Neurocritical Care

, Volume 14, Issue 1, pp 109–117 | Cite as

Recombinant Osteopontin Attenuates Brain Injury after Intracerebral Hemorrhage in Mice

  • Bihua Wu
  • Qingyi Ma
  • Hidenori Suzuki
  • Chunhua Chen
  • Wenwu Liu
  • Jiping Tang
  • John Zhang
Translational Research

Abstract

Background

Osteopontin (OPN), an extracellular matrix glycoprotein, has been reported to inhibit inducible nitric oxide synthase (iNOS). We examined if recombinant OPN (r-OPN) inhibits iNOS and prevents brain injury in a mouse collagenase-induced intracerebral hemorrhage (ICH) model.

Methods

One hundred one mice were randomly assigned to five groups: sham, ICH + vehicle, ICH + r-OPN (10, 50, or 100 ng per mouse) groups. Vehicle or r-OPN was administered via an intracerebroventricular infusion 20 min pre-ICH. Neurological scores and brain water content were evaluated at 24 and 72 h, and hemoglobin assay, Nissl staining and Western blot for iNOS, Stat1, matrix metalloproteinase (MMP)-9 and zonula occludens (ZO)-1 were performed at 24 h post-ICH.

Results

r-OPN did not affect hematoma formation. Middle (50 ng)- and high (100 ng)-dose, but not low (10 ng)-dose of r-OPN treatment significantly improved neurological scores and brain water content compared with the vehicle group. The protective effect of r-OPN was associated with significantly rescued neuronal cells in the peri-hematoma region as well as a decrease in the Stat1 phosphorylation, iNOS induction, MMP-9 activation, and ZO-1 degradation.

Conclusions

This study suggests that r-OPN may down-regulate iNOS expression by the inhibition of Stat1 phosphorylation, and therefore suppressing the MMP-9 activation, preventing ICH-induced brain injury in mice.

Keywords

Brain edema Collagenase Intracerebral hemorrhage Inducible nitric oxide synthase Osteopontin 

References

  1. 1.
    Aronowski J, Hall CE. New horizons for primary intracerebral hemorrhage treatment: experience from preclinical studies. Neurol Res. 2005;27(3):268–79.CrossRefPubMedGoogle Scholar
  2. 2.
    Xue M, Yong VW. Matrix metalloproteinases in intracerebral hemorrhage. Neurol Res. 2008;30(8):775–82.CrossRefPubMedGoogle Scholar
  3. 3.
    Kim DW, Im SH, Kim JY, Kim DE, Oh GT, Jeong SW. Decreased brain edema after collagenase-induced intracerebral hemorrhage in mice lacking the inducible nitric oxide synthase gene. Laboratory investigation. J Neurosurg. 2009;111(5):995–1000.CrossRefPubMedGoogle Scholar
  4. 4.
    Denhardt DT, Noda M, O’Regan AW, Pavlin D, Berman JS. Osteopontin as a means to cope with environmental insults: regulation of inflammation, tissue remodeling, and cell survival. J Clin Invest. 2001;107(9):1055–61.CrossRefPubMedGoogle Scholar
  5. 5.
    Lee YJ, Park SJ, Lee WK, Ko JS, Kim HM. MG63 osteoblastic cell adhesion to the hydrophobic surface precoated with recombinant osteopontin fragments. Biomaterials. 2003;24(6):1059–66.CrossRefPubMedGoogle Scholar
  6. 6.
    Suzuki H, Ayer R, Sugawara T, et al. Protective effects of recombinant osteopontin on early brain injury after subarachnoid hemorrhage in rats. Crit Care Med. 2010;38(2):612–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Yan YP, Lang BT, Vemuganti R, Dempsey RJ. Persistent migration of neuroblasts from the subventricular zone to the injured striatum mediated by osteopontin following intracerebral hemorrhage. J Neurochem. 2009;109(6):1624–35.CrossRefPubMedGoogle Scholar
  8. 8.
    Arafat HA, Katakam AK, Chipitsyna G, et al. Osteopontin protects the islets and beta-cells from interleukin-1 beta-mediated cytotoxicity through negative feedback regulation of nitric oxide. Endocrinology. 2007;148(2):575–84.CrossRefPubMedGoogle Scholar
  9. 9.
    Gao C, Guo H, Mi Z, Grusby MJ, Kuo PC. Osteopontin induces ubiquitin-dependent degradation of STAT1 in RAW264.7 murine macrophages. J Immunol. 2007;178(3):1870–81.PubMedGoogle Scholar
  10. 10.
    Scott JA, Weir ML, Wilson SM, Xuan JW, Chambers AF, McCormack DG. Osteopontin inhibits inducible nitric oxide synthase activity in rat vascular tissue. Am J Physiol. 1998;275((6 Pt 2)):H2258–65.PubMedGoogle Scholar
  11. 11.
    Singh K, Balligand JL, Fischer TA, Smith TW, Kelly RA. Glucocorticoids increase osteopontin expression in cardiac myocytes and microvascular endothelial cells. Role in regulation of inducible nitric oxide synthase. J Biol Chem. 1995;270(47):28471–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Tang J, Liu J, Zhou C, et al. Role of NADPH oxidase in the brain injury of intracerebral hemorrhage. J Neurochem. 2005;94(5):1342–50.CrossRefPubMedGoogle Scholar
  13. 13.
    Doyle KP, Yang T, Lessov NS, et al. Nasal administration of osteopontin peptide mimetics confers neuroprotection in stroke. J Cereb Blood Flow Metab. 2008;28(6):1235–48.CrossRefPubMedGoogle Scholar
  14. 14.
    Lo W, Bravo T, Jadhav V, Titova E, Zhang JH, Tang J. NADPH oxidase inhibition improves neurological outcomes in surgically-induced brain injury. Neurosci Lett. 2007;414(3):228–32.CrossRefPubMedGoogle Scholar
  15. 15.
    Tsuchiyama R, Sozen T, Manaenko A, Zhang JH, Tang J. The effects of nicotinamide adenine dinucleotide on intracerebral hemorrhage-induced brain injury in mice. Neurol Res. 2009;31(2):179–82.CrossRefPubMedGoogle Scholar
  16. 16.
    Tang J, Liu J, Zhou C, et al. Mmp-9 deficiency enhances collagenase-induced intracerebral hemorrhage and brain injury in mutant mice. J Cereb Blood Flow Metab. 2004;24(10):1133–45.CrossRefPubMedGoogle Scholar
  17. 17.
    Chen W, Jadhav V, Tang J, Zhang JH. HIF-1alpha inhibition ameliorates neonatal brain injury in a rat pup hypoxic-ischemic model. Neurobiol Dis. 2008;31(3):433–41.CrossRefPubMedGoogle Scholar
  18. 18.
    Ostrowski RP, Colohan AR, Zhang JH. Mechanisms of hyperbaric oxygen-induced neuroprotection in a rat model of subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2005;25(5):554–71.CrossRefPubMedGoogle Scholar
  19. 19.
    Lee CZ, Xue Z, Zhu Y, Yang GY, Young WL. Matrix metalloproteinase-9 inhibition attenuates vascular endothelial growth factor-induced intracerebral hemorrhage. Stroke. 2007;38(9):2563–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Pearse DD, Chatzipanteli K, Marcillo AE, Bunge MB, Dietrich WD. Comparison of iNOS inhibition by antisense and pharmacological inhibitors after spinal cord injury. J Neuropathol Exp Neurol. 2003;62(11):1096–107.PubMedGoogle Scholar
  21. 21.
    Wada K, Chatzipanteli K, Kraydieh S, Busto R, Dietrich WD. Inducible nitric oxide synthase expression after traumatic brain injury and neuroprotection with aminoguanidine treatment in rats. Neurosurgery. 1998;43(6):1427–36.CrossRefPubMedGoogle Scholar
  22. 22.
    Zhao X, Zhang Y, Strong R, Zhang J, Grotta JC, Aronowski J. Distinct patterns of intracerebral hemorrhage-induced alterations in NF-kappaB subunit, iNOS, and COX-2 expression. J Neurochem. 2007;101(3):652–63.CrossRefPubMedGoogle Scholar
  23. 23.
    Jung KH, Chu K, Jeong SW, et al. HMG-CoA reductase inhibitor, atorvastatin, promotes sensorimotor recovery, suppressing acute inflammatory reaction after experimental intracerebral hemorrhage. Stroke. 2004;35(7):1744–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Sinn DI, Lee ST, Chu K, et al. Proteasomal inhibition in intracerebral hemorrhage: neuroprotective and anti-inflammatory effects of bortezomib. Neurosci Res. 2007;58(1):12–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Pannu R, Singh I. Pharmacological strategies for the regulation of inducible nitric oxide synthase: neurodegenerative versus neuroprotective mechanisms. Neurochem Int. 2006;49(2):170–82.CrossRefPubMedGoogle Scholar
  26. 26.
    Tejima E, Zhao BQ, Tsuji K, et al. Astrocytic induction of matrix metalloproteinase-9 and edema in brain hemorrhage. J Cereb Blood Flow Metab. 2007;27(3):460–8.CrossRefPubMedGoogle Scholar
  27. 27.
    Mahajan SD, Aalinkeel R, Sykes DE, et al. Tight junction regulation by morphine and HIV-1 tat modulates blood-brain barrier permeability. J Clin Immunol. 2008;28(5):528–41.CrossRefPubMedGoogle Scholar
  28. 28.
    Rangaswami H, Bulbule A, Kundu GC. Osteopontin: role in cell signaling and cancer progression. Trends Cell Biol. 2006;16(2):79–87.CrossRefPubMedGoogle Scholar
  29. 29.
    Xie Z, Singh M, Siwik DA, Joyner WL, Singh K. Osteopontin inhibits interleukin-1beta-stimulated increases in matrix metalloproteinase activity in adult rat cardiac fibroblasts: role of protein kinase C-zeta. J Biol Chem. 2003;278(49):48546–52.CrossRefPubMedGoogle Scholar
  30. 30.
    Hwang SM, Lopez CA, Heck DE, et al. Osteopontin inhibits induction of nitric oxide synthase gene expression by inflammatory mediators in mouse kidney epithelial cells. J Biol Chem. 1994;269(1):711–5.PubMedGoogle Scholar
  31. 31.
    Rollo EE, Laskin DL, Denhardt DT. Osteopontin inhibits nitric oxide production and cytotoxicity by activated RAW264.7 macrophages. J Leukoc Biol. 1996;60(3):397–404.PubMedGoogle Scholar
  32. 32.
    Kilbourn RG, Traber DL, Szabo C. Nitric oxide and shock. Dis Mon. 1997;43(5):277–348.PubMedGoogle Scholar
  33. 33.
    Guo H, Wai PY, Mi Z, Gao C, Zhang J, Kuo PC. Osteopontin mediates Stat1 degradation to inhibit iNOS transcription in a cecal ligation and puncture model of sepsis. Surgery. 2008;144(2):182–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Wan S, Zhan R, Zheng S, Hua Y, Xi G. Activation of c-Jun-N-terminal kinase in a rat model of intracerebral hemorrhage: the role of iron. Neurosci Res. 2009;63(2):100–5.CrossRefPubMedGoogle Scholar
  35. 35.
    Meller R, Stevens SL, Minami M, et al. Neuroprotection by osteopontin in stroke. J Cereb Blood Flow Metab. 2005;25(2):217–25.CrossRefPubMedGoogle Scholar
  36. 36.
    James ML, Warner DS, Laskowitz DT. Preclinical models of intracerebral hemorrhage: a translational perspective. Neurocrit Care. 2008;9(1):139–52.CrossRefPubMedGoogle Scholar
  37. 37.
    MacLellan CL, Silasi G, Poon CC, et al. Intracerebral hemorrhage models in rat: comparing collagenase to blood infusion. J Cereb Blood Flow Metab. 2008;28(3):516–25.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Bihua Wu
    • 1
    • 4
  • Qingyi Ma
    • 1
  • Hidenori Suzuki
    • 1
  • Chunhua Chen
    • 1
  • Wenwu Liu
    • 1
  • Jiping Tang
    • 1
  • John Zhang
    • 1
    • 2
    • 3
    • 5
  1. 1.Department of Physiology and PharmacologyLoma Linda UniversityLoma LindaUSA
  2. 2.Department of NeurosurgeryLoma Linda UniversityLoma LindaUSA
  3. 3.Department of AnesthesiologyLoma Linda UniversityLoma LindaUSA
  4. 4.Department of NeurologyAffiliated Hospital, North Sichuan Medical CollegeNanchong CityChina
  5. 5.Department of PhysiologyLoma Linda University School of MedicineLoma LindaUSA

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