title: Effects of chronic cerebral hypoperfusion and low-dose progesterone treatment on apoptotic processes, expression and subcellular localization of key elements within Akt and Erk signaling pathways in rat hippocampus.
abstract: The present study attempted to investigate how chronic cerebral hypoperfusion (CCH) and repeated low-dose progesterone (P) treatment affect gene and protein expression, subcellular distribution of key apoptotic elements within protein kinase B (Akt) and extracellular signal-regulated kinases (Erk) signal transduction pathways, as well as neurodegenerative processes and behavior. The results revealed the absence of Erk activation in CCH in cytosolic and synaptosomal fractions, indicating a lower threshold of Akt activation in brain ischemia, while P increased their levels above control values. CCH induced an increase in caspase 3 (Casp 3) and poly (ADP-ribose) polymerase (PARP) gene and protein expression. However, P restored expression of examined molecules in all observed fractions, except for the levels of Casp 3 in synapses which highlighted its possible non-apoptotic or even protective function. Our study showed the absence of nuclear factor kappa-light-chain-enhancer of activated b cells (NF-κB) response to this type of ischemic condition and its strong activation under the influence of P. Further, the initial increase in the number of apoptotic cells and amount of DNA fragmentation induced by CCH was significantly reduced by P. Finally, P reversed the CCH-induced reduction in locomotor activity, while promoting a substantial decrease in anxiety-related behavior. Our findings support the concept that repeated low-dose post-ischemic P treatment reduces CCH-induced neurodegeneration in the hippocampus. Neuroprotection is initiated through the activation of investigated kinases and regulation of their downstream molecules in subcellular specific manner, indicating that this treatment may be a promising therapy for alleviation of CCH-induced pathologies.
authors.affiliation: Department of Molecular Biology and Endocrinology, Institute of Nuclear Sciences "Vinča", University of Belgrade, Belgrade, Serbia. Electronic address: milos.stanojlovic@vinca.rs.
authors.forename: M
authors.initials: M
authors.lastname: Stanojlović
authors.affiliation: Department of Molecular Biology and Endocrinology, Institute of Nuclear Sciences "Vinča", University of Belgrade, Belgrade, Serbia.
authors.forename: I
authors.initials: I
authors.lastname: Guševac
authors.affiliation: Department of Molecular Biology and Endocrinology, Institute of Nuclear Sciences "Vinča", University of Belgrade, Belgrade, Serbia.
authors.forename: I
authors.initials: I
authors.lastname: Grković
authors.affiliation: Department of Molecular Biology and Endocrinology, Institute of Nuclear Sciences "Vinča", University of Belgrade, Belgrade, Serbia.
authors.forename: J
authors.initials: J
authors.lastname: Zlatković
authors.affiliation: Department of Molecular Biology and Endocrinology, Institute of Nuclear Sciences "Vinča", University of Belgrade, Belgrade, Serbia.
authors.forename: N
authors.initials: N
authors.lastname: Mitrović
authors.affiliation: Department of Molecular Biology and Endocrinology, Institute of Nuclear Sciences "Vinča", University of Belgrade, Belgrade, Serbia.
authors.forename: M
authors.initials: M
authors.lastname: Zarić
authors.affiliation: Department of Molecular Biology and Endocrinology, Institute of Nuclear Sciences "Vinča", University of Belgrade, Belgrade, Serbia.
authors.forename: A
authors.initials: A
authors.lastname: Horvat
authors.affiliation: Department of Molecular Biology and Endocrinology, Institute of Nuclear Sciences "Vinča", University of Belgrade, Belgrade, Serbia.
authors.forename: D
authors.initials: D
authors.lastname: Drakulić
mesh_terms: D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000503:physiopathology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002340:Carotid Artery Diseases; D002561:Cerebrovascular Disorders / Q000188:drug therapy* / Q000503:physiopathology*; D002908:Chronic Disease; D004195:Disease Models, Animal; D006970:Disorders of Excessive Somnolence; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D011374:Progesterone / Q000008:administration & dosage*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011897:Random Allocation; D017208:Rats, Wistar
chemical_list: D018696:Neuroprotective Agents; D011374:Progesterone; D051057:Proto-Oncogene Proteins c-akt
keywords: apoptosis; chronic cerebral hypoperfusion; neurodegeneration; progesterone