Figure 3.

Estrogen mechanisms of action that lead to neurotrophic and neuroprotective outcomes. Top, 17-β-Estradiol (E2) acting via a membrane-associated site (mER) activates a cascade required for multiple responses that lead to enhanced neural plasticity, morphogenesis, neurogenesis, and neural survival. The signaling sequence induced by E2 at the membrane site is as follows: (1) E2 binding to mER, (2) E2–mER complexes with p85 to activate PI3K, (3) activating calcium-independent PKC, (4) phosphorylating the L-type calcium channel, (5) inducing calcium influx, (6) activating calcium-dependent PKCs, (7) activating Src kinase, (8) activating the MEK/ERK1/2 pathway, (9) ERK translocates to the nucleus, (10) activating and phosphorylating CREB, (11) enhancing transcription of antiapoptotic genes Bcl-2 and Bcl-xl, which enhance mitochondrial vitality, and spinophilin, which encourages synaptic growth, (12) simultaneously, estrogen activation of PI3K leads to activation of Akt, which phosphorylates and inhibits the proapoptotic protein BAD. Middle, Estrogen-induced neuroprotective mechanisms converge on mitochondria. Estrogen-activated cellular signaling cascade promotes enhanced mitochondrial function, leading to increased calcium load tolerance, enhanced electron transport chain efficiency, and promotion of antioxidant defense mechanisms. These actions are mediated by the regulation of both nuclear and mitochondrial encoded genes initiated by the activation of second-messenger signaling cascades. Bottom, Conceptual schematic of NeuroSERM design and therapeutic use. Consistent with the healthy cell bias of estrogen benefit hypothesis, NeuroSERM or PhytoSERM molecules would be administered before neurodegenerative insult while neurons are still healthy. NeuroSERM exposure would lead to enhanced neural survival mechanisms, represented as mitochondria with Bcl-2 additions, that promote neural defense against neurodegenerative insults associated with age-associated diseases such as Alzheimer's and Parkinson's. Designer NeuroSERM molecules target the membrane site of estrogen action, whereas PhytoSERM molecules preferentially target estrogen receptor β. AMPAR, AMPA receptor; C, cytochrome oxidase; F₀, F₁, ATPase subunits; LTD, long-term depression; LTP, long-term potentiation; NAD, nicotinamide adenine dinucleotide; NADH, nicotinamide adenine dinucleotide; VDCC, voltage-dependent calcium channel.