Membrane fluidity effects of estratrienes
Introduction
Neurodegenerative diseases, such as Alzheimer’s disease (AD), are associated with neuronal death or degeneration 31, 36, 39. Estrogens, or more broadly, estratrienes, exert potent neuroprotective activity 3, 11, 12, 18, 37, 38. These protective functions result from estrogen receptor (ER) and/or non-ER mediated processes. Estrogen interacts with ERs, initiating a cascade of events, resulting in increased specific protein synthesis. This, in turn, aids the cell’s response to toxic insults. It has also been noted that there are early effects that aid in cytoprotection which could not be accounted via new protein synthesis. Cytoprotective effects can also be observed in cells not containing the classical ER 25, 26, 29. These facts imply non-genomic roles for estrogen cytoprotection.
The estratrienes’ lipophilic nature encourages accumulation or partitioning within hydrophobic environments such as the plasma membrane. It is likely the accumulation of estratrienes in the cell membrane will alter lipid packing, leading to consequences on cellular functions. A global approach accounting for differences in lipid packing is to address the geometries of lipid tail groups. Terms such as liquid crystalline, fluid phase, gel, or ordered state are used to describe lipid ordering in model membranes 32, 40, 42, 43. These distinct arrangements behave differently in regard to transport of compounds 30, 33. Other biological processes (i.e., cell signalling), which must occur through the membrane, would also be susceptible to alterations in lipid packing.
The goal of these studies was to evaluate the ability of estratrienes to influence lipid packing. Liposome fusion was used as a model of membrane interaction and a second model addressed alterations in membrane fluidity using diphenylhexatriene (DPH). A second goal of the study was to address whether lipid interactions could be altered via rational design of estratrienes. The investigational results indicated estratrienes affect membrane packing in liposome and plasma membranes and that the 17th carbon of estratrienes can be used as a position for pendant modification that impacts the membrane interactions. Although a direct correlation between alterations in membrane packing and cellular protection has not been proven at this time, there was a demonstrable cellular protection with the estratriene nucleus which could be potentiated by chemical modification.
Section snippets
Chemicals
Dioleoyl phosphatidylethanolamine (PE), L-α-phosphatidylserine (PS), L-α-phosphatidylcholine (egg PC), N-(7-nitro-2,1,3,benzoxadiazol-4-yl)-phosphatidylethanolamine (NBD-PE), and N-(lissamine rhodamine-sulfonyl) phosphatidylethanolamine (Rh-PE) were purchased from Avanti Polar Lipids (Alabaster, AL, USA). Cholesteryl hemisuccinate (CHEMS) and DPH were purchased from Aldrich Chemicals (St. Louis, MO, USA). HT-22 cells were a gift from David Schulbert, Salk Institute. The estrogen building block
Results
The working hypothesis was estratrienes elicit a portion of their biological effects at the plasma membrane. If this tenant is correct, estratrienes with an increased tendency to partition into the membrane are expected to potentiate the effect. In these studies we used five commercially available compounds and synthesized a new compound, 17 β-estradiol octyl ether (BEOE) (Fig. 2). BEOE was expected to demonstrate a greater membrane effect due to its aliphatic anchor placed at the 17th
Discussion
Recent examples 15, 20, 34, 35, 36 of the clinical efficacy of estrogen in AD has spurred researchers to determine its mechanism of action. Estrogen has been shown to protect cultured hippocampal neurons against glutamate [4], hypoglycemia [37], and oxidative stress [4].
Most steroid hormones act via a long-recognized traditional route: they migrate through the plasma lipid membrane and bind to intracellular receptors, which are relatively specific for each steroid class. Receptor binding
Acknowledgements
This study was supported in part by NIH R29-HI 55779 and POI-AG10485. The authors would like to express their gratitude to the Center of Gene Therapy and Center of Neurobiology of Aging at the University of Florida for their continued help and support.
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