Neuroprotection selective Estrogen or Genistein in Spinal Cord Injury

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DESCRIPTION (provided by applicant): With the continuing controversy over the clinical efficiency and use of methylprednisolone after spinal cord injury (SCI), interest is renewed is discovering new therapeutic targets for neuroprotection. Recently, 17¿-estradiol was found to be beneficial in SCI which suggests that estrogen receptors (ERs) could be therapeutic targets. Estrogen binds with equal affinity to two subtypes of the ER, the classical ERa and the more recently discovered ERa. However, which subtype is necessary for neuroprotective effects remains controversial and has not been investigated in SCI. Also, no subtype selective antagonists are available to tease apart specific effects. A clue that selective ERp activation may confer protection is SCI comes from studies of plant-derived estrogens, or phytoestrogens. Genistein, a phytoestrogen from soy and a preferential ERp agonist, dose-dependently confers protection in models of neuronal injury and cardiac ischemia. We hypothesize that selective activation of the ER¿ by genistein will produce significant protection in SCI. We will test this hypothesis, in aim 1, by administering either a low, medium or high dose of genistein 30 minutes after a moderate thoracic spinal cord injury in rats. An additional group will receive co-administration of genistein and the ER antagonist ICI 182,780. At seven days post-SCI, we will evaluate acute injury markers including: cell death, ER expression, and expression of apoptosis related proteins bcl-2, bax, and activated caspase-3. In aim 2, we will administer genistein with and without the ER antagonist ICI 182,780 and evaluate sub-acute markers of secondary injury including locomotor impairment, white matter sparing, lesion volume, and lower urinary tract function. The experiments in this proposal explore the clinically relevant possibility that preferentially targeting the non-feminizing ER¿ is neuroprotective in SCI by evaluating the neuroprotective potential of a natural, plant- derived estrogen, genistein.