Skip to main content
SpringerLink
Log in

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

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Dumont RJ, Verma S, Okonkwo DO et al (2001) Acute spinal cord injury, part II: contemporary pharmacotherapy. Clin Neuropharmacol 24(5):265–279

    Article  PubMed  CAS  Google Scholar 

  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 947

    CAS  Google Scholar 

  3. Bracken MB, Collins WF, Freeman DF et al (1984) Efficacy of methylprednisolone in acute spinal cord injury. JAMA 251(1):45–52

    Article  PubMed  CAS  Google Scholar 

  4. Hurlbert RJ (2000) Methylprednisolone for acute spinal cord injury: an inappropriate standard of care. J Neurosurg 93(1 Suppl):1–7

    PubMed  CAS  Google Scholar 

  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):478–482

    Article  PubMed  CAS  Google Scholar 

  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):370–377

    Article  PubMed  CAS  Google Scholar 

  7. Young W (1985) The role of calcium in spinal cord injury. Cent Nerv Syst Trauma 2(2):109–114

    PubMed  CAS  Google Scholar 

  8. Happel RD, Smith KP, Banik NL et al (1981) Ca2+-accumulation in experimental spinal cord trauma. Brain Res 211(2):476–479

    Article  PubMed  CAS  Google Scholar 

  9. Stokes BT, Fox P, Hollinden G (1983) Extracellular calcium activity in the injured spinal cord. Exp Neurol 80(3):561–572

    Article  PubMed  CAS  Google Scholar 

  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):1191–1198

    Article  PubMed  CAS  Google Scholar 

  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):1592–1600

    Article  PubMed  CAS  Google Scholar 

  12. Lewen A, Matz P, Chan PH (2000) Free radical pathways in CNS injury. J Neurotrauma 17(10):871–890

    Article  PubMed  CAS  Google Scholar 

  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):369–415

    Article  PubMed  CAS  Google Scholar 

  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):3067–3070

    Article  PubMed  CAS  Google Scholar 

  15. Carlson SL, Parrish ME, Springer JE et al (1998) Acute inflammatory response in spinal cord following impact injury. Exp Neurol 151(1):77–88

    Article  PubMed  CAS  Google Scholar 

  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):443–449

    Article  PubMed  CAS  Google Scholar 

  17. Barut S, Canbolat A, Bilge T et al (1993) Lipid peroxidation in experimental spinal cord injury: time-level relationship. Neurosurg Rev 16(1):53–59

    Article  PubMed  CAS  Google Scholar 

  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):95–104

    Article  PubMed  CAS  Google Scholar 

  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):179–188

    Article  PubMed  CAS  Google Scholar 

  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):1116–1119

    PubMed  CAS  Google Scholar 

  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):2210–2216

    Article  PubMed  CAS  Google Scholar 

  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):173–189

    Article  PubMed  CAS  Google Scholar 

  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):2437–2442

    Article  PubMed  CAS  Google Scholar 

  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):489–496

    Article  PubMed  CAS  Google Scholar 

  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):53–72

    Article  PubMed  CAS  Google Scholar 

  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):10191–10198

    Article  PubMed  CAS  Google Scholar 

  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):633–643

    PubMed  CAS  Google Scholar 

  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):683–690

    PubMed  CAS  Google Scholar 

  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 159–160

    Article  PubMed  CAS  Google Scholar 

  30. Sribnick EA, Ray SK, Banik NL (2004) Estrogen as a multi-active neuroprotective agent in traumatic injuries. Neurochem Res 29(11):2007–2014

    Article  PubMed  CAS  Google Scholar 

  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 1199:90–94

    Article  PubMed  CAS  Google Scholar 

  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):8867–8872

    Article  PubMed  CAS  Google Scholar 

  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):123–136

    Article  PubMed  CAS  Google Scholar 

  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 1276:159–170

    Article  PubMed  CAS  Google Scholar 

  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):688–696

    Article  PubMed  CAS  Google Scholar 

  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):1738–1750

    PubMed  CAS  Google Scholar 

  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):1064–1075

    Article  PubMed  CAS  Google Scholar 

  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 Neurotrauma

  39. Swartz KR, Fee DB, Joy KM et al (2007) Gender differences in spinal cord injury are not estrogen-dependent. J Neurotrauma 24(3):473–480

    Article  PubMed  Google Scholar 

  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):149–159

    PubMed  Google Scholar 

  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):348–357

    Article  PubMed  CAS  Google Scholar 

  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):305–311

    Article  PubMed  CAS  Google Scholar 

  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 1199:86–89

    Article  PubMed  CAS  Google Scholar 

  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):240–249

    Article  PubMed  CAS  Google Scholar 

  45. Suzuki S, Brown CM, Wise PM (2009) Neuroprotective effects of estrogens following ischemic stroke. Front Neuroendocrinol 30(2):201–211

    Article  PubMed  CAS  Google Scholar 

  46. Bourque M, Dluzen DE, Di Paolo T (2009) Neuroprotective actions of sex steroids in Parkinson’s disease. Front Neuroendocrinol 30(2):142–157

    Article  PubMed  CAS  Google Scholar 

  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):283–293

    Article  PubMed  CAS  Google Scholar 

  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):293–306

    Article  PubMed  Google Scholar 

  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):830–852

    Article  PubMed  Google Scholar 

  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 1203:177–188

    Article  PubMed  CAS  Google Scholar 

  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 10:77

    Article  PubMed  Google Scholar 

  52. Quinn R (2005) Comparing rat’s to human’s age: how old is my rat in people years? Nutrition 21(6):775–777

    Article  PubMed  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

  1. Division of Neurology, Department of Neurosciences, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 309, Clinical Sciences Building, P.O. Box 250606, Charleston, SC, 29425, USA

    Supriti Samantaray, Joshua A. Smith, Arabinda Das, Denise D. Matzelle & Naren L. Banik

  2. Division of Neurosurgery, Department of Neurosciences, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 428 CSB, P.O. Box 250616, Charleston, SC, 29425, USA

    Abhay K. Varma

  3. Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC, 29209, USA

    Swapan K. Ray

Authors
  1. Supriti Samantaray
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joshua A. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arabinda Das
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Denise D. Matzelle
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Abhay K. Varma
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Swapan K. Ray
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Naren L. Banik
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Naren L. Banik.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Samantaray, S., Smith, J.A., Das, A. et al. 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. Neurochem Res 36, 1809–1816 (2011). https://doi.org/10.1007/s11064-011-0498-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-011-0498-y

Keywords

Search

Navigation