Systemic Administration of 17β-Estradiol Reduces Apoptotic Cell Death and Improves Functional Recovery following Traumatic Spinal Cord Injury in Rats

Abstract

Recent evidence indicates that estrogen exerts neuroprotective effects in both brain injury and neurodegenerative diseases. We examined the protective effect of estrogen on functional recovery after spinal cord injury (SCI) in rats. 17β-estradiol (3, 100, or 300 μg/kg) was administered intravenously 1-2 h prior to injury (pre-treatment), and animals were then subjected to a mild, weight-drop spinal cord contusion injury. Estradiol treatment significantly improved hind limb motor function as determined by the Basso-Beattie-Bresnahan (BBB) locomotor open field behavioral rating test. Fifteen to 30 days after SCI, BBB scores were significantly higher in estradiol-treated (100 μg/kg) rats when compared to vehicle-treated rats. Morphological analysis showed that lesion sizes increased progressively in either vehicle-treated or 17β-estradiol-treated spinal cords. However, in response to treatment with 17β-estradiol, the lesion size was significantly reduced 18-28 days after SCI when compared to vehicle-treated controls. Terminal deoxynucleotidyl transferase-mediated UTP nickend labeling (TUNEL) staining and DNA gel electrophoresis revealed that apoptotic cell death peaked 24-48 h after injury. Also, SCI induced a marked increase in activated caspase-3 in the spinal cord, evident by 4 h after injury. However, administration of 17β-estradiol significantly reduced the SCI-induced increase in apoptotic cell death and caspase-3 activity after SCI. Furthermore, 17β-estradiol significantly increased expression of the anti-apoptotic genes, bcl-2 and bcl-x, after SCI while expression of the pro-apoptotic genes, bad and bax, was not affected by drug treatment. Finally, intravenous administration of 17β-estradiol (100 μg/kg) immediately after injury (post-treatment) also significantly improved hind limb motor function 19-30 days after SCI compared to vehicle-treated controls. These data suggest that after SCI, 17 β-estradiol treatment improved functional recovery in the injured rat, in part, by reducing apoptotic cell death.