Astrocyte-derived growth factors and estrogen neuroprotection: Role of transforming growth factor-α in estrogen-induced upregulation of glutamate transporters in astrocytes

• Estrogen upregulates glutamate transporter GLT-1 expression in astrocytes.
• Estrogen increases GLT-1 expression via GPR30 using the NF-κB and CREB pathways.
• TGF-α mediates estrogen-induced upregulation of GLT-1 and GLAST in astrocytes.
• Tamoxifen, a selective estrogen receptor modulator, enhances GLT-1 expression via NF-κB and CREB.
• Estrogen and tamoxifen attenuate manganese-induced reduction of GLT-1 expression.

Extensive studies from the past decade have completely revolutionized our understanding about the role of astrocytes in the brain from merely supportive cells to an active role in various physiological functions including synaptic transmission via cross-talk with neurons and neuroprotection via releasing neurotrophic factors. Particularly, numerous studies have reported that astrocytes mediate the neuroprotective effects of 17β-estradiol (E2) and selective estrogen receptor modulators (SERMs) in various clinical and experimental models of neuronal injury. Astrocytes contain two main glutamate transporters, glutamate aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1), that play a key role in preventing excitotoxic neuronal death, a process associated with most neurodegenerative diseases. E2 has been shown to increase expression of both GLAST and GLT-1 mRNA and protein and glutamate uptake in astrocytes. Growth factors such as transforming growth factor-α (TGF-α) appear to mediate E2-induced enhancement of these transporters. These findings suggest that E2 exerts neuroprotection against excitotoxic neuronal injuries, at least in part, by enhancing astrocytic glutamate transporter levels and function. Therefore, the present review will discuss proposed mechanisms involved in astrocyte-mediated E2 neuroprotection, with a focus on glutamate transporters.