17 Beta-oestradiol attenuates dexamethasone-induced lethal and sublethal neuronal damage in the striatum and hippocampus.
Abnormal corticosteroid release is extensively associated with mood disorders. This association may result from the toxic actions of endogenous corticosteroids which can induce apoptosis of hippocampal neurons. Similarly, dexamethasone, a synthetic corticosteroid, can induce lethal and sublethal damage to rat hippocampal and striatal neurons and can result in steroid-induced psychoses in humans. The experiments reported here tested the hypothesis that pre-treatment with oestrogen would also attenuate dexamethasone-induced neuronal damage as oestrogens have neuroprotective actions against a variety of insults and falling levels of oestrogen are associated with increased vulnerability to mood disorders. Male Sprague-Dawley rats received three systemic injections which were a combination of vehicle, 17-beta-oestradiol (0.2 mg/kg, s.c.), the oestrogen receptor antagonist tamoxifen (10 mg/kg, s.c.) and dexamethasone (0.7 mg/kg, i.p.) and were killed 24 h after the final injection. Injections of dexamethasone (when preceded by vehicle injections) resulted in elevated levels of apoptosis and sub-lethal damage, as demonstrated by reduced levels of microtubule-associated protein-2-immunopositive neurons, in the striatum and hippocampus. This damage was regional with the dorsomedial caudate putamen and the dentate gyrus and CA1 and CA3 hippocampal sub-fields being particularly affected. Pretreatment with oestrogen substantially attenuated the dexamethasone-induced neuronal damage. This oestrogen-induced neuronal protection was in turn virtually eliminated by giving an initial injection of tamoxifen. These results suggest, therefore, that oestrogens can protect from corticosteroid-induced neuronal damage via an oestrogen receptor-mediated process.
Haynes
L E
LE
School of Biomedical Sciences, The Medical School, Queens Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK. linda.haynes@nottingham.ac.uk
Lendon
C L
CL
Barber
D J
DJ
Mitchell
I J
IJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D003907:Dexamethasone; D004958:Estradiol / Q000008:administration & dosage / Q000378:metabolism*; D004965:Estrogen Antagonists / Q000494:pharmacology; D005938:Glucocorticoids; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006652:Histological Techniques; D008297:Male; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000494:pharmacology
D004965:Estrogen Antagonists; D005938:Glucocorticoids; D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D013629:Tamoxifen; D004958:Estradiol; D003907:Dexamethasone