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Repeated Estradiol Treatment Attenuates Chronic Cerebral Hypoperfusion-Induced Neurodegeneration in Rat Hippocampus

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Abstract

Although a substantial number of pre-clinical and experimental studies have investigated effects of 17β-estradiol, its precise molecular mechanism of action in the early state of chronic cerebral hypoperfusion remains controversial. The present study attempted to verify whether post-ischemic estradiol treatment (33.3 μg/kg for seven consecutive days) affects previously reported number of hippocampal apoptotic cells and amount of DNA fragmentation characteristic for apoptosis as well as the expression of key elements within synaptosomal Akt and Erk signal transduction pathways (NF-κB, Bax, Bcl-2, cytochrome C, caspase 3, and PARP). Additionally, alterations of aforementioned molecules linked to protection in various neurodegenerative disorders were monitored in the cytosolic, mitochondrial, and nuclear fractions associating investigated kinases and NF-κB with gene expression of their downstream effectors—Bcl-2, Bax, and caspase 3. The results revealed that an initial increase in the number of apoptotic cells and amount of DNA fragmentation induced by chronic cerebral hypoperfusion was significantly reduced by 17β-estradiol. In synaptic regions, an altered profile with respect to the protein expression of Bcl-2 and phosphorylated Akt was detected, although the level of other examined proteins was not modified. In other investigated sub-cellular fractions, 17β-estradiol elicited phosphorylation and translocation of Akt and Erk along with modulation of the expression of their subsequent effectors. Our findings support the concept that repeated post-ischemic 17β-estradiol treatment attenuates neurodegeneration induced by chronic cerebral hypoperfusion in hippocampus through the activation of investigated kinases and regulation of their downstream molecules in sub-cellular manner indicating a time window and regime of its administration as a valid therapeutic intervention.

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Acknowledgments

This work was funded by Ministry of Education, Science and Technological Development of Republic of Serbia, Project Nos. 173044 and 41014.

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Authors and Affiliations

  1. Department of Molecular Biology and Endocrinology, VINCA Institute of Nuclear Sciences, University of Belgrade, P.O.Box 522, Belgrade, 11001, Republic of Serbia

    Miloš Stanojlović, Ivana Guševac, Ivana Grković, Nataša Mitrović, Jelena Zlatković, Anica Horvat & Dunja Drakulić

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  1. Miloš Stanojlović
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  2. Ivana Guševac
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  4. Nataša Mitrović
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  7. Dunja Drakulić
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Correspondence to Dunja Drakulić.

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Stanojlović, M., Guševac, I., Grković, I. et al. Repeated Estradiol Treatment Attenuates Chronic Cerebral Hypoperfusion-Induced Neurodegeneration in Rat Hippocampus. Cell Mol Neurobiol 36, 989–999 (2016). https://doi.org/10.1007/s10571-015-0289-0

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