Combinación de estradiol y progesterona: un tratamiento potencialmente valioso para el ictus isquémico en humanos / Combined estradiol and progesterone: a potentially valuable therapeutic treatment for human ischemic stroke

ABSTRACT

Introduction: Ischemic stroke leads adult’s mortality and long-term disability. Thus, new therapeutic approaches are needed. Estradiol (E2) and progesterone (P4) protect a variety of neuronal cells under stroke-like conditions in vitro; and the rodent brain against injury in vivo when administered prior to the ischemic insult, namely middle cerebral artery occlusion (MCAO). But, their therapeutic value after MCAO has been hardly studied. Less is known when coadministered under this paradigm. E2 and P4 also protect the neuronal cell death in vitro from ischemic-like injury, by reducing apoptotic cell death and enhancing cell survival signals. Here, we assessed the effect of combined E2 and P4 treatment in rats after permanent MCAO (pMCAO), which best mimics human ischemic stroke, analyzing the phosphatidylinositol 3-kinase (PI3-K)/Akt/glycogen synthase kinase 3 (GSK3)/ß-catenin signal pathway and the activation status of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in the infarct core (i.e., the ipsilateral frontoparietal cortex, ipsi-Ctx). Materials and Methods: Age-matched male Wistar rats (n=48) underwent pMCAO or sham operation and received either vehicle (ethanol 1% in saline) or combined E2 and P4 (0.04 mg/kg and 4 mg/kg, respectively) treatment at 6, 24, and 48 hrs after surgery. All animals were sacrificed 6 hrs after the last treatment dose and ipsi-Ctx homogenates were analyzed by immunoblotting. Results: pMCAO downregulated the PI3-K/Akt/GSK3/ß-catenin survival pathway and activated the proapoptotic protein SAPK/JNK in the ipsi-Ctx, effects which were reversed by E2 and P4 coadministration. Conclusions: Our data show that combined E2 and P4 treatment exerts a neuroprotective effect against brain injury when administered after the ischemic insult, which is mediated by modification of the activity of PI3-K/Akt/GSK3/ß-catenin signal pathway and that of SAPK/JNK. Hence, we provide experimental evidence that combined E2 and P4 comprise a potentially valuable therapeutic treatment for human ischemic stroke (AU)