17beta-Oestradiol stimulation of G-proteins in aged and Alzheimer's human brain: comparison with phytoestrogens.
The neuroprotective action of oestrogens and oestrogen-like compounds is in the focus of basic and clinical research. Although such action has been shown to be associated with neuronal plasma membranes, the implication of G-proteins remains to be elucidated. This study revealed that micromolar concentrations (microM) of 17beta-oestradiol and phytoestrogens, genistein and daidzein, significantly (P < 0.05) stimulate G-proteins ([(35)S]GTP gamma S binding) in the post-mortem hippocampal membranes of age-matched control women with the respective maximum effects of 28, 20 and 15% at 10 microM. In the frontocortical membranes, the stimulation of G-proteins did not differ significantly from that in hippocampal membranes. Although in the hippocampus and frontal cortex of the Alzheimer's disease (AD) women's brain, 10 microM 17beta-oestradiol produced significantly (P < 0.05) lower stimulation of G-proteins than in the control regions, stimulation by phytoestrogens revealed no remarkable decline. 17beta-Oestradiol, genistein and daidzein revealed a selective effect on various G-proteins (G(alphas), G(alpha o), G(alpha i1) or G(alpha 11) plus G(beta 1 gamma 2)) expressed in Sf9 cells. At a concentration of 10 microM, 17beta-oestradiol suppressed the H(2)O(2) and homocysteine stimulated G-proteins in the frontocortical membranes of control women to a greater extent than phytoestrogens. In AD, the suppressing effect of each compound was lower than in the controls. In the cell-free systems, micromolar concentrations of phytoestrogens scavenged OH(*) and the 2.2-diphenyl-1-picrylhydrazyl free radical (DPPH(*)) more than 17beta-oestradiol did. In the frontocortical membranes of control women, the 20 microM 17beta-oestradiol stimulated adenylate cyclase with 20% maximal effect, whereas, in AD, the effect was insignificant. Genistein did not stimulate enzyme either in control or AD frontocortical membranes. Our data confirm that the agents stimulate G-proteins in control and AD women's brains, although 17beta-oestradiol and phytoestrogens have similarities and differences in this respect. We suggest that, besides the ER-dependent one, the ER-independent antioxidant mechanism is responsible for the oestrogen stimulation of G-proteins in the brain membranes. Both of these mechanisms could be involved in the neuroprotective signalling of oestrogens that contributes to their preventive/therapeutic action against postmenopausal neurological disorders.
Jefremov
V
V
Department of Biochemistry, Tartu University, Tartu, Estonia.
Rakitin
A
A
Mahlapuu
R
R
Zilmer
K
K
Bogdanovic
N
N
Zilmer
M
M
Karelson
E
E
D000262:Adenylyl Cyclases / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D016022:Case-Control Studies; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D019833:Genistein / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology; D008297:Male; D008954:Models, Biological; D048789:Phytoestrogens / Q000494:pharmacology*; D011485:Protein Binding
D016166:Free Radical Scavengers; D007529:Isoflavones; D048789:Phytoestrogens; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D004958:Estradiol; C004742:daidzein; D019833:Genistein; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases