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 P4 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.
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Acknowledgements
We thank Milorad Dragić for providing his unselfish technical support with Nissl staining and image analyses. We show gratitude to our retired colleague dr Anica Horvat who provided the original funding, knowledge, and expertise that greatly assisted the research.
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This work was funded by the Ministry of Education, Science and Technological Development of the Republic of Serbia, grants 173044 and 41014.
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MS and IGS performed experiments and analyzed data. MZ assisted during biochemical measurements. IGS, MZ, JM, NM, and IG edited the manuscript. DD designed and supervised experimental setup, participated in the interpretation of obtained results, and wrote the manuscript. All authors approved the final version of the manuscript.
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Stanojlović, M., Guševac Stojanović, I., Zarić, M. et al. Progesterone Protects Prefrontal Cortex in Rat Model of Permanent Bilateral Common Carotid Occlusion via Progesterone Receptors and Akt/Erk/eNOS. Cell Mol Neurobiol 40, 829–843 (2020). https://doi.org/10.1007/s10571-019-00777-2
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DOI: https://doi.org/10.1007/s10571-019-00777-2