Therapeutic benefit of urocortin in rats with intracerebral hemorrhage

Laboratory investigation

Restricted access

Object

Intracerebral hemorrhage (ICH) accounts for about 15% of all deaths due to stroke. It frequently causes brain edema, leading to an expansion of brain volume that exerts a negative impact on ICH outcomes. The ICH-induced brain edema involves inflammatory mechanisms. The authors' in vitro study shows that urocortin (UCN) exhibits antiinflammatory and neuroprotective effects. Therefore, the neuroprotective effect of UCN on ICH in rats was investigated.

Methods

Intracerebral hemorrhage was induced by an infusion of bacteria collagenase type VII-S or autologous blood into the unilateral striatum of anesthetized rats. At 1 hour after the induction of ICH, UCN (0.05, 0.5, and 5 μg) was infused into the lateral ventricle on the ipsilateral side. The authors examined the injury area, brain water content, blood-brain barrier permeability, and neurological function.

Results

The UCN, administered in the ipsilateral lateral ventricle, was able to penetrate into the injured striatum. Posttreatment with UCN reduced the injury area, brain edema, and blood-brain barrier permeability and improved neurological deficits of rats with ICH.

Conclusions

Posttreatment with UCN through improving neurological deficits of rats with ICH dose dependently provided a potential therapeutic agent for patients with ICH or other brain injuries.

Abbreviations used in this paper: BBB = blood-brain barrier; CRH = corticotropin-releasing hormone; CRHR = CRH receptor; ICH = intracerebral hemorrhage; ICV = intracerebroventricular; MABP = mean arterial blood pressure; mNSS = modified Neurological Severity Score; TNF-α = tumor necrosis factor–α; UCN = urocortin.

Article Information

* Mr. Liew and Dr. Hsu contributed equally to this work.

† Drs. J. Y. Wang and Pang share senior authorship of this work.

Address correspondence to: Cheng-Yoong Pang, Ph.D., Department of Medical Research, Tzu Chi General Hospital, No. 707, Section 3, Chung-Yang Road, Hualien 970, Taiwan. email: cypang@mail.tcu.edu.tw.

Please include this information when citing this paper: published online October 7, 2011; DOI: 10.3171/2011.8.JNS101637.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Dose-dependent effects of UCN posttreatment on mNSS of rats with ICH. A: Collagenase-induced ICH rats were injected with saline (vehicle) or UCN (0.05, 0.5, and 5 μg, ICV) at 1 hour after the ICH. The mNSS was measured on 1, 2, 3, and 7 days after ICH insult. p < 0.001 versus saline group (by Tukey post hoc test following repeated-measures ANOVA) (6 rats). B: Autologous blood infusion–induced ICH rats were injected with saline or UCN (5 μg, ICV). Data represent means ± SEM. p < 0.05 versus saline group (by 2-way ANOVA) (6 rats). The mNSS of all rats before the ICH was 0 on Day 0. The higher the mNSS scores, the more severe the deficit. C: Changes in MABP over 3 hours after UCN administration (5 μg ICV) (4 rats).

  • View in gallery

    Bar graphs showing the effects of UCN posttreatment on brain water content on Day 3 after collagenase-induced ICH. The water content was significantly increased in contralateral (#p < 0.05) and ipsilateral (##p < 0.01) hemispheres of the ICH + saline group (6 rats) compared with the sham ICH control (4 rats). These increases were significantly reduced (*p < 0.05 for the contralateral and ipsilateral sides) in the ICH + UCN group (posttreatment with UCN, 6 rats). Note that the reduced water content in the ipsilateral hemisphere (#p < 0.05) of the ICH + UCN and ICH + saline groups was still greater than that in the sham ICH control. The water content in the cerebellum appeared to be unchanged in all groups. Data represent means ± SEM analyzed by Student t-test.

  • View in gallery

    Effect of UCN posttreatment on the injured area on Days 3 and 7 after ICH. A: Photographs of representative brain sections showing changes of the injured areas in the ICH + saline and the ICH + UCN groups on Days 3 and 7. Histograms show that the ICH + UCN significantly reduced the injured area on Day 3 (**p < 0.01, 6 rats) and Day 7 (*p < 0.05, 6 rats) compared with ICH + saline on Day 3 (6 rats) and Day 7 (6 rats). B: Brain sections show sizes of hemorrhagic areas in a sham ICH rat and 6 ICH rats killed at 1, 3, and 6 hours, and 1, 3, and 7 days. C: The accumulated hemorrhagic volume determined at 24 hours post-ICH was not significantly different between the ICH + UCN and ICH + saline groups (5 rats in each group).

  • View in gallery

    Quantitative analysis of Evans blue dye concentration in sections of the striatum on Day 3 after the collagenase-induced ICH. Posttreatment with UCN (ICH + UCN, 6 rats) significantly reduced BBB leakage within ipsilateral striatum (*p < 0.05) compared with the vehicle control (ICH + saline, 6 rats).

  • View in gallery

    Striatal histological sections stained with DAPI and fluorescence-labeled UCN. Urocortin labeled with Alex Fluor 488 dye was injected into the lateral ventricle (LV) 1 hour after collagenase-induced ICH. At 3 hours after the labeled-UCN injection, DAPI (A and D, blue), and fluorescence-labeled UCN (B and E, green) were detected by fluorescent microscopy in the injured striatum (St). Both DAPI and labeled UCN were colocalized in cell nuclei (C and F, merge).

References

  • 1

    Abuirmeileh AHarkavyi ALever RBiggs CSWhitton 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 4:192007

    • Search Google Scholar
    • Export Citation
  • 2

    Agnello DBertini RSacco SMeazza CVilla PGhezzi P: Corticosteroid-independent inhibition of tumor necrosis factor production by the neuropeptide urocortin. Am J Physiol 275:E757E7621998

    • Search Google Scholar
    • Export Citation
  • 3

    Bayatti NZschocke JBehl C: Brain region-specific neuroprotective action and signaling of corticotropin-releasing hormone in primary neurons. Endocrinology 144:405140602003

    • Search Google Scholar
    • Export Citation
  • 4

    Brar BKJonassen AKStephanou ASantilli GRailson JKnight RA: Urocortin protects against ischemic and reperfusion injury via a MAPK-dependent pathway. J Biol Chem 275:850885142000

    • Search Google Scholar
    • Export Citation
  • 5

    Chen CYDoong MLRivier JETaché Y: Intravenous urocortin II decreases blood pressure through CRF(2) receptor in rats. Regul Pept 113:1251302003

    • Search Google Scholar
    • Export Citation
  • 6

    Chen JLi YWang LZhang ZLu DLu M: Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke 32:100510112001

    • Search Google Scholar
    • Export Citation
  • 7

    Chen ZWHuang YYang QLi XWei WHe GW: Urocortin-induced relaxation in the human internal mammary artery. Cardiovasc Res 65:9139202005

    • Search Google Scholar
    • Export Citation
  • 8

    Chu KJeong SWJung KHHan SYLee STKim M: Celecoxib induces functional recovery after intracerebral hemorrhage with reduction of brain edema and perihematomal cell death. J Cereb Blood Flow Metab 24:9269332004

    • Search Google Scholar
    • Export Citation
  • 9

    Dieterle TMeili-Butz SBühler KMorandi CJohn DBuser PT: Immediate and sustained blood pressure lowering by urocortin 2: a novel approach to antihypertensive therapy?. Hypertension 53:7397442009

    • Search Google Scholar
    • Export Citation
  • 10

    Esen FErdem TAktan DOrhan MKaya MEraksoy H: Effect of magnesium sulfate administration on blood-brain barrier in a rat model of intraperitoneal sepsis: a randomized controlled experimental study. Crit Care 9:R18R232005

    • Search Google Scholar
    • Export Citation
  • 11

    Facci LStevens DAPangallo MFranceschini DSkaper SDStrijbos PJ: Corticotropin-releasing factor (CRF) and related peptides confer neuroprotection via type 1 CRF receptors. Neuropharmacology 45:6236362003

    • Search Google Scholar
    • Export Citation
  • 12

    Gordon JMDusting GJWoodman OLRitchie RH: Cardioprotective action of CRF peptide urocortin against simulated ischemia in adult rat cardiomyocytes. Am J Physiol Heart Circ Physiol 284:H330H3362003

    • Search Google Scholar
    • Export Citation
  • 13

    Hoff JTXi G: Brain edema from intracerebral hemorrhage. Acta Neurochir Suppl (Wien) 86:11152003

  • 14

    Kastin AJAkerstrom VPan W: Activation of urocortin transport into brain by leptin. Peptides 21:181118172000

  • 15

    Kihara NFujimura MYamamoto IItoh EInui AFujimiya M: Effects of central and peripheral urocortin on fed and fasted gastroduodenal motor activity in conscious rats. Am J Physiol Gastrointest Liver Physiol 280:G406G4192001

    • Search Google Scholar
    • Export Citation
  • 16

    Kitaoka THua YXi GNagao SHoff JTKeep RF: Effect of delayed argatroban treatment on intracerebral hemorrhage-induced edema in the rat. Acta Neurochir Suppl (Wien) 86:4574612003

    • Search Google Scholar
    • Export Citation
  • 17

    Lawrence KMChanalaris AScarabelli THubank MPasini ETownsend PA: K(ATP) channel gene expression is induced by urocortin and mediates its cardioprotective effect. Circulation 106:155615622002

    • Search Google Scholar
    • Export Citation
  • 18

    Lee STChu KJung KHKim JKim EHKim SJ: Memantine reduces hematoma expansion in experimental intracerebral hemorrhage, resulting in functional improvement. J Cereb Blood Flow Metab 26:5365442006

    • Search Google Scholar
    • Export Citation
  • 19

    Lee STChu KSinn DIJung KHKim EHKim SJ: Erythropoietin reduces perihematomal inflammation and cell death with eNOS and STAT3 activations in experimental intracerebral hemorrhage. J Neurochem 96:172817392006

    • Search Google Scholar
    • Export Citation
  • 20

    Liu CNYang CLiu XYLi S: In vivo protective effects of urocortin on ischemia-reperfusion injury in rat heart via free radical mechanisms. Can J Physiol Pharmacol 83:4594652005

    • Search Google Scholar
    • Export Citation
  • 21

    Macey DJKoob GFMarkou A: CRF and urocortin decreased brain stimulation reward in the rat: reversal by a CRF receptor antagonist. Brain Res 866:82912000

    • Search Google Scholar
    • Export Citation
  • 22

    MacLellan CLSilasi GPoon CCEdmundson CLBuist RPeeling J: Intracerebral hemorrhage models in rat: comparing collagenase to blood infusion. J Cereb Blood Flow Metab 28:5165252008

    • Search Google Scholar
    • Export Citation
  • 23

    Nakamura TKeep RFHua YPark JWItano TNagao S: Intracerebral hemorrhage induces edema and oxidative stress and alters N-methyl-D-aspartate receptor subunits expression. Acta Neurochir Suppl (Wien) 95:4214242005

    • Search Google Scholar
    • Export Citation
  • 24

    Pan WAkerstrom VZhang JPejovic VKastin AJ: Modulation of feeding-related peptide/protein signals by the blood-brain barrier. J Neurochem 90:4554612004

    • Search Google Scholar
    • Export Citation
  • 25

    Pan WKastin AJ: Urocortin and the brain. Prog Neurobiol 84:1481562008

  • 26

    Park HKChu KLee STJung KHKim EHLee KB: Granulocyte colony-stimulating factor induces sensorimotor recovery in intracerebral hemorrhage. Brain Res 1041:1251312005

    • Search Google Scholar
    • Export Citation
  • 27

    Pedersen WAWan RZhang PMattson 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 22:4044122002

    • Search Google Scholar
    • Export Citation
  • 28

    Perrin MHVale WW: Corticotropin releasing factor receptors and their ligand family. Ann N Y Acad Sci 885:3123281999

  • 29

    Pouratian NKassell NFDumont AS: Update on management of intracerebral hemorrhage. Neurosurg Focus 15:4E22003

  • 30

    Rincon FMayer SA: Novel therapies for intracerebral hemorrhage. Curr Opin Crit Care 10:941002004

  • 31

    Ropper AH: Lateral displacement of the brain and level of consciousness in patients with an acute hemispheral mass. N Engl J Med 314:9539581986

    • Search Google Scholar
    • Export Citation
  • 32

    Stevens SLShaw TEDykhuizen ELessov NSHill JKWurst W: 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 23:115111592003

    • Search Google Scholar
    • Export Citation
  • 33

    Tu HKastin AJPan W: Corticotropin-releasing hormone receptor (CRHR)1 and CRHR2 are both trafficking and signaling receptors for urocortin. Mol Endocrinol 21:7007112007

    • Search Google Scholar
    • Export Citation
  • 34

    Van Pett KViau VBittencourt JCChan RKLi HYArias C: Distribution of mRNAs encoding CRF receptors in brain and pituitary of rat and mouse. J Comp Neurol 428:1912122000

    • Search Google Scholar
    • Export Citation
  • 35

    Vaughan JDonaldson CBittencourt JPerrin MHLewis KSutton S: Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature 378:2872921995

    • Search Google Scholar
    • Export Citation
  • 36

    Wagner KRHua Yde Courten-Myers GMBroderick JPNishimura RNLu SY: Tin-mesoporphyrin, a potent heme oxygenase inhibitor, for treatment of intracerebral hemorrhage: in vivo and in vitro studies. Cell Mol Biol (Noisy-legrand) 46:5976082000

    • Search Google Scholar
    • Export Citation
  • 37

    Wang JDoré S: Inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab 27:8949082007

  • 38

    Wang JRogove ADTsirka AETsirka SE: Protective role of tuftsin fragment 1–3 in an animal model of intracerebral hemorrhage. Ann Neurol 54:6556642003

    • Search Google Scholar
    • Export Citation
  • 39

    Wang JTsirka SE: Tuftsin fragment 1–3 is beneficial when delivered after the induction of intracerebral hemorrhage. Stroke 36:6136182005

    • Search Google Scholar
    • Export Citation
  • 40

    Wang MJLin SZKuo JSHuang HYTzeng SFLiao CH: Urocortin modulates inflammatory response and neurotoxicity induced by microglial activation. J Immunol 179:620462142007

    • Search Google Scholar
    • Export Citation
  • 41

    Wu GHuang FP: Effects of venom defibrase on brain edema after intracerebral hemorrhage in rats. Acta Neurochir Suppl (Wien) 95:3813872005

    • Search Google Scholar
    • Export Citation
  • 42

    Xi GHua YKeep RFYounger JGHoff JT: Systemic complement depletion diminishes perihematomal brain edema in rats. Stroke 32:1621672001

    • Search Google Scholar
    • Export Citation
  • 43

    Xi GKeep RFHoff JT: Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol 5:53632006

  • 44

    Xi GWu JJiang YHua YKeep RFHoff JT: Thrombin preconditioning upregulates transferrin and transferrin receptor and reduces brain edema induced by lysed red blood cells. Acta Neurochir Suppl (Wien) 86:4494522003

    • Search Google Scholar
    • Export Citation
  • 45

    Yang GYBetz ALHoff JT: The effects of blood or plasma clot on brain edema in the rat with intracerebral hemorrhage. Acta Neurochir Suppl (Wien) 60:5555571994

    • Search Google Scholar
    • Export Citation
  • 46

    Zazulia ARDiringer MNDerdeyn CPPowers WJ: Progression of mass effect after intracerebral hemorrhage. Stroke 30:116711731999

TrendMD

Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 147 147 6
Full Text Views 100 100 0
PDF Downloads 118 118 0
EPUB Downloads 0 0 0

PubMed

Google Scholar