Mitochondria as therapeutic targets of estrogen action in the central nervous system.
Neuron viability and defense against neurodegenerative disease can be achieved by targeting mitochondrial function to reduce oxidative stress, increase mitochondrial defense mechanisms, or promote energetic metabolism and Ca2+ homeostasis. Exposure to estrogen prior to contact with toxic agents can protect neurons against a wide range of degenerative insults. The proactive defense state induced by estrogen is mediated by complex mechanisms ranging from chemical to biochemical to genomic but which converge upon regulation of mitochondria function. Estrogen preserves ATP levels via increased/enhanced oxidative phosphorylation and reduced ATPase activity thereby increasing mitochondrial respiration efficiency, resulting in a lower oxidative load. In addition, estrogen increases antiapoptotic proteins, Bcl-2 and Bcl-xL, which prevents activation of the permeability transition pore protecting against estrogen-induced increase in mitochondrial Ca2+ sequestration. These effects are likely to be enhanced by antioxidant effects of estrogen, preventing the initiation of the deleterious "mitochondrial spiral". The extent to which each of these mechanisms contribute to the overall proactive defense state induced by estrogen remains to be determined. However, each aspect of the cascade appears to make a significant if not obligatory impact on the neuroprotective effects of estrogens. Moreover each component of the cascade is required for estrogen regulation of mitochondrial function. Mechanisms of estrogen action and results of the clinical efficacy of estrogen therapy for prevention or treatment of Alzheimer's disease are considered in the context of clinical use of estrogen therapy and the design of brain selective estrogens or NeuroSERMs.
Nilsen
Jon
J
Department of Molecular Pharmacology and Toxicology, University of Southern California, Pharmaceutical Sciences Center, Los Angeles 90033, USA. jnilsen@usc.edu
Brinton
Roberta Diaz
RD
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004967:Estrogens / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism
D004967:Estrogens; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2