17β-Estradiol Inhibits Apoptotic Cell Death of Oligodendrocytes by Inhibiting RhoA-JNK3 Activation after Spinal Cord Injury

A delayed oligodendrocyte cell death after spinal cord injury (SCI) contributes to chronic demyelination of spared axons, leading to a permanent neurological deficit. Therefore, therapeutic approaches to prevent oligodendrocyte cell death after SCI should be considered. Estrogens are well known to have a broad neuroprotective effect, but the protective effect of estrogens on oligodendrocytes after injury is largely unknown. Here, we demonstrated that 17 beta-estradiol attenuates apoptosis of oligodendrocytes by inhibiting RhoA and c-Jun-N-terminal kinase activation after SCI. Estrogen receptor (ER)-alpha and -beta were expressed in oligodendrocytes of the spinal cord, and 17 beta-estradiol treatment significantly inhibited oligodendrocyte cell death at 7 d after injury as compared with vehicle (cyclodextrin) control. 17 beta-Estradiol also attenuated caspase-3 and -9 activation at 7 d and reduced the loss of axons from progressive degeneration. In addition, 17 beta-estradiol inhibited RhoA and JNK3 activation, which were activated and peaked at 3 and/or 5 d after injury. Furthermore, administration of Rho inhibitor, PEP-1-C3 exoenzyme, inhibited RhoA and JNK3 activation, and decreased phosphorylated c-Jun level at 5 d after injury. Additionally, the attenuation of RhoA and JNK3 activation as well as oligodendrocyte cell death by 17 beta-estradiol was reversed by ER antagonist, ICI182780. Our results thus indicate that 17 beta-estradiol treatment improves functional recovery after SCI in part by reducing oligodendrocyte cell death via inhibition of RhoA and JNK3 activation, which were ER dependent. Furthermore, improvement of hindlimb motor function by posttreatment of 17 beta-estradiol suggests its potential as a therapeutic agent for SCI patients. (Endocrinology 153: 3815-3827, 2012)