Chronic treatment with high doses of corticosterone decreases cytoskeletal proteins in the rat hippocampus.
Hypercortisolism is a common trait of Cushing's disease and depression. These two disorders also share hippocampal volume decrease and cognitive deficits. However, experimentally induced hypercortisolism induces neuronal atrophy, which has been proposed to be the phenomenon underlying the hippocampal shrinkage. We hypothesized that the above-mentioned atrophy is due to a deleterious effect of high concentrations of glucocorticoids on cytoskeletal proteins. One or two pellets (100 mg each) of corticosterone were subcutaneously implanted in adult rats. Twenty-one days later, light, medium and heavy subunits of intermediate neurofilaments (NFL, NFM and NFH) and the microtubule-associated protein 2 (MAP2) were quantified by immunohistochemistry in Ammon's horn and dentate gyrus. We also evaluated the in vitro glutamate release in hippocampal slices. Both doses of corticosterone induced a decrement of NFL, NFM and NFH in both hippocampal areas but only 200 mg decreased MAP2. This dose also diminished the potassium-stimulated glutamate release. All of these changes seemed not to be due to neuron loss, as no decrement in neuron-specific nuclear protein-positive cells was found. With the exception of NFL, the above-mentioned diminution was not observed in the globus pallidus, one of the brain regions with the lowest glucocorticoid receptor density. These results provide a subcellular insight into the trophic changes found in experimental models of hypercortisolism. The coincidence between decrements in MAP2 and glutamate release suggests possible links between high glucocorticoid levels, dendritic atrophy and the cognitive impairment reported in patients suffering from Cushing's disease and depression.
Cereseto
Marina
M
Instituto de Investigaciones Farmacológicas (ININFA, UBA-CONICET), Junín 956 5to. piso (1113), Buenos Aires, Argentina. mcereset@ffyb.uba.ar
Reinés
Analía
A
Ferrero
Alejandro
A
Sifonios
Laura
L
Rubio
Modesto
M
Wikinski
Silvia
S
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000097:blood; D002452:Cell Count / Q000379:methods; D003345:Corticosterone / Q000008:administration & dosage* / Q000097:blood; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000235:genetics*; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000033:anatomy & histology / Q000187:drug effects*; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D008297:Male; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar
D000893:Anti-Inflammatory Agents; D003598:Cytoskeletal Proteins; D018698:Glutamic Acid; D010751:Phosphopyruvate Hydratase; D003345:Corticosterone