title: Repeated low-dose 17β-estradiol treatment prevents activation of apoptotic signaling both in the synaptosomal and cellular fraction in rat prefrontal cortex following cerebral ischemia.
abstract: Disturbance in blood circulation is associated with numerous pathological conditions characterized by cognitive decline and neurodegeneration. Activation of pro-apoptotic signaling previously detected in the synaptosomal fraction may underlie neurodegeneration in the prefrontal cortex of rats submitted to permanent bilateral common carotid arteries occlusion (two-vessel occlusion, 2VO). 17β-Estradiol (E) exerts potent neuroprotective effects in the brain affecting, among other, ischemia-induced pathological changes. As most significant changes in rats submitted to 2VO were observed on 7th day following the insult, of interest was to examine whether 7 day treatment with low dose of E (33.3 µg/kg/day) prevents formerly reported neurodegeneration and may represent additional therapy during the early post-ischemic period. Role of E treatment on apoptotic pathway was monitored on Bcl-2 family members, cytochrome c, caspase 3 and PARP protein level in the synaptosomal (P2) fraction of the prefrontal cortex. Furthermore, changes of these proteins were examined in the cytosolic, mitochondrial and nuclear fraction, with the emphasis on potential involvement of extracellular signal-regulated kinases (ERK) and protein kinase B (Akt) activation and their role in nuclear translocation of transcriptional nuclear factor kappa B (NF-kB) associated with alteration of Bax and Bcl-2 gene expression. The extent of cellular damage was determined using DNA fragmentation and Fluoro-Jade B staining. The absence of activation of apoptotic cascade both in the P2 and cell accompanied with decreased DNA fragmentation and number of degenerating neurons clearly indicates that E treatment ensures the efficient protection against ischemic insult. Moreover, E-mediated modulation of pro-apoptotic signaling in the cortical cellular fractions involves cooperative activation of ERK and Akt, which may be implicated in the observed prevention of neurodegenerative changes.
authors.affiliation: Department of Molecular Biology and Endocrinology, Institute of Nuclear Sciences "Vinča", University of Belgrade, Belgrade, Serbia.
authors.forename: Miloš
authors.initials: M
authors.lastname: Stanojlović
authors.affiliation: Department of Molecular Biology and Endocrinology, Institute of Nuclear Sciences "Vinča", University of Belgrade, Belgrade, Serbia. Electronic address: jelenazlatkovic@vinca.rs.
authors.forename: Jelena
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: Ivana
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: Ivana
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: Nataša
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: Marina
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: Anica
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: Dunja
authors.initials: D
authors.lastname: Drakulić
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism*; D004195:Disease Models, Animal; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D018696:Neuroprotective Agents; D004958:Estradiol
keywords: 17β-Estradiol (E); Permanent bilateral common carotid arteries occlusion (two-vessel occlusion, 2VO); Prefrontal cortex; Pro-apoptotic signaling