Mitochondria play a central role in estrogen-induced neuroprotection.
Oxidative stress, bioenergetic impairment and mitochondrial failure have all been implicated in the etiology of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), as well as retinal degeneration in glaucoma and retinitis pigmentosa. Moreover, at least 75 debilitating, and often lethal, diseases are directly attributable to deletions or mutations in mitochondrial DNA, or in nuclear-encoded proteins destined for delivery to the mitochondria. Such widespread mitochondrial involvement in disease reflects the regulatory position mitochondrial failure plays in both acute necrotic cell death, and in the less catastrophic process of apoptosis. The potent feminizing hormone, 17 beta-estradiol (E2), has shown cytoprotective activities in a host of cell and animal models of stroke, myocardial infarct and neurodegenerative diseases. The discovery that 17alpha-estradiol, an isomer of E2, is equally as cytoprotective as E2 yet is >200-fold less active as a hormone, has permitted development of novel, more potent analogs where cytoprotection is independent of hormonal potency. Studies of structure-activity-relationships, glutathione interactions and mitochondrial function have led to a mechanistic model in which these steroidal phenols intercalate into cell membranes where they block lipid peroxidation reactions, and are in turn recycled via glutathione. Such a mechanism would be particularly germane in mitochondria where function is directly dependent on the impermeability of the inner membrane, and where glutathione levels are maintained at extraordinarily high 8-10mM concentrations. Indeed, the parental estrogens and novel analogs stabilize mitochondria under Ca(2+) loading otherwise sufficient to collapse membrane potential. The cytoprotective and mitoprotective potencies for 14 of these analogs are significantly correlated, suggesting that these compounds prevent cell death in large measure by maintaining functionally intact mitochondria. This therapeutic strategy is germane not only to sudden mitochondrial failure in acute circumstances, such as during a stroke or myocardial infarction, but also to gradual mitochondrial dysfunction associated with chronic degenerative disorders such as AD, PD and HD.
Simpkins
James W
JW
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76102, USA. jsimpkin@hsc.unt.edu
Wang
Jian
J
Wang
Xiaofei
X
Perez
Evelyn
E
Prokai
Laszlo
L
Dykens
James A
JA
D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D004967:Estrogens / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D028361:Mitochondrial Diseases / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D009422:Nervous System Diseases / Q000188:drug therapy / Q000209:etiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
D004967:Estrogens; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D002118:Calcium