extracts from Chinese herbals, has been used for the treatment of sepsis and ischemic disorders linked to multiple organ dysfunction syndromes. The current study was to find interventions that can enhance effectiveness of these drugs and further to provide a fundamental for their rational application in clinical practice. Thus, we examined how apoptosis signal in the hippocampus is engaged in a facilitating role of UTI and XBJ in improving neural injury and neurological functions after transient cerebral ischemia.

Methods: CA was induced by asphyxia followed by cardiopulmonary resuscitation in rats. Western Blot analysis and ELISA were employed to determine the protein expression of Caspase-3 and Caspase-9 in the hippocampus; and representative apoptosis pathways. The modified neurological severity score (mNSS) and spatial working memory performance were used to assess neurological deficiencies in CA rats.

Results: CA increased Caspase-3 and Caspase-9 in the hippocampus CA1 region. A lower dose of UTI did not attenuate upregulation of apoptosis signal pathways evoked by CA. However, a systemic administration of XBJ significantly amplified the inhibitory effects of the lower dose of UTI on apoptosis signal of the hippocampus. In addition, a combination of UTI and XBJ improved mNSS and spatial working memory performance to a greater degree.

Conclusions: Our data indicate that a combination of XBJ and UTI plays a facilitating role in improving neuronal injury and neurological deficits observed in transient cerebral ischemia; and an inhibition of apoptosis signal pathways is involved in neuroprotective effects of united XBJ and UTI.

Keywords: Ulinastatin, Xuebijing, cardiopulmonary resuscitation, cardiac arrest, cerebral ischemia, apoptosis.

Nolan JP, Neumar RW, Adrie C, et al. Post-cardiac arrest syndrome: Epidemiology, pathophysiology, treatment, and prognostication: A Scientific Statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; the Council on Stroke. Resuscitation 2008; 79: 350-79.
Inoue K, Takano H. Urinary trypsin inhibitor as a therapeutic option for endotoxin-related inflammatory disorders. Expert Opin Investig Drugs 2010; 19: 513-20.
Karnad DR, Bhadade R, Verma PK, et al. Intravenous administration of ulinastatin (human urinary trypsin inhibitor) in severe sepsis: a multicenter randomized controlled study. Intensive Care Med 2014; 40: 830-8.
Wang G, Wen J, Wilbur RR, Wen P, Zhou SF, Xiao X. The effect of somatostatin, ulinastatin and Salvia miltiorrhiza on severe acute pancreatitis treatment. Am J Med Sci 2013; 346: 371-6.
Inoue K, Takano H, Yanagisawa R, Yoshikawa T. Protective effects of urinary trypsin inhibitor on systemic inflammatory response induced by lipopolysaccharide. J Clin Biochem Nutr 2008; 43: 139-42.
Jiang XM, Hu JH, Wang LL, Ma C, Wang X, Liu XL. Effects of Ulinastatin on Global Ischemia via Brain Pro-inflammation Signal. Transl Neurosci 2016; 7: 158-63.
Shi H, Hong Y, Qian J, Cai X, Chen S. Xuebijing in the treatment of patients with sepsis. Am J Emerg Med 2017; 35: 285-91.
Zheng J, Xiang X, Xiao B, et al. Xuebijing combined with ulinastation benefits patients with sepsis: A meta-analysis. Am J Emerg Med 2018; 36(3): 480-7.
Chen X, Feng Y, Shen X, et al. Anti-sepsis protection of Xuebijing injection is mediated by differential regulation of pro- and anti-inflammatory Th17 and T regulatory cells in a murine model of polymicrobial sepsis. J Ethnopharmacol 2018; 211: 358-65.
Chen Y, Tong H, Pan Z, et al. Xuebijing injection attenuates pulmonary injury by reducing oxidative stress and proinflammatory damage in rats with heat stroke. Exp Ther Med 2017; 13: 3408-16.
Gao CJ, Niu L, Ren PC, et al. Hypoxic preconditioning attenuates global cerebral ischemic injury following asphyxial cardiac arrest through regulation of delta opioid receptor system. Neuroscience 2012; 202: 352-62.
Salvesen GS. Caspases: opening the boxes and interpreting the arrows. Cell Death Differ 2002; 9: 3-5.
Ghavami S, Hashemi M, Ande SR, et al. Apoptosis and cancer: mutations within caspase genes. J Med Genet 2009; 46: 497-510.
Bosoi CR, Yang X, Huynh J, et al. Systemic oxidative stress is implicated in the pathogenesis of brain edema in rats with chronic liver failure. Free Radic Biol Med 2012; 52: 1228-35.
Marc Simard J, Geng Z, Kyoon Woo S, et al. Glibenclamide reduces inflammation, vasogenic edema, and caspase-3 activation after subarachnoid hemorrhage. J Cereb Blood Flow Metab 2008; 29: 317-30.
Dong YS, Wang JL, Feng DY, et al. Protective effect of quercetin against oxidative stress and brain edema in an experimental rat model of subarachnoid hemorrhage. Int J Med Sci 2014; 11: 282-90.
Jiang XM, Hu JH, Wang LL, Ma C, Wang X, Liu XL. Ulinastatin alleviates neurological deficiencies evoked by transient cerebral ischemia via improving autophagy, Nrf-2-ARE and apoptosis signals in hippocampus. Physiol Res 2018; 67: 637-46.
Saito K, Suyama K, Nishida K, Sei Y, Basile AS. Early increases in TNF-alpha, IL-6 and IL-1 beta levels following transient cerebral ischemia in gerbil brain. Neurosci Lett 1996; 206: 149-52.
Oppenheim JJ. Cytokines: past, present, and future. Int J Hematol 2001; 74: 3-8.
Xing J, Lu J. HIF-1alpha activation attenuates IL-6 and TNF-alpha pathways in hippocampus of rats following transient global ischemia. Cell Physiol Biochem 2016; 39: 511-20.
Moi P, Chan K, Asunis I, Cao A, Kan YW. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci USA 1994; 91: 9926-30.
Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012; 367: 1098-107.
Itoh K, Chiba T, Takahashi S, et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 1997; 236: 313-22.
Sekhar KR, Rachakonda G, Freeman ML. Cysteine-based regulation of the CUL3 adaptor protein Keap1. Toxicol Appl Pharmacol 2010; 244: 21-6.
Yamamoto T, Suzuki T, Kobayashi A, et al. Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity. Mol Cell Biol 2008; 28: 2758-70.

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy