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The apoE-mimetic Peptide, COG1410, Improves Functional Recovery in a Murine Model of Intracerebral Hemorrhage

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Abstract

Background

Apolipoprotein E has previously been demonstrated to modulate acute brain injury responses, and administration of COG1410, an apoE-mimetic peptide derived from the receptor-binding region of apoE, improves outcome in preclinical models of acute neurological injury. In the current study, we sought to establish the optimal dose and timing of peptide administration associated with improved functional outcome in a murine model of intracerebral hemorrhage (ICH).

Methods

Ten to twelve-week-old C57/BL6 male mice were injured by collagenase-induced ICH and randomly selected to receive either vehicle or one of four doses of COG1410 (0.5, 1, 2, or 4 mg/kg) via tail vein injection at 30 min after injury and then daily for 5 days. The injured mice were euthanized at various time points to assess inflammatory mediators, cerebral edema, and hematoma volume. Over the first 5 days following injury, vestibulomotor function was tested via Rotorod (RR) latency. After an optimal dose was demonstrated, a final cohort of animals was injured with ICH and randomly assigned to receive the first dose of COG1410 or vehicle at increasingly longer treatment initiation times after injury. The mice were then assessed for functional deficit via RR testing over the first 5 days following injury.

Results

The mice receiving 2 mg/kg of COG1410 after injury demonstrated reduced functional deficit, decreased brain concentrations of inflammatory proteins, and less cerebral edema, although hematoma volume did not vary. The improved RR performance was maintained when peptide administration was delayed for up to 2 h after ICH.

Conclusions

COG1410 administered at a dose of 2 mg/kg within 2 h after injury improves functional recovery in a murine model of ICH.

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References

  1. Broderick JP, Adams HP Jr, Barsan W, Feinberg W, Feldmann E, Grotta J, Kase C, Krieger D, Mayberg M, Tilley B, Zabramski JM, Zuccarello M. Guidelines for the management of spontaneous intracerebral hemorrhage: a statement for healthcare professionals from a special writing group of the stroke council, American heart association. Stroke. 1999;30:905–15.

    Article  PubMed  CAS  Google Scholar 

  2. James ML, Sullivan PM, Lascola CD, Vitek MP, Laskowitz DT. Pharmacogenomic effects of apolipoprotein e on intracerebral hemorrhage. Stroke. 2009;40:632–9.

    Article  PubMed  CAS  Google Scholar 

  3. James ML, Wang H, Venkatraman T, Song P, Lascola CD, Laskowitz DT. Brain natriuretic peptide improves long-term functional recovery after acute CNS injury in mice. J Neurotrauma. 2009;27:217–28.

    Article  Google Scholar 

  4. James ML, Blessing R, Bennett E, Laskowitz DT. Apolipoprotein E modifies neurological outcome by affecting cerebral edema but not hematoma size after intracerebral hemorrhage in humans. J Stroke Cerebrovasc Dis. 2009;18:144–9.

    Article  PubMed  Google Scholar 

  5. James ML, Warner DS, Laskowitz DT. Preclinical models of intracerebral hemorrhage: a translational perspective. Neurocrit Care. 2007;9(1):135–52.

    Google Scholar 

  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;365:387–97.

    PubMed  Google Scholar 

  7. Aono M, Bennett ER, Kim KS, Lynch JR, Myers J, Pearlstein RD, Warner DS, Laskowitz DT. Protective effect of apolipoprotein E-mimetic peptides on N-methyl-d-aspartate excitotoxicity in primary rat neuronal-glial cell cultures. Neuroscience. 2003;116:437–45.

    Article  PubMed  CAS  Google Scholar 

  8. Vitek MP, Brown CM, Colton CA. APOE genotype-specific differences in the innate immune response. Neurobiol Aging. 2009;30:1350–60.

    Article  PubMed  CAS  Google Scholar 

  9. Aono M, Lee Y, Grant ER, Zivin RA, Pearlstein RD, Warner DS, Bennett ER, Laskowitz DT. Apolipoprotein E protects against NMDA excitotoxicity. Neurobiol Dis. 2002;11:214–20.

    Article  PubMed  CAS  Google Scholar 

  10. Colton CA, Brown CM, Czapiga M, Vitek MP. Apolipoprotein-E allele-specific regulation of nitric oxide production. Ann N Y Acad Sci. 2002;962:212–25.

    Article  PubMed  CAS  Google Scholar 

  11. Laskowitz DT, Goel S, Bennett ER, Matthew WD. Apolipoprotein E suppresses glial cell secretion of TNF alpha. J Neuroimmunol. 1997;76:70–4.

    Article  PubMed  CAS  Google Scholar 

  12. Laskowitz DT, Thekdi AD, Thekdi SD, Han SK, Myers JK, Pizzo SV, Bennett ER. Downregulation of microglial activation by apolipoprotein E and apoE-mimetic peptides. Exp Neurol. 2001;167:74–85.

    Article  PubMed  CAS  Google Scholar 

  13. Lomnitski L, Oron L, Sklan D, Michaelson DM. Distinct alterations in phospholipid metabolism in brains of apolipoprotein E-deficient mice. J Neurosci Res. 1999;58:586–92.

    Article  PubMed  CAS  Google Scholar 

  14. Lynch JR, Morgan D, Mance J, Matthew WD, Laskowitz DT. Apolipoprotein E modulates glial activation and the endogenous central nervous system inflammatory response. J Neuroimmunol. 2001;114:107–13.

    Article  PubMed  CAS  Google Scholar 

  15. Lynch JR, Tang W, Wang H, Vitek MP, Bennett ER, Sullivan PM, Warner DS, Laskowitz DT. APOE genotype and an ApoE-mimetic peptide modify the systemic and central nervous system inflammatory response. J Biol Chem. 2003;278:48529–33.

    Article  PubMed  CAS  Google Scholar 

  16. Miyata M, Smith JD. Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and beta-amyloid peptides. Nat Genet. 1996;14:55–61.

    Article  PubMed  CAS  Google Scholar 

  17. Nathan BP, Bellosta S, Sanan DA, Weisgraber KH, Mahley RW, Pitas RE. Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro. Science. 1994;264:850–2.

    Article  PubMed  CAS  Google Scholar 

  18. Hoane MR, Kaufman N, Vitek MP, McKenna SE. COG1410 improves cognitive performance and reduces cortical neuronal loss in the traumatically injured brain. J Neurotrauma. 2009;26:121–9.

    Article  PubMed  Google Scholar 

  19. Laskowitz DT, Vitek MP. Apolipoprotein E and neurological disease: therapeutic potential and pharmacogenomic interactions. Pharmacogenomics. 2007;8:959–69.

    Article  PubMed  CAS  Google Scholar 

  20. Lynch JR, Wang H, Mace B, Leinenweber S, Warner DS, Bennett ER, Vitek MP, McKenna S, Laskowitz DT. A novel therapeutic derived from apolipoprotein E reduces brain inflammation and improves outcome after closed head injury. Exp Neurol. 2005;192:109–16.

    Article  PubMed  CAS  Google Scholar 

  21. Tukhovskaya EA, Yukin AY, Khokhlova ON, Murashev AN, Vitek MP. COG1410, a novel apolipoprotein-E mimetic, improves functional and morphological recovery in a rat model of focal brain ischemia. J Neurosci Res. 2009;87:677–82.

    Article  PubMed  CAS  Google Scholar 

  22. Gao J, Wang H, Sheng H, Lynch JR, Warner DS, Durham L, Vitek MP, Laskowitz DT. A novel apoE-derived therapeutic reduces vasospasm and improves outcome in a murine model of subarachnoid hemorrhage. Neurocrit Care. 2006;4:25–31.

    Article  PubMed  CAS  Google Scholar 

  23. Mesis RG, Wang H, Lombard FW, Yates R, Vitek MP, Borel CO, Warner DS, Laskowitz DT. Dissociation between vasospasm and functional improvement in a murine model of subarachnoid hemorrhage. Neurosurg Focus. 2006;21:E4.

    Article  PubMed  Google Scholar 

  24. Christensen DJ, Ohkubo N, Oddo J, Van Kanegan MJ, Neil J, Li F, Colton CA, Vitek MP. Apolipoprotein-E and peptide mimetics modulate inflammation by binding the SET protein and activating protein phosphatase 2A. J Immunol. 2011;186(4):2535–42.

    Article  PubMed  CAS  Google Scholar 

  25. Rosenberg GA, Estrada E, Wesley M, Kyner WT. Autoradiographic patterns of brain interstitial fluid flow after collagenase-induced haemorrhage in rat. Acta Neurochir Suppl (Wien). 1990;51:280–2.

    CAS  Google Scholar 

  26. Hamm RJ, Pike BR, O’Dell DM, Lyeth BG, Jenkins LW. The rotarod test: an evaluation of its effectiveness in assessing motor deficits following traumatic brain injury. J Neurotrauma. 1994;11:187–96.

    Article  PubMed  CAS  Google Scholar 

  27. Garcia JH, Wagner S, Liu KF, Hu XJ. Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats: statistical validation. Stroke J Cereb Circ. 1995;26:627–34. (discussion 35).

    Article  CAS  Google Scholar 

  28. Song EC, Chu K, Jeong SW, Jung KH, Kim SH, Kim M, Yoon BW. Hyperglycemia exacerbates brain edema and perihematomal cell death after intracerebral hemorrhage. Stroke. 2003;34:2215–20.

    Article  PubMed  CAS  Google Scholar 

  29. Dawson HN, Cantillana V, Chen L, Vitek MP. The tau N279 K exon 10 splicing mutation recapitulates frontotemporal dementia and parkinsonism linked to chromosome 17 tauopathy in a mouse model. J Neurosci. 2007;27:9155–68.

    Article  PubMed  CAS  Google Scholar 

  30. Dawson HN, Cantillana V, Jansen M, Wang H, Vitek MP, Wilcock DM, Lynch JR, Laskowitz DT. Loss of tau elicits axonal degeneration in a mouse model of Alzheimer’s disease. Neuroscience. 2010;169:516–31.

    Article  PubMed  CAS  Google Scholar 

  31. West MJ, Slomianka L, Gundersen HJ. Unbiased stereological estimation of the total number of neurons in thesubdivisions of the rat hippocampus using the optical fractionator. Anat Rec. 1991;231:482–97.

    Article  PubMed  CAS  Google Scholar 

  32. Hoe HS, Pocivavsek A, Chakraborty G, Fu Z, Vicini S, Ehlers MD, Rebeck GW. Apolipoprotein E receptor 2 interactions with the N-methyl-d-aspartate receptor. J Biol Chem. 2006;281:3425–31.

    Article  PubMed  CAS  Google Scholar 

  33. Misra UK, Adlakha CL, Gawdi G, McMillian MK, Pizzo SV, Laskowitz DT. Apolipoprotein E and mimetic peptide initiate a calcium-dependent signaling response in macrophages. J Leukoc Biol. 2001;70:677–83.

    PubMed  CAS  Google Scholar 

  34. Laskowitz DT, McKenna SE, Song P, Wang H, Durham L, Yeung N, Christensen D, Vitek MP. COG1410, a novel apolipoprotein E-based peptide, improves functional recovery in a murine model of traumatic brain injury. J Neurotrauma. 2007;24:1093–107.

    Article  PubMed  Google Scholar 

  35. 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;28:516–25.

    Article  PubMed  CAS  Google Scholar 

  36. MacLellan CL, Silasi G, Auriat AM, Colbourne F. Rodent models of intracerebral hemorrhage. Stroke J Cereb Circ. 2010;41:S95–8.

    Article  Google Scholar 

  37. Laskowitz DT, Fillit H, Yeung N, Toku K, Vitek MP. Apolipoprotein E-derived peptides reduce CNS inflammation: implications for therapy of neurological disease. Acta Neurol Scand Suppl. 2006;185:15–20.

    Article  PubMed  CAS  Google Scholar 

  38. Leira R, Davalos A, Silva Y, Gil-Peralta A, Tejada J, Garcia M, Castillo J. Early neurologic deterioration in intracerebral hemorrhage: predictors and associated factors. Neurology. 2004;63:461–7.

    PubMed  CAS  Google Scholar 

  39. Wang J, Dore S. Inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab. 2007;27:894–908.

    Article  PubMed  CAS  Google Scholar 

  40. Wasserman JK, Zhu X, Schlichter LC. Evolution of the inflammatory response in the brain following intracerebral hemorrhage and effects of delayed minocycline treatment. Brain Res. 2007;1180:140–54.

    Article  PubMed  CAS  Google Scholar 

  41. Fujimoto S, Katsuki H, Ohnishi M, Takagi M, Kume T, Akaike A. Thrombin induces striatal neurotoxicity depending on mitogen-activated protein kinase pathways in vivo. Neuroscience. 2007;144:694–701.

    Article  PubMed  CAS  Google Scholar 

  42. Ohnishi M, Katsuki H, Fujimoto S, Takagi M, Kume T, Akaike A. Involvement of thrombin and mitogen-activated protein kinase pathways in hemorrhagic brain injury. Exp Neurol. 2007;206:43–52.

    Article  PubMed  CAS  Google Scholar 

  43. Li M, Makkinje A, Damuni Z. The myeloid leukemia-associated protein SET is a potent inhibitor of protein phosphatase 2A. J Biol Chem. 1996;271:11059–62.

    Article  PubMed  CAS  Google Scholar 

  44. Ivaska J, Nissinen L, Immonen N, Eriksson JE, Kahari VM, Heino J. Integrin alpha 2 beta 1 promotes activation of protein phosphatase 2A and dephosphorylation of Akt and glycogen synthase kinase 3 beta. Mol Cell Biol. 2002;22:1352–9.

    Article  PubMed  CAS  Google Scholar 

  45. Shanley TP, Vasi N, Denenberg A, Wong HR. The serine/threonine phosphatase, PP2A: endogenous regulator of inflammatory cell signaling. J Immunol. 2001;166:966–72.

    PubMed  CAS  Google Scholar 

  46. Liu Q, Hofmann PA. Protein phosphatase 2A-mediated cross-talk between p38 MAPK and ERK in apoptosis of cardiac myocytes. Am J Physiol Heart Circ Physiol. 2004;286:H2204–12.

    Article  PubMed  CAS  Google Scholar 

  47. Kray AE, Carter RS, Pennington KN, Gomez RJ, Sanders LE, Llanes JM, Khan WN, Ballard DW, Wadzinski BE. Positive regulation of IkappaB kinase signaling by protein serine/threonine phosphatase 2A. J Biol Chem. 2005;280:35974–82.

    Article  PubMed  CAS  Google Scholar 

  48. Singh K, Chaturvedi R, Asim M, Barry DP, Lewis ND, Vitek MP, Wilson KT. The apolipoprotein E-mimetic peptide COG112 inhibits the inflammatory response to citrobacter rodentium in colonic epithelial cells by preventing NF-kappa B activation. J Biol Chem. 2008;283:16752–61.

    Article  PubMed  CAS  Google Scholar 

  49. Singh K, Chaturvedi R, Barry DP, Coburn LA, Asim M, Lewis ND, Piazuelo MB, Washington MK, Vitek MP, Wilson KT. The apolipoprotein E-mimetic peptide COG112 inhibits NF-{kappa}B signaling, proinflammatory cytokine expression, and disease activity in murine models of colitis. J Biol Chem. 2011;286(5):3839–50.

    Article  PubMed  CAS  Google Scholar 

  50. Li FQ, Sempowski GD, McKenna SE, Laskowitz DT, Colton CA, Vitek MP. Apolipoprotein E-derived peptides ameliorate clinical disability and inflammatory infiltrates into the spinal cord in a murine model of multiple sclerosis. J Pharmacol Exp Ther. 2006;318:956–65.

    Article  PubMed  CAS  Google Scholar 

  51. McAdoo JD, Warner DS, Goldberg RN, Vitek MP, Pearlstein R, Laskowitz DT. Intrathecal administration of a novel apoE-derived therapeutic peptide improves outcome following perinatal hypoxic–ischemic injury. Neurosci Lett. 2005;381:305–8.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors would like to thank Jessica Oddo for technical assistance. This research was made possible through grants from R43NS064651-01A1 (DJC), the American Heart Association Scientist Development Grant (MLJ), and Foundation of Anesthesia Education and Research Mentored Research Training Grant (MLJ). COG1410 was provided by Cognosci, Inc. (Research Triangle Park, NC, USA).

Conflict of interest

Dr. Laskowitz served as a consultant for Cognosci, Inc., ending greater than 6 months ago. Dale Christensen served as a Research associate for Cognosci, Inc. Michael P. Vitek served as an Executive officer at Cognosci, Inc. BeiLei Lei, Hana N. Dawson, Haichen Wang, Steven Bellows, and Michael L. James declare that they have no conflict of interest.

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Authors and Affiliations

  1. Departments of Medicine (Neurology), Neurobiology, and Anesthesiology, Multidisciplinary Neuroprotection Laboratories, Duke University, Durham, NC, USA

    Daniel T. Laskowitz

  2. Department of Anesthesiology, Multidisciplinary Neuroprotection Laboratories, Duke University, Durham, NC, USA

    Beilei Lei

  3. Department of Medicine (Neurology), Multidisciplinary Neuroprotection Laboratories, Duke University, Durham, NC, USA

    Hana N. Dawson & Haichen Wang

  4. Department of Anesthesiology, Duke University, Durham, NC, USA

    Steven T. Bellows

  5. Department of Medicine (Hematology), Duke University, Durham, NC, USA

    Dale J. Christensen

  6. Cognosci, Inc., Research Triangle Park, NC, USA

    Dale J. Christensen & Michael P. Vitek

  7. Departments of Medicine (Neurology) and Neurobiology, Duke University, Durham, NC, USA

    Michael P. Vitek

  8. Departments of Anesthesiology and Medicine (Neurology), Multidisciplinary Neuroprotection Laboratories, Duke University, DUMC 3094, Durham, NC, 27710, USA

    Michael L. James

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  1. Daniel T. Laskowitz
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Correspondence to Michael L. James.

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Laskowitz, D.T., Lei, B., Dawson, H.N. et al. The apoE-mimetic Peptide, COG1410, Improves Functional Recovery in a Murine Model of Intracerebral Hemorrhage. Neurocrit Care 16, 316–326 (2012). https://doi.org/10.1007/s12028-011-9641-5

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