Molecular and Chemical Neuropathology

, Volume 31, Issue 1, pp 1–11

Progesterone protects against lipid peroxidation following traumatic brain injury in rats

  • Robin L. Roof
  • Stuart W. Hoffman
  • Donald G. Stein
Original Articles

Abstract

The gonadal hormone, progesterone, has been shown to have neuroprotective effects in injured nervous system, including the severity of postinjury cerebral edema. Progesterone’s attenuation of edema is accompanied by a sparing of neurons from secondary neuronal death and with improvements in cognitive outcome. In addition, we recently reported that postinjury blood-brain barrier (BBB) leakage, as measured by albumin immunostaining, was significantly lower in progesteronetreated than in nontreated rats, supporting a possible protective action of progesterone on the BBB. Because lipid membrane peroxidation is a major contributor to BBB breakdown, we hypothesized that progesterone limits this free radical-induced damage. An antioxidant action, neuroprotective in itself, would also account for progesterone’s effects on the BBB, edema, and cell survival after traumatic brain injury. To test progesterone’s possible antiperoxidation ef-fect, we compared brain levels of 8-isoprostaglandin F (8-isoPGF), a marker of lipid peroxidation, 24, 48, and 72 h after cortical contusion in male rats treated with either progesterone or the oil vehicle. The brains of progesteronetreated rats contained approximately one-third of the 8-isoPGF found in oil-treated rats. These data suggest progesterone has antioxidant effects and support its potential as a treatment for brain injury.

Index Entries

8-isoPGF free radicals antioxidant contusion steroid neuroprotection blood-brain barrier immunocytochemistry 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Audrus K. L., Guillot F. L., and Braughler J. M. (1991) Evidence for 21-aminosteroid association with the hydrophilic domains of brain microvessel endothelial cells.Free Radical Biol Med. 11, 361–371.CrossRefGoogle Scholar
  2. Behl C., Widmann M., Trapp T. and Holsboer F. (1995) 17-beta estradiol protects neurons from oxidative stress-induced cell death in vitro.Biochem. Biophys. Res. Commun. 216, 473–482.PubMedCrossRefGoogle Scholar
  3. Belelli D., Bolger M. B. and Gee K. W. (1989) Anticonvulsant profile of the progesterone metabolite 5α-pregnane.-3α-ol-20-one.Eur. J. Pharm. 166, 325–329.CrossRefGoogle Scholar
  4. Betz A. L. and Coester H. C. (1990) Effects of steroids on edema and sodium uptake of the brain during focal ischemia in rats.Stroke 21(8), 199–204.Google Scholar
  5. Betz A. L., Iannotti F., and Hoff J. T. (1989) Brain edema: A classification based on blood-brain barrier integrity.Cerebrovas. Brain Metab. Rev. 1, 133–154.Google Scholar
  6. Braughler J. M. and Hall E. D. (1989) Central nervous system trauma and stroke. I. Biochemical considerations for oxygen radical formation and lipid peroxidation.Free Radical Biol. Med. 6, 289–301.CrossRefGoogle Scholar
  7. Braughler J. M., Pregenzer J. F. and Chase R. L. (1989) The 21-aminosteroids: Potent inhibitors of lipid peroxidation for the treatment of central nervous system trauma and ischemia.Drugs Future 14, 143–152.Google Scholar
  8. Cervos-Navarro J. and Lafuente J. V. (1991) Traumatic brain injuries: structural changes.J. Neurol. Sci. 103, S3-S14.PubMedCrossRefGoogle Scholar
  9. Chan P. H., Longar S., and Fishman R. A. (1985) Oxygen, free radicals: potential edema mediators in brain injury, inBrain Edema, Springer-Verlag, Tokyo., pp. 317–323.Google Scholar
  10. Demopoulos H. B., Flamm E. S., Pietronigro D. D. and Seligman M. L. (1980) The free radical pathology and the microcirculation in the major central nervous system disorders.Acta Physiol. Scand. 492 (Suppl), 91–119.Google Scholar
  11. Demopoulos H. B., Flamm E. S., Seligman M. L., Pietronigro J., Tomasula J. and DeCrescito V. (1982) Further studies on free-radical pathology in the major central nervous system disorders: effect of very high doses of methylprednisolone on the functional outcome, morphology, and chemistry of experimental spinal cord impact injury.Can. J. Physiol. Pharm. 60, 1415–1424.Google Scholar
  12. Duvdevani R., Roof R. L., Fulop Z., Hoffman S. W. and Stein D. G. (1995) Blood-brain barrier breakdown and edema formation following frontal cortical contusion—Does hormonal status play a role?J. Neurotrauma 12, 65–75.PubMedGoogle Scholar
  13. Faden A. I., Demediuk P., Painter S. S., and Vink R. (1989) The role of excitatory amino acids and NMDA receptors in traumatic brain injury.Science 244, 798–800.PubMedCrossRefGoogle Scholar
  14. Frye C. A. (1995) The neurosteroid 3 alpha, 5 alpha-THP has antiseizure and possible neuroprotective effects in an animal model of epilepsy.Brain Res. 696, 1–2.CrossRefGoogle Scholar
  15. Gee K. W., Bolger M. B., Brinton R. E., Coirini H. and McEwen B. S. (1988) Steroid modulation of the chloride ionophore in rat brain: structure-activity requirements, regional dependence and mechanism of action.J. Pharmacol. Exp. Ther. 246, 803–812.PubMedGoogle Scholar
  16. Goodman Y., Bruce A. J., Bin C. and Mattson M. P. (1996) Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid β-peptide toxicity in hippocampal neurons.J. Neurochem. 66, 1836–1944.PubMedCrossRefGoogle Scholar
  17. Greenwood J. (1991) Mechanisms of blood-brain barrier breakdown.Neuroradiology 33, 95–100.PubMedCrossRefGoogle Scholar
  18. Hall E. D. (1985) High-dose glucocorticoid treatment improves neurological recovery in head-injured mice.J. Neurosurg. 62, 882–887.PubMedGoogle Scholar
  19. Hall E. D. (1989) Free radicals and CNS injury.Crit. Care Clin. 5, 793–805.PubMedGoogle Scholar
  20. Hall E. D. (1993) Lipid antioxidants in acute central nervous system injury.Ann. Emerg. Med. 22, 1022–1027.PubMedCrossRefGoogle Scholar
  21. Hall E. D. and Braughler J. M. (1989) Central nervous system trauma and stroke. II. Physiological and pharmacological evidence for involvement of oxygen radicals and lipid peroxidation.Free Radical Biol. Med. 6, 303–313.CrossRefGoogle Scholar
  22. Hall E. D. and Braughler J. M. (1993) Free radicals in CNS injury, inMolecular and Cellular Approaches to the Treatment of Neurological Disease, Raven, New York, pp. 81–105.Google Scholar
  23. Hall E. D. and Travis M. A. (1988) Inhibition of arachidonic acid-induced vasogenic brain edema by the non-glucocorticoid 21-aminosteroid U74006F.Brain Res. 451, 350–352.PubMedCrossRefGoogle Scholar
  24. Hall E. D., Yonkers P. A., McCall J. M. and Braughler J. M. (1988) Effect of the 21-aminosteroid U-74006F on experimental head injury in mice.J. Neurosurg. 68, 456–461.PubMedGoogle Scholar
  25. Hall E. D., Andrus P. K. and Yonkers P. A. (1993) Brain hydroxyl radical generation in acute experimental head injury.J. Neurochem. 60, 588–594.PubMedCrossRefGoogle Scholar
  26. Hall E. D., McCall J. M. and Means E. D. (1994) Therapeutic potential of the lazaroids (21-aminosteroids) in acute central nervous system trauma, ischemia and subarachnoid hemorrhage.Adv. Pharmacol. 28, 221–268.PubMedGoogle Scholar
  27. Harrison N. L., Majewska M. D., Harrington J. W. and Barker J. L. (1987) Structureactivity relationship for steroid interaction with the gamma-aminobutyric acid-A receptor complex.J. Pharmacol. Exp. Ther. 241, 346–352.PubMedGoogle Scholar
  28. Hoffman S. W., Roff R. L. and Stein D. G. (1996) A reliable and sensitive enzyme immunoassay method for measuring 8-isoprostaglandin F2α: A marker for lipid peroxidation after experimental brain injury.J. Neurosci. Methods 68, 133–136.PubMedCrossRefGoogle Scholar
  29. Hogskilde S., Wagner J., Carl P., Anker N., Angelo H. R. and Sorensen M. B. (1988) Anticonvulsant properties of pregnanolone emulsion compared with althesin and theipentone in mice.Br. J. Anesthesiol. 61, 462–467.CrossRefGoogle Scholar
  30. Kokate T. G., Svensson B. E. and Rogawski M. A. (1994) Anticonvulsant activity of neurosteroids: Correlation with γ-aminobutyric acid-evoked chloride current potentiation.J. Pharmacol. Exp. Ther. 270, 1223–1229.PubMedGoogle Scholar
  31. Kontos H. A. and Povlishock J. T. (1986) Oxygen radicals in brain injury.CNS Trauma 3(4), 257–263.Google Scholar
  32. Kontos H. A., Wei E. P., Povlishock J. T., Dietrich W. D., Magiera C. J. and Ellis E. F. (1980) Cerebral arteriolar damage by arachidonic acid and prostaglandin G2.Science 209, 1242–1244.PubMedCrossRefGoogle Scholar
  33. Kukreja R. C., Kontos H. A., Hess M. L. and Ellis E. F. (1986) PGH synthase and lipoxygenase generate superoxide in the presence of NADH and NADPH.Circ. Res. 59, 612–619.PubMedGoogle Scholar
  34. Majewska M. D., Harrison N. L., Schwartz R. D., Barker J. L. and Paul S. M. (1986) Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor.Science 232, 1004–1007.PubMedCrossRefGoogle Scholar
  35. McIntosh T. K. (1994) Neurochemical sequelae of traumatic brain injury: Therapeutic implications.Cerebrovasc. Brain Metab. Rev. 6, 109–162.PubMedGoogle Scholar
  36. McIntosh T. K., Vink R., Soares H., Hayes R. and Simon R. (1990) Effects of noncompetitive blockade ofN-methyl-d-aspartate receptors on the neurochemical sequelae of experimental brain injury.J. Neurochem. 55, 1170–1179.PubMedCrossRefGoogle Scholar
  37. Morrow J., Hill K., Burk R., Nammour T., Badr K. and Roberts L. (1990) A series of prostaglandin F2-like compounds are produced in vivo in humans by a noncyclooxygenase, free radical-catalyzed mechanism.Proc. Natl. Acad. Sci. USA 87, 9383–9387.PubMedCrossRefGoogle Scholar
  38. Olson J. J., Poor M. M. and Beck D. W. (1988) Methylprednisolone reduces the bulk flow of water across an in-vitro blood-brain barrier.Brain Res. 439, 259–265.PubMedCrossRefGoogle Scholar
  39. Panter S. S. and Faden A. I. (1992) Pretreatment with NMDA antagonists limits release of excitatory amino acids following traumatic brain injury.Neurosci. Lett. 136, 165–168.PubMedCrossRefGoogle Scholar
  40. Roof R. L., Duvdevani R. and Stein D. G. (1992) Progesterone treatment attenuates brain edema following contusion injury in male and female rats.Restor. Neurol. Neurosci. 4, 425–427.Google Scholar
  41. Roof R. L., Duvdevani R. and Stein D. G. (1993) Gender influences outcome of brain injury: Progesterone plays protective role.Brain Res. 607, 333–336.PubMedCrossRefGoogle Scholar
  42. Roof R. L., Braswell L. K., Duvdevani R. and Stein D. G. (1994) Progesterone facilitates cognitive recovery and reduces secondary neuronal loss following cortical contusion injury in male rats.Exp. Neurol. 129, 64–69.PubMedCrossRefGoogle Scholar
  43. Roof R. L., Duvdevani R., Heyburn J. W. and Stein D. G. (1996a) Progesterone rapidly decreases brain edema: Treatment delayed up to 24 hours is still effective.Exp. Neurol. 138, 246–251.PubMedCrossRefGoogle Scholar
  44. Roof R. L., Duvdevani R., Heyburn J. W. and Stein D. G. (1996b) Progesterone improves blood-brain barrier integrity after traumatic brain injury.J. Neurotrauma, submitted.Google Scholar
  45. Seligman M. L., Mitamura L. J., Shera N. and Demopoulos H. B. (1979) Corticosteroid (methylprednisolone) modulation of photoperoxidation by UV light in Liposomes.Photochem. Photobiol. 29, 549–558.CrossRefGoogle Scholar
  46. Shimamura K., Sugino N., Yoshida Y., Nakamura Y., Ogino K. and Kato H. (1995) Changes in lipid peroxide and antioxidant enzyme activities in corpora lutea during pseudopregnancy in rats.J. Reprod. Fertil. 105, 253–257.PubMedCrossRefGoogle Scholar
  47. Smith S. S. (1991) Progesterone administration attenuates excitatory amino acid responses of cerebellar Purkinje cells.Neuroscience 42, 309–320.PubMedCrossRefGoogle Scholar
  48. Smith S. L., Adrus P. K., Zhang J.-R. and Hall E. D. (1994) Direct measurement of hydroxyl radicals, lipid peroxidation, and blood-brain barrier disruption following unilateral cortical impact head injury in the rat.J. Neurotrauma 11, 393–404.PubMedCrossRefGoogle Scholar
  49. Stein D. G. and Roof R. L. (1996) Mechanisms of injury and repair in traumatic brain injury inImaging in Neuroglic Rehabilitation. Demos Vermande, New York, pp. 79–90.Google Scholar
  50. Stein D. G., Halks-Miller M., and Hoffman S. W. (1991) Intracerebral administration of Alpha-Tocopherol-containing liposomes facilitates behavioral recovery in rats with bilateral lesions of the frontal cortex.J. Neurotrauma 8(4), 281–292.PubMedCrossRefGoogle Scholar
  51. Wahl M., Schilling L., Unterberg A., and Baethmann A. (1993) Mediators of vascular and parenchymal mechanisms in secondary brain damage.Acta Neurochir. Suppl. (Wien) 57, 64–72.Google Scholar
  52. Walsh S. W. (1994) Lipid peroxidation in pregnancy.Hypertens. Pregnancy 13(1), 1–32.CrossRefGoogle Scholar
  53. Wei E., Kontos H., Dietrich W., Povlishock J. and Ellis E. (1981) Inhibition by free radical scavengers and cyclooxygenase inhibitors of pial arteriolar abnormalities from concussive brain injury in cats.Circ. Res. 48, 95–103.PubMedGoogle Scholar
  54. Whiting K. P., Brain P. F. and Restall C. J. (1995) Steroid hormone induced effects on membrane fluidity.Biochem Soc. Trans. 23, 4385.Google Scholar
  55. Yonkers P. A., Hall E. D., Taylor B., Sun F. F., Guido D. M. and Mathews, W. R. (1993) Mechanism of action of methylprednisolone in acute spinal cord injury: inhibition of phospholipase A2 vs. inhibition of lipid peroxidation.J. Neurotrauma 10, S92.Google Scholar
  56. Zuccarello M. and Anderson D. K. (1989) Protective effect of a 21-aminosteroid on the blood-brain barrier following subarachnoid hemorrhage in rats.Stroke 20, 367–371.PubMedGoogle Scholar

Copyright information

© Humana Press Inc 1997

Authors and Affiliations

  • Robin L. Roof
    • 1
  • Stuart W. Hoffman
    • 2
  • Donald G. Stein
    • 3
  1. 1.Department of Psychology and Neuroscience ProgramTexas Christian UniversityFort Worth
  2. 2.Department of Pharmacology/Toxicology, Medical College of VirginiaVirginia Commonwealth UniversityRichmond
  3. 3.Department of NeurologyEmory UniversityAtlanta

Personalised recommendations