Systemic administration of urocortin after intracerebral hemorrhage reduces neurological deficits and neuroinflammation in rats

Journal of Neuroinflammation

Jia-Yi Wang²  Jon-Son Kuo³  Hsiao-Fen Peng¹  Ting-Yi Li¹  Mei-Jen Wang³  Chih-Wei Hsu⁴  Cheng-Yoong Pang³  Hock-Kean Liew¹ 

[1] Department of Medical Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan;Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan;Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan;School of Medicine, Tzu Chi University, Hualien, Taiwan

关键词: urocortin;    intracerebral hemorrhage;    brain edema;    anti-neuroinflammation;   

Others  :  1212864
DOI  :  10.1186/1742-2094-9-13

 received in 2011-07-08, accepted in 2012-01-19,  发布年份 2012

【 摘 要 】

Background

Intracerebral hemorrhage (ICH) remains a serious clinical problem lacking effective treatment. Urocortin (UCN), a novel anti-inflammatory neuropeptide, protects injured cardiomyocytes and dopaminergic neurons. Our preliminary studies indicate UCN alleviates ICH-induced brain injury when administered intracerebroventricularly (ICV). The present study examines the therapeutic effect of UCN on ICH-induced neurological deficits and neuroinflammation when administered by the more convenient intraperitoneal (i.p.) route.

Methods

ICH was induced in male Sprague-Dawley rats by intrastriatal infusion of bacterial collagenase VII-S or autologous blood. UCN (2.5 or 25 μg/kg) was administered i.p. at 60 minutes post-ICH. Penetration of i.p. administered fluorescently labeled UCN into the striatum was examined by fluorescence microscopy. Neurological deficits were evaluated by modified neurological severity score (mNSS). Brain edema was assessed using the dry/wet method. Blood-brain barrier (BBB) disruption was assessed using the Evans blue assay. Hemorrhagic volume and lesion volume were assessed by Drabkin's method and morphometric assay, respectively. Pro-inflammatory cytokine (TNF-α, IL-1β, and IL-6) expression was evaluated by enzyme-linked immunosorbent assay (ELISA). Microglial activation and neuronal loss were evaluated by immunohistochemistry.

Results

Administration of UCN reduced neurological deficits from 1 to 7 days post-ICH. Surprisingly, although a higher dose (25 μg/kg, i.p.) also reduced the functional deficits associated with ICH, it is significantly less effective than the lower dose (2.5 μg/kg, i.p.). Beneficial results with the low dose of UCN included a reduction in neurological deficits from 1 to 7 days post-ICH, as well as a reduction in brain edema, BBB disruption, lesion volume, microglial activation and neuronal loss 3 days post-ICH, and suppression of TNF-α, IL-1β, and IL-6 production 1, 3 and 7 days post-ICH.

Conclusion

Systemic post-ICH treatment with UCN reduces striatal injury and neurological deficits, likely via suppression of microglial activation and inflammatory cytokine production. The low dose of UCN necessary and the clinically amenable peripheral route make UCN a potential candidate for development into a clinical treatment regimen.

【 授权许可】

   
2012 Liew et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, Hanley DF: Spontaneous intracerebral hemorrhage. N Engl J Med 2001, 344:1450-1460.
• [2]Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, Hailpern SM, Ho M, Howard V, Kissela B, et al.: Heart disease and stroke statistics--2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2008, 117:e25-146.
• [3]Hanggi D, Steiger HJ: Spontaneous intracerebral haemorrhage in adults: a literature overview. Acta Neurochir (Wien) 2008, 150:371-379. discussion 379
• [4]Pouratian N, Kassell NF, Dumont AS: Update on management of intracerebral hemorrhage. Neurosurg Focus 2003, 15:E2.
• [5]Hankey GJ, Hon C: Surgery for primary intracerebral hemorrhage: is it safe and effective? A systematic review of case series and randomized trials. Stroke 1997, 28:2126-2132.
• [6]Mendelow AD, Gregson BA, Fernandes HM, Murray GD, Teasdale GM, Hope DT, Karimi A, Shaw MD, Barer DH: Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet 2005, 365:387-397.
• [7]Morgenstern LB, Demchuk AM, Kim DH, Frankowski RF, Grotta JC: Rebleeding leads to poor outcome in ultra-early craniotomy for intracerebral hemorrhage. Neurology 2001, 56:1294-1299.
• [8]Wang J: Preclinical and clinical research on inflammation after intracerebral hemorrhage. Prog Neurobiol 2010, 92:463-477.
• [9]Fekete EM, Zorrilla EP: Physiology, pharmacology, and therapeutic relevance of urocortins in mammals: ancient CRF paralogs. Front Neuroendocrinol 2007, 28:1-27.
• [10]Hsu SY, Hsueh AJ: Human stresscopin and stresscopin-related peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor. Nat Med 2001, 7:605-611.
• [11]Pedersen WA, Wan R, Zhang P, Mattson MP: Urocortin, but not urocortin II, protects cultured hippocampal neurons from oxidative and excitotoxic cell death via corticotropin-releasing hormone receptor type I. J Neurosci 2002, 22:404-412.
• [12]Perrin MH, Vale WW: Corticotropin releasing factor receptors and their ligand family. Ann N Y Acad Sci 1999, 885:312-328.
• [13]Stevens SL, Shaw TE, Dykhuizen E, Lessov NS, Hill JK, Wurst W, Stenzel-Poore MP: Reduced cerebral injury in CRH-R1 deficient mice after focal ischemia: a potential link to microglia and atrocytes that express CRH-R1. J Cereb Blood Flow Metab 2003, 23:1151-1159.
• [14]Van Pett K, Viau V, Bittencourt JC, Chan RK, Li HY, Arias C, Prins GS, Perrin M, Vale W, Sawchenko PE: Distribution of mRNAs encoding CRF receptors in brain and pituitary of rat and mouse. J Comp Neurol 2000, 428:191-212.
• [15]Pan W, Kastin AJ: Urocortin and the brain. Prog Neurobiol 2008, 84:148-156.
• [16]Torpy DJ, Webster EL, Zachman EK, Aguilera G, Chrousos GP: Urocortin and inflammation: confounding effects of hypotension on measures of inflammation. Neuroimmunomodulation 1999, 6:182-186.
• [17]Brar BK, Jonassen AK, Stephanou A, Santilli G, Railson J, Knight RA, Yellon DM, Latchman DS: Urocortin protects against ischemic and reperfusion injury via a MAPK-dependent pathway. J Biol Chem 2000, 275:8508-8514.
• [18]Gordon JM, Dusting GJ, Woodman OL, Ritchie RH: Cardioprotective action of CRF peptide urocortin against simulated ischemia in adult rat cardiomyocytes. Am J Physiol Heart Circ Physiol 2003, 284:H330-336.
• [19]Lawrence KM, Chanalaris A, Scarabelli T, Hubank M, Pasini E, Townsend PA, Comini L, Ferrari R, Tinker A, Stephanou A, et al.: K(ATP) channel gene expression is induced by urocortin and mediates its cardioprotective effect. Circulation 2002, 106:1556-1562.
• [20]Liu CN, Yang C, Liu XY, Li S: In vivo protective effects of urocortin on ischemia-reperfusion injury in rat heart via free radical mechanisms. Can J Physiol Pharmacol 2005, 83:459-465.
• [21]Abuirmeileh A, Harkavyi A, Lever R, Biggs CS, Whitton PS: Urocortin, a CRF-like peptide, restores key indicators of damage in the substantia nigra in a neuroinflammatory model of Parkinson's disease. J Neuroinflammation 2007, 4:19. BioMed Central Full Text
• [22]Huang HY, Lin SZ, Chen WF, Li KW, Kuo JS, Wang MJ: Urocortin modulates dopaminergic neuronal survival via inhibition of glycogen synthase kinase-3beta and histone deacetylase. Neurobiol Aging 2011, 32:1662-1677.
• [23]Wang MJ, Lin SZ, Kuo JS, Huang HY, Tzeng SF, Liao CH, Chen DC, Chen WF: Urocortin modulates inflammatory response and neurotoxicity induced by microglial activation. J Immunol 2007, 179:6204-6214.
• [24]Liew HK, Hsu CW, Wang MJ, Kuo JS, Li TY, Peng HF, Wang JY, Pang CY: Therapeutic benefit of urocortin in rats with intracerebral hemorrhage. J Neurosurg 2011. DOI: 10.3171/2011.8.JNS101637
• [25]Abdelrahman AM, Lin Lim S, Pang CC: Influence of urocortin and corticotropin releasing factor on venous tone in conscious rats. Eur J Pharmacol 2005, 510:107-111.
• [26]Abdelrahman AM, Pang CC: Regional haemodynamic effects of urocortin in the anaesthetized rat. Eur J Pharmacol 2003, 466:317-321.
• [27]Gardiner SM, March JE, Kemp PA, Bennett T: A comparison between the cardiovascular actions of urocortin 1 and urocortin 2 (stresscopin-related peptide) in conscious rats. J Pharmacol Exp Ther 2007, 321:221-226.
• [28]Parkes DG, May CN: Urocortin: A Novel Player in Cardiac Control. News Physiol Sci 2000, 15:264-268.
• [29]Parkes DG, Weisinger RS, May CN: Cardiovascular actions of CRH and urocortin: an update. Peptides 2001, 22:821-827.
• [30]MacLellan CL, Silasi G, Poon CC, Edmundson CL, Buist R, Peeling J, Colbourne F: Intracerebral hemorrhage models in rat: comparing collagenase to blood infusion. J Cereb Blood Flow Metab 2008, 28:516-525.
• [31]Rosenberg GA, Mun-Bryce S, Wesley M, Kornfeld M: Collagenase-induced intracerebral hemorrhage in rats. Stroke 1990, 21:801-807.
• [32]Chen J, Li Y, Wang L, Zhang Z, Lu D, Lu M, Chopp M: Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke 2001, 32:1005-1011.
• [33]Xue M, Del Bigio MR: Intracerebral injection of autologous whole blood in rats: time course of inflammation and cell death. Neurosci Lett 2000, 283:230-232.
• [34]Yang GY, Betz AL, Chenevert TL, Brunberg JA, Hoff JT: Experimental intracerebral hemorrhage: relationship between brain edema, blood flow, and blood-brain barrier permeability in rats. J Neurosurg 1994, 81:93-102.
• [35]Chu K, Jeong SW, Jung KH, Han SY, Lee ST, Kim M, Roh JK: Celecoxib induces functional recovery after intracerebral hemorrhage with reduction of brain edema and perihematomal cell death. J Cereb Blood Flow Metab 2004, 24:926-933.
• [36]Park HK, Chu K, Lee ST, Jung KH, Kim EH, Lee KB, Song YM, Jeong SW, Kim M, Roh JK: Granulocyte colony-stimulating factor induces sensorimotor recovery in intracerebral hemorrhage. Brain Res 2005, 1041:125-131.
• [37]Jung KH, Chu K, Jeong SW, Han SY, Lee ST, Kim JY, Kim M, Roh JK: HMG-CoA reductase inhibitor, atorvastatin, promotes sensorimotor recovery, suppressing acute inflammatory reaction after experimental intracerebral hemorrhage. Stroke 2004, 35:1744-1749.
• [38]Esen F, Erdem T, Aktan D, Orhan M, Kaya M, Eraksoy H, Cakar N, Telci L: Effect of magnesium sulfate administration on blood-brain barrier in a rat model of intraperitoneal sepsis: a randomized controlled experimental study. Crit Care 2005, 9:R18-23. BioMed Central Full Text
• [39]Moreau JL, Kilpatrick G, Jenck F: Urocortin, a novel neuropeptide with anxiogenic-like properties. Neuroreport 1997, 8:1697-1701.
• [40]Spina MG, Merlo-Pich E, Akwa Y, Balducci C, Basso AM, Zorrilla EP, Britton KT, Rivier J, Vale WW, Koob GF: Time-dependent induction of anxiogenic-like effects after central infusion of urocortin or corticotropin-releasing factor in the rat. Psychopharmacology (Berl) 2002, 160:113-121.
• [41]De Fanti BA, Martinez JA: Central urocortin activation of sympathetic-regulated energy metabolism in Wistar rats. Brain Res 2002, 930:37-41.
• [42]Kastin AJ, Akerstrom V, Pan W: Activation of urocortin transport into brain by leptin. Peptides 2000, 21:1811-1817.
• [43]Kastin AJ, Akerstrom V: Glucose and insulin increase the transport of leptin through the blood-brain barrier in normal mice but not in streptozotocin-diabetic mice. Neuroendocrinology 2001, 73:237-242.
• [44]Kastin AJ, Akerstrom V: Pretreatment with glucose increases entry of urocortin into mouse brain. Peptides 2001, 22:829-834.
• [45]Pan W, Akerstrom V, Zhang J, Pejovic V, Kastin AJ: Modulation of feeding-related peptide/protein signals by the blood-brain barrier. J Neurochem 2004, 90:455-461.
• [46]Peruzzo B, Pastor FE, Blazquez JL, Schobitz K, Pelaez B, Amat P, Rodriguez EM: A second look at the barriers of the medial basal hypothalamus. Exp Brain Res 2000, 132:10-26.
• [47]Kettenmann H, Hanisch UK, Noda M, Verkhratsky A: Physiology of microglia. Physiol Rev 2011, 91:461-553.
• [48]Wang J, Dore S: Inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab 2007, 27:894-908.
• [49]Wang J, Tsirka SE: Tuftsin fragment 1-3 is beneficial when delivered after the induction of intracerebral hemorrhage. Stroke 2005, 36:613-618.
• [50]Aronowski J, Hall CE: New horizons for primary intracerebral hemorrhage treatment: experience from preclinical studies. Neurol Res 2005, 27:268-279.
• [51]Zhao X, Grotta J, Gonzales N, Aronowski J: Hematoma resolution as a therapeutic target: the role of microglia/macrophages. Stroke 2009, 40:S92-94.
• [52]Zhao X, Sun G, Zhang J, Strong R, Song W, Gonzales N, Grotta JC, Aronowski J: Hematoma resolution as a target for intracerebral hemorrhage treatment: role for peroxisome proliferator-activated receptor gamma in microglia/macrophages. Ann Neurol 2007, 61:352-362.
• [53]Wu J, Yang S, Xi G, Fu G, Keep RF, Hua Y: Minocycline reduces intracerebral hemorrhage-induced brain injury. Neurol Res 2009, 31:183-188.
• [54]Gonzalez-Rey E, Chorny A, Varela N, O'Valle F, Delgado M: Therapeutic effect of urocortin on collagen-induced arthritis by down-regulation of inflammatory and Th1 responses and induction of regulatory T cells. Arthritis Rheum 2007, 56:531-543.
• [55]Torricelli M, Voltolini C, Bloise E, Biliotti G, Giovannelli A, De Bonis M, Imperatore A, Petraglia F: Urocortin increases IL-4 and IL-10 secretion and reverses LPS-induced TNF-alpha release from human trophoblast primary cells. Am J Reprod Immunol 2009, 62:224-231.
• [56]Xu Y, Zhang R, Chen J, Zhang Q, Wang J, Hu J, Guan X, Jin L, Fu H, Gui B, et al.: Urocortin promotes the development of vasculitis in a rat model of thromboangiitis obliterans via corticotrophin-releasing factor type 1 receptors. Br J Pharmacol 2009, 157:1368-1379.
• [57]Cureton EL, Ereso AQ, Victorino GP, Curran B, Poole DP, Liao M, Harken AH, Bhargava A: Local secretion of urocortin 1 promotes microvascular permeability during lipopolysaccharide-induced inflammation. Endocrinology 2009, 150:5428-5437.
• [58]Kohno M, Kawahito Y, Tsubouchi Y, Hashiramoto A, Yamada R, Inoue KI, Kusaka Y, Kubo T, Elenkov IJ, Chrousos GP, et al.: Urocortin expression in synovium of patients with rheumatoid arthritis and osteoarthritis: relation to inflammatory activity. J Clin Endocrinol Metab 2001, 86:4344-4352.
• [59]Wu Y, Xu Y, Zhou H, Tao J, Li S: Expression of urocortin in rat lung and its effect on pulmonary vascular permeability. J Endocrinol 2006, 189:167-178.
• [60]Davidson SM, Yellon DM: Urocortin: a few inflammatory remarks. Endocrinology 2009, 150:5205-5207.