Estrogen and progesterone attenuate glutamate neurotoxicity via regulation of EAAT3 and GLT-1 in a rat model of ischemic stroke

Objective(s): Glutamate is the most widespread neurotransmitter in the central nervous system and has several functions as a neuromodulator in the brain although in pathological conditions like ischemia it is excessively released causing cell death. Under physiological conditions, glutamate is rapidly scavenged from the synaptic cleft by excitatory amino-acid transporters (EAATs). An imbalance in glutamatergic neurotransmission could influence the expression of glutamate transporters and is a pathological feature in several neurological disorders. It has been shown that estrogen and progesterone act as neuroprotective agents after brain injury. This study aims to investigate the role of hormone therapy after middle cerebral artery occlusion (tMCAO) in the expression of GLT-1 and EAAT3 as glutamate transporters. Materials and Methods: Middle cerebral artery occlusion technique was performed in Wistar rats in order to induce focal cerebral ischemia. Estrogen, progesterone, and a combination of both hormones were injected subcutaneously in the early minutes of reperfusion. Sensorimotor functional tests were performed and infarct volume was calculated by TTC staining of brain section. Gene and protein expression of EAAT3 and GLT-1 were evaluated by RT-PCR, immunoblotting, and immunohistochemistry. Results: Behavioral scores were increased and infarct volume was reduced by hormone therapy. RTPCR, immunoblotting, and immunohistochemistry data showed that the expression of GLT-1 and EAAT3 increased after ischemia. Also, estrogen and progesterone treatment enhanced mRNA and protein expression levels of GLT-1 and EAAT3 compared with ischemia. Conclusion: Steroids may protect brain tissue against ischemia-induced tissue degeneration by decreasing extracellular glutamate levels through the induction of glutamate transporters.