Translational Significance of Selective Estrogen Receptor Modulators in Psychiatric Disorders

Figure 1

Possible signaling mechanisms of SERM actions in neurocognition and neuroprotection. Over the last few years, others and we have shown that SERMs can mediate their actions by initiating genomic (gene expression) and/or nongenomic signaling that involve kinases and phosphatases. In CNS tissues, SERMs can bind and activate both classical estrogen receptors-α and β (ERα or ERβ) as well as nonclassical transmembrane G protein-coupled ER (GPER1). Via agonist action at GPER1, SERMs can activate the PI3K/Akt and MAPK/ERK pathways (Figure 1, box 1), which have been shown to be involved in neuroprotection and reduction of oxidative stress and neuronal cell death by increasing the expression of antioxidant enzymes (CAT, SOD, GPx, and eNOS), Bcl2, and other trophic factors. Via agonist action at the classical ERα or ERβ, SERMs can activate gene expression/genomic signaling (Figure 1, box 2) of various growth factors and proteins involved in synaptic plasticity, neurogenesis, memory, and cognition. SERMs can also enhance interaction of ERα or ERβ with MNAR/PELP1, a scaffold/coactivator protein highly expressed in neurons and astrocytes [165,166]. The resultant ER-MNAR/PELP1 complex can then initiate nongenomic signaling by activating the PI3K/Akt, MAPK/ERK, and Wnt/β-catenin/GSK3β signaling pathways (Figure 1, box 3). These pathways have been shown to regulate neurogenesis, synaptogenesis, and cognitive behaviors in the normal and model animals of diseases. SERMs can reduce brain inflammation by acting on astroglia via ERα or ERβ. They can reduce microglia proliferation (Figure 1, box 4) as well as production of inflammatory cytokines and chemokines including IL-1, IL-6, and TNFα via inhibition of nuclear factor-kappa-B (Nf-KB) transactivation (Figure 1, box 5). Inhibition of this pathway has been shown to induce neuroprotection and reduce neuronal cell death in various cellular and animal models of brain injury. Red arrows indicate increase (upward) or decrease (downward) in the magnitude of response by SERMs.