Proteomic analysis identifies alterations in cellular morphology and cell death pathways in mouse brain after chronic corticosterone treatment.
Some patients with Major Depression and other neurological afflictions display hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. HPA hyperactivity may be due to impaired feedback inhibition and manifested as increased levels of circulating cortisol. Subcutaneous implants of corticosterone pellets were used to mimic this situation in mice to gain insight into any effects on brain function by comparative proteomic analysis using two-dimensional Differential In-Gel Electrophoresis. A total of 150 different protein spots were altered by corticosterone treatment in the hypothalamus, hippocampus and cerebral cortex. Of these, 117 spots were identified by matrix-assisted laser desorption/ionization-time of flight mass fingerprinting equating to 51 different proteins. Association of these corticosterone-modulated proteins with biological functions using the Ingenuity Pathways Analysis tool showed that cell morphology was significantly altered in the hippocampus and cerebral cortex, whereas the hypothalamus showed significant changes in cell death. Ingenuity Pathways Analysis of the canonical signaling pathways showed that glycolysis and gluconeogenesis were altered in the hypothalamus and the hippocampus and all three brain regions showed changes in phenylalanine, glutamate and nitrogen metabolism. Further elucidation of these pathways could lead to identification of biomarkers for the development of pharmacological therapies targeted at neuropsychiatric disorders.
Skynner
Heather A
HA
Department of Molecular and Cellular Neuroscience, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex, UK.
Amos
Doran P
DP
Murray
Fraser
F
Salim
Kamran
K
Knowles
Michael R
MR
Munoz-Sanjuan
Ignacio
I
Camargo
Luis M
LM
Bonnert
Timothy P
TP
Guest
Paul C
PC
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001931:Brain Mapping; D016923:Cell Death / Q000187:drug effects; D003345:Corticosterone / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D015180:Electrophoresis, Gel, Two-Dimensional / Q000379:methods; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D051379:Mice; D008954:Models, Biological; D009434:Neural Pathways / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D040901:Proteomics / Q000379:methods*
D000893:Anti-Inflammatory Agents; D003345:Corticosterone