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Instytut Medycyny Doświadczalnej i Klinicznej im. M. Mossakowskiego PAN
Contributor:Zabłocka, Barbara (Promotor) ; Beręsewicz-Haller, Małgorzata (Promotor pomocniczy)
Place of publishing: Date issued/created: Degree name: Level of degree: Degree discipline : Type of object: Subject and Keywords:Endogenous neuroprotection ; Brain ischemia ; Nrf2
Abstract:
Stroke is not only a leading cause of mortality worldwide responsible for a significant number of deaths annually, but it also results in a significant number of disabilities and disorders. Despite many years of research, the available treatments for stroke remain limited. This state of affairs implies the need for a new approach to the search for effective neuroprotection. So it is that the activation of natural adaptive mechanisms (called endogenous neuroprotection) is now discussed increasingly as a promising therapeutic method. An example of endogenous neuroprotection is the resistance to ischemia-reperfusion (I/R) episode of the abdominal region of hippocampus (CA2-3, DG) versus the dorsal, ischemia-vulnerable region (CA1). Here, using gerbil model of 5-minute bilateral carotid artery ligation, followed by 15 and 30 minutes, and 1, 2, 3, 24, 36, 48, 72 and 96 hours of reperfusion, it was shown that Nrf2 activity is higher in CA2-3, DG compared to CA1 already in control gerbils. Moreover, I/R results in a brief and short-lived Nrf2 activation in CA1, and a delayed and prolonged activation in CA2-3, DG seen 48h after I/R. Interestingly, sub-regional differences in Nrf2 activity correlate with Nrf2 target proteins, including heme oxygenase 1 (HO-1), the catalytic (GCLC) and modulatory (GCLM) sub-units of glutamate-cysteine ligase, and glutathione peroxidase 1 (GPx1). Furthermore, pharmacological activation of Nrf2 by sulforaphane significantly protects neurons in CA1 region from death both in vivo and ex vivo models (transient global forebrain I/R in gerbils and organotypic hippocampal slice culture, respectively). Sulforaphane is also effective when administered later in relation to the stimulus, which gives hope for a wide therapeutic window in clinical studies. To investigate new genes regulated by Nrf2, which may be involved in the mechanisms of CA2-3, DG resistance to ischemic insult, an in silico analysis was performed. Using RNA-seq atlas of control mouse hippocampus and database of Nrf2-regulated genes, 15 genes were identified that show higher expression in CA2-3, DG than in CA1. The results of in silico analysis were verified in the hippocampus of control gerbils and showed that 20% of them had higher expression in CA2-3, DG sector than in CA1. Subsequently, the expression of selected genes and their proteins was examined after I/R to show potential correlations with observed changes in Nrf2 activity after I/R in CA2-3, DG. Six of these genes and six of its proteins showed increased mRNA and/or protein expression in CA2-3, DG after I/R. These genes and proteins can be described as Nrf2-induced genes/proteins under stress conditions, making them of interest in the context of endogenous neuroprotection. To conclude, the study conducted is novel as it indicates new molecular pathways behind the phenomenon of ischemia-resistance of CA2-3, DG region of hippocampus. Presented data show that the activity of the cytoprotective transcription factor Nrf2 is higher in CA2-3, DG than in CA1 in control hippocampus and after I/R. What's more, the activity of Nrf2 is followed by high activity of its effector proteins, connected with antioxidant pathways (HO1, GCLM, GPx1) and post-ischemic activation of newly selected genes that may participate in the defense reaction of cells, and results in its survival. The genes and their proteins indicated here are part of various metabolic pathways and have not been studied so far in the context of brain ischemia. These results may also be an indication for the search for new neuroprotective therapies in ischemic brain pathology.
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Digitizing institution:Mossakowski Medical Research Institute PAS
Original in:Library of the Mossakowski Medical Research Institute PAS
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