Estrogen replacement therapy (ERT) engenders much debate since several studies contradict its efficacy as a palliative therapy for cognitive decline and neurodegenerative diseases. Signaling transduction pathways alter brain cell activity, survival, and morphology by facilitating transcription factor activation and protein production. The steroidal hormone estrogen and the anti-depressant drug lithium can interact also through these signaling transduction pathways resulting in transcription factor activation. The transcription factor cAMP response element binding protein (CREB) is affected by both estrogen and lithium, and CREB regulates genes involved in learning, memory and neuronal survival. CREB is activated upon phosphorylation at serine 133 by protein kinases and, estrogen and its receptors (ER) facilitate this phosphorylation. Glycogen synthase kinase-3beta (GSK-3beta) attenuates CREB’s transcriptional properties via subsequent phosphorylation of its serine 129, and lithium is known as a negative regulator of GSK-3beta, thus facilitating CREB response element binding. Interestingly, ERalpha function and DNA-binding properties are facilitated by GSK-3beta. In this review we include protein modeling depicting the interaction of CREB/GSK-3beta and ERalpha/GSK-3beta using I-TASSER and PatchDock web servers. Understanding the molecular pathways of estrogen will assist in identifying a palliative therapy for menopause-related dementia, and lithium may serve this purpose by acting as a selective estrogen-mediated signaling modulator.
estrogen; lithium; hormone therapy; brain
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