Progesterone Protects Prefrontal Cortex in Rat Model of Permanent Bilateral Common Carotid Occlusion via Progesterone Re
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ORIGINAL RESEARCH
Progesterone Protects Prefrontal Cortex in Rat Model of Permanent Bilateral Common Carotid Occlusion via Progesterone Receptors and Akt/Erk/eNOS Miloš Stanojlović1 · Ivana Guševac Stojanović1 · Marina Zarić1 · Jelena Martinović1 · Nataša Mitrović1 · Ivana Grković1 · Dunja Drakulić1 Received: 18 January 2019 / Accepted: 10 December 2019 © Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract Sustained activation of pro-apoptotic signaling due to a sudden and prolonged disturbance of cerebral blood circulation governs the neurodegenerative processes in prefrontal cortex (PFC) of rats whose common carotid arteries are permanently occluded. The adequate neuroprotective therapy should minimize the activation of toxicity pathways and increase the activity of endogenous protective mechanisms. Several neuroprotectants have been proposed, including progesterone ( P4). However, the underlying mechanism of its action in PFC following permanent bilateral occlusion of common carotid arteries is not completely investigated. We, thus herein, tested the impact of post-ischemic P4 treatment (1.7 mg/kg for seven consecutive days) on previously reported aberrant neuronal morphology and amount of DNA fragmentation, as well as the expression of progesterone receptors along with the key elements of Akt/Erk/eNOS signal transduction pathway (Bax, Bcl-2, cytochrome C, caspase 3, PARP, and the level of nitric oxide). The obtained results indicate that potential amelioration of histological changes in PFC might be associated with the absence of activation of Bax/caspase 3 signaling cascade and the decline of DNA fragmentation. The study also provides the evidence that P 4 treatment in repeated regiment of administration might be effective in neuronal protection against ischemic insult due to re-establishment of the compromised action of Akt/Erk/ eNOS-mediated signaling pathway and the upregulation of progesterone receptors. Keywords Progesterone · Neuroprotection · Cerebral hypoperfusion · Prefrontal cortex
Introduction Brain damage due to a sudden and prolonged disturbance of cerebral blood flow underlies pathological conditions associated with neurodegeneration, cognitive decline, and motor dysfunction, including Alzheimer’s disease and vascular and Miloš Stanojlović and Ivana Guševac Stojanović contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10571-019-00777-2) contains supplementary material, which is available to authorized users. * Dunja Drakulić [email protected] 1
Department of Molecular Biology and Endocrinology, VINČA Institute of Nuclear Sciences, University of Belgrade, P.O. Box 522, Belgrade 11001, Republic of Serbia
aging dementia (De Jong et al. 1999; de la Torre 2002a, b; Farkas et al. 2007; Villapol et al. 2014; Nelson et al. 2016; Clark et al. 2017; Rius-Pérez et al. 2018). Since the first descriptions of these impairments, the treatment has remained challenging and numerous studies have
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