Advertisement

Neurochemical Research

, Volume 36, Issue 10, pp 1809–1816 | Cite as

Low dose Estrogen Prevents Neuronal Degeneration and Microglial Reactivity in an Acute Model of Spinal Cord Injury: Effect of Dosing, Route of Administration, and Therapy Delay

  • Supriti Samantaray
  • Joshua A. Smith
  • Arabinda Das
  • Denise D. Matzelle
  • Abhay K. Varma
  • Swapan K. Ray
  • Naren L. BanikEmail author
Original Paper

Abstract

Spinal cord injury (SCI), depending on the severity of injury, leads to neurological dysfunction and paralysis. Methylprednisolone, the only currently available therapy renders limited protection in SCI. Therefore, other therapeutic agents must be tested to maximize neuroprotection and functional recovery. Previous data from our laboratory indicate that estrogen (17β-estradiol) at a high dose may attenuate multiple damaging pathways involved in SCI and improve locomotor outcome. Since use of high dose estrogen may have detrimental side effects and therefore may never be used in the clinic, the current study investigated the efficacy of this steroid hormone at very low doses in SCI. In particular, we tested the impact of dosing (1–10 μg/kg), mode of delivery (intravenous vs. osmotic pump), and delay in estrogen application (15 min–4 h post-SCI) on microgliosis and neuronal death in acute SCI in rats. Treatment with 17β-estradiol (1–10 μg/kg) significantly reduced microglial activation and also attenuated apoptosis of neurons compared to untreated SCI animals. The attenuation of cell death and inflammation by estrogen was observed regardless of mode and time of delivery following injury. These findings suggest estrogen as a potential agent for the treatment of individuals with SCI.

Keywords

Spinal cord injury Estrogen Neurodegeneration Apoptosis Microgliosis 

Notes

Acknowledgments

Completion of this project was made possible by funding from the National Institutes of Health (NIH) and National Institute of Neurological Disorders and Stroke (NINDS): (NS-31622, NS-38146, and NS-41088) and the State of South Carolina Spinal Cord Injury Research Fund (SCSCIRF).

References

  1. 1.
    Dumont RJ, Verma S, Okonkwo DO et al (2001) Acute spinal cord injury, part II: contemporary pharmacotherapy. Clin Neuropharmacol 24(5):265–279PubMedCrossRefGoogle Scholar
  2. 2.
    Peter Vellman W, Hawkes AP, Lammertse DP (2003) Administration of corticosteroids for acute spinal cord injury: the current practice of trauma medical directors and emergency medical system physician advisors. Spine (Phila Pa 1976) 28(9):941–947: discussion 947Google Scholar
  3. 3.
    Bracken MB, Collins WF, Freeman DF et al (1984) Efficacy of methylprednisolone in acute spinal cord injury. JAMA 251(1):45–52PubMedCrossRefGoogle Scholar
  4. 4.
    Hurlbert RJ (2000) Methylprednisolone for acute spinal cord injury: an inappropriate standard of care. J Neurosurg 93(1 Suppl):1–7PubMedGoogle Scholar
  5. 5.
    Liu D, Liu J, Wen J (1999) Elevation of hydrogen peroxide after spinal cord injury detected by using the Fenton reaction. Free Radic Biol Med 27(3–4):478–482PubMedCrossRefGoogle Scholar
  6. 6.
    Sakurai M, Nagata T, Abe K et al (2003) Survival and death-promoting events after transient spinal cord ischemia in rabbits: induction of Akt and caspase3 in motor neurons. J Thorac Cardiovasc Surg 125(2):370–377PubMedCrossRefGoogle Scholar
  7. 7.
    Young W (1985) The role of calcium in spinal cord injury. Cent Nerv Syst Trauma 2(2):109–114PubMedGoogle Scholar
  8. 8.
    Happel RD, Smith KP, Banik NL et al (1981) Ca2+-accumulation in experimental spinal cord trauma. Brain Res 211(2):476–479PubMedCrossRefGoogle Scholar
  9. 9.
    Stokes BT, Fox P, Hollinden G (1983) Extracellular calcium activity in the injured spinal cord. Exp Neurol 80(3):561–572PubMedCrossRefGoogle Scholar
  10. 10.
    Ray SK, Matzelle DD, Wilford GG et al (2000) Increased calpain expression is associated with apoptosis in rat spinal cord injury: calpain inhibitor provides neuroprotection. Neurochem Res 25(9–10):1191–1198PubMedCrossRefGoogle Scholar
  11. 11.
    Springer JE, Azbill RD, Kennedy SE et al (1997) Rapid calpain I activation and cytoskeletal protein degradation following traumatic spinal cord injury: attenuation with riluzole pretreatment. J Neurochem 69(4):1592–1600PubMedCrossRefGoogle Scholar
  12. 12.
    Lewen A, Matz P, Chan PH (2000) Free radical pathways in CNS injury. J Neurotrauma 17(10):871–890PubMedCrossRefGoogle Scholar
  13. 13.
    Michaelis EK (1998) Molecular biology of glutamate receptors in the central nervous system and their role in excitotoxicity, oxidative stress and aging. Prog Neurobiol 54(4):369–415PubMedCrossRefGoogle Scholar
  14. 14.
    Mills CD, Xu GY, Johnson KM et al (2000) AIDA reduces glutamate release and attenuates mechanical allodynia after spinal cord injury. Neuroreport 11(14):3067–3070PubMedCrossRefGoogle Scholar
  15. 15.
    Carlson SL, Parrish ME, Springer JE et al (1998) Acute inflammatory response in spinal cord following impact injury. Exp Neurol 151(1):77–88PubMedCrossRefGoogle Scholar
  16. 16.
    Sharma HS, Olsson Y, Nyberg F et al (1993) Prostaglandins modulate alterations of microvascular permeability, blood flow, edema and serotonin levels following spinal cord injury: an experimental study in the rat. Neuroscience 57(2):443–449PubMedCrossRefGoogle Scholar
  17. 17.
    Barut S, Canbolat A, Bilge T et al (1993) Lipid peroxidation in experimental spinal cord injury: time-level relationship. Neurosurg Rev 16(1):53–59PubMedCrossRefGoogle Scholar
  18. 18.
    Wingrave JM, Schaecher KE, Sribnick EA et al (2003) Early induction of secondary injury factors causing activation of calpain and mitochondria-mediated neuronal apoptosis following spinal cord injury in rats. J Neurosci Res 73(1):95–104PubMedCrossRefGoogle Scholar
  19. 19.
    Agrawal SK, Nashmi R, Fehlings MG (2000) Role of L- and N-type calcium channels in the pathophysiology of traumatic spinal cord white matter injury. Neuroscience 99(1):179–188PubMedCrossRefGoogle Scholar
  20. 20.
    Li S, Jiang Q, Stys PK (2000) Important role of reverse Na(+)–Ca(2+) exchange in spinal cord white matter injury at physiological temperature. J Neurophysiol 84(2):1116–1119PubMedGoogle Scholar
  21. 21.
    Sribnick EA, Matzelle DD, Banik NL et al (2007) Direct evidence for calpain involvement in apoptotic death of neurons in spinal cord injury in rats and neuroprotection with calpain inhibitor. Neurochem Res 32(12):2210–2216PubMedCrossRefGoogle Scholar
  22. 22.
    Ray SK, Banik NL (2003) Calpain and its involvement in the pathophysiology of CNS injuries and diseases: therapeutic potential of calpain inhibitors for prevention of neurodegeneration. Curr Drug Targets CNS Neurol Disord 2(3):173–189PubMedCrossRefGoogle Scholar
  23. 23.
    Pike BR, Zhao X, Newcomb JK et al (1998) Regional calpain and caspase-3 proteolysis of alpha-spectrin after traumatic brain injury. Neuroreport 9(11):2437–2442PubMedCrossRefGoogle Scholar
  24. 24.
    Banik NL, Chou CH, Deibler GE et al (1994) Peptide bond specificity of calpain: proteolysis of human myelin basic protein. J Neurosci Res 37(4):489–496PubMedCrossRefGoogle Scholar
  25. 25.
    Gao G, Dou QP (2000) N-terminal cleavage of bax by calpain generates a potent proapoptotic 18-kDa fragment that promotes bcl-2-independent cytochrome C release and apoptotic cell death. J Cell Biochem 80(1):53–72PubMedCrossRefGoogle Scholar
  26. 26.
    Blomgren K, Zhu C, Wang X et al (2001) Synergistic activation of caspase-3 by m-calpain after neonatal hypoxia-ischemia: a mechanism of “pathological apoptosis”? J Biol Chem 276(13):10191–10198PubMedCrossRefGoogle Scholar
  27. 27.
    Pang Z, Bondada V, Sengoku T et al (2003) Calpain facilitates the neuron death induced by 3-nitropropionic acid and contributes to the necrotic morphology. J Neuropathol Exp Neurol 62(6):633–643PubMedGoogle Scholar
  28. 28.
    Nath R, Raser KJ, Stafford D et al (1996) Non-erythroid alpha-spectrin breakdown by calpain and interleukin 1 beta-converting-enzyme-like protease(s) in apoptotic cells: contributory roles of both protease families in neuronal apoptosis. Biochem J 319(Pt 3):683–690PubMedGoogle Scholar
  29. 29.
    Sribnick EA, Wingrave JM, Matzelle DD et al (2003) Estrogen as a neuroprotective agent in the treatment of spinal cord injury. Ann N Y Acad Sci 993:125–133: discussion 159–160PubMedCrossRefGoogle Scholar
  30. 30.
    Sribnick EA, Ray SK, Banik NL (2004) Estrogen as a multi-active neuroprotective agent in traumatic injuries. Neurochem Res 29(11):2007–2014PubMedCrossRefGoogle Scholar
  31. 31.
    Samantaray S, Sribnick EA, Das A et al (2010) Neuroprotective efficacy of estrogen in experimental spinal cord injury in rats. Ann NY Acad Sci 1199:90–94PubMedCrossRefGoogle Scholar
  32. 32.
    Moosmann B, Behl C (1999) The antioxidant neuroprotective effects of estrogens and phenolic compounds are independent from their estrogenic properties. Proc Natl Acad Sci USA 96(16):8867–8872PubMedCrossRefGoogle Scholar
  33. 33.
    Dimayuga FO, Reed JL, Carnero GA et al (2005) Estrogen and brain inflammation: effects on microglial expression of MHC, costimulatory molecules and cytokines. J Neuroimmunol 161(1–2):123–136PubMedCrossRefGoogle Scholar
  34. 34.
    Sribnick EA, Del Re AM, Ray SK et al (2009) Estrogen attenuates glutamate-induced cell death by inhibiting Ca2+ influx through L-type voltage-gated Ca2+ channels. Brain Res 1276:159–170PubMedCrossRefGoogle Scholar
  35. 35.
    Sribnick EA, Ray SK, Nowak MW et al (2004) 17beta-estradiol attenuates glutamate-induced apoptosis and preserves electrophysiologic function in primary cortical neurons. J Neurosci Res 76(5):688–696PubMedCrossRefGoogle Scholar
  36. 36.
    Sribnick EA, Samantaray S, Das A et al (2010) Postinjury estrogen treatment of chronic spinal cord injury improves locomotor function in rats. J Neurosci Res 88(8):1738–1750PubMedGoogle Scholar
  37. 37.
    Sribnick EA, Matzelle DD, Ray SK et al (2006) Estrogen treatment of spinal cord injury attenuates calpain activation and apoptosis. J Neurosci Res 84(5):1064–1075PubMedCrossRefGoogle Scholar
  38. 38.
    Kwon BK, Okon E, Hillyer J et al. (2011, in press) A systematic review of non-invasive pharmacologic neuroprotective treatments for acute spinal cord injury. J NeurotraumaGoogle Scholar
  39. 39.
    Swartz KR, Fee DB, Joy KM et al (2007) Gender differences in spinal cord injury are not estrogen-dependent. J Neurotrauma 24(3):473–480PubMedCrossRefGoogle Scholar
  40. 40.
    Perot PL Jr, Lee WA, Hsu CY et al (1987) Therapeutic model for experimental spinal cord injury in the rat: I. Mortality and motor deficit. Cent Nerv Syst Trauma 4(3):149–159PubMedGoogle Scholar
  41. 41.
    Samantaray S, Sribnick EA, Das A et al (2008) Melatonin attenuates calpain upregulation, axonal damage and neuronal death in spinal cord injury in rats. J Pineal Res 44(4):348–357PubMedCrossRefGoogle Scholar
  42. 42.
    Ray SK, Schaecher KE, Shields DC et al (2000) Combined TUNEL and double immunofluorescent labeling for detection of apoptotic mononuclear phagocytes in autoimmune demyelinating disease. Brain Res Brain Res Protoc 5(3):305–311PubMedCrossRefGoogle Scholar
  43. 43.
    Samantaray S, Matzelle DD, Ray SK et al (2010) Physiological low dose of estrogen-protected neurons in experimental spinal cord injury. Ann NY Acad Sci 1199:86–89PubMedCrossRefGoogle Scholar
  44. 44.
    Brown CM, Suzuki S, Jelks KA et al (2009) Estradiol is a potent protective, restorative, and trophic factor after brain injury. Semin Reprod Med 27(3):240–249PubMedCrossRefGoogle Scholar
  45. 45.
    Suzuki S, Brown CM, Wise PM (2009) Neuroprotective effects of estrogens following ischemic stroke. Front Neuroendocrinol 30(2):201–211PubMedCrossRefGoogle Scholar
  46. 46.
    Bourque M, Dluzen DE, Di Paolo T (2009) Neuroprotective actions of sex steroids in Parkinson’s disease. Front Neuroendocrinol 30(2):142–157PubMedCrossRefGoogle Scholar
  47. 47.
    Sribnick EA, Wingrave JM, Matzelle DD et al (2005) Estrogen attenuated markers of inflammation and decreased lesion volume in acute spinal cord injury in rats. J Neurosci Res 82(2):283–293PubMedCrossRefGoogle Scholar
  48. 48.
    Yune TY, Kim SJ, Lee SM et al (2004) Systemic administration of 17beta-estradiol reduces apoptotic cell death and improves functional recovery following traumatic spinal cord injury in rats. J Neurotrauma 21(3):293–306PubMedCrossRefGoogle Scholar
  49. 49.
    Chaovipoch P, Jelks KA, Gerhold LM et al (2006) 17beta-estradiol is protective in spinal cord injury in post- and pre-menopausal rats. J Neurotrauma 23(6):830–852PubMedCrossRefGoogle Scholar
  50. 50.
    Ritz MF, Hausmann ON (2008) Effect of 17beta-estradiol on functional outcome, release of cytokines, astrocyte reactivity and inflammatory spreading after spinal cord injury in male rats. Brain Res 1203:177–188PubMedCrossRefGoogle Scholar
  51. 51.
    Rahimi-Movaghar V, Saadat S, Vaccaro AR et al (2009) The efficacy of surgical decompression before 24 hours versus 24–72 hours in patients with spinal cord injury from T1 to L1–with specific consideration on ethics: a randomized controlled trial. Trials 10:77PubMedCrossRefGoogle Scholar
  52. 52.
    Quinn R (2005) Comparing rat’s to human’s age: how old is my rat in people years? Nutrition 21(6):775–777PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Supriti Samantaray
    • 1
  • Joshua A. Smith
    • 1
  • Arabinda Das
    • 1
  • Denise D. Matzelle
    • 1
  • Abhay K. Varma
    • 2
  • Swapan K. Ray
    • 3
  • Naren L. Banik
    • 1
    Email author
  1. 1.Division of Neurology, Department of NeurosciencesMedical University of South CarolinaCharlestonUSA
  2. 2.Division of Neurosurgery, Department of NeurosciencesMedical University of South CarolinaCharlestonUSA
  3. 3.Department of Pathology, Microbiology, and ImmunologyUniversity of South Carolina School of MedicineColumbiaUSA

Personalised recommendations