Abstract
Understanding proteomic changes in the ischemic penumbra are crucial to rescue those salvageable cells and reduce the damage of an ischemic stroke. Since the penumbra region is dynamic with heterogeneous cells/tissues, tissue sampling from animal models of stroke for the molecular study is a challenge. In this study, cultured hippocampal HT22 cells under hypoxia treatment for 17.5 h with 0.69 mM low glucose (H+LG) could mimic ischemic penumbral cells since they had much higher cell viability and viable cell number compared to hypoxia without glucose (H−G) treatment. To validate established cell-based ischemic penumbral model and understand the beneficial effects of low glucose (LG), quantitative proteomics analysis was performed on H+LG, H−G, and normoxia with normal 22 mM glucose (N+G) treated cells. We identified 427 differentially abundant proteins (DAPs) between H−G and N+G and further identified 105 DAPs between H+LG and H−G. Analysis of 105 DAPs revealed that LG promotes cell survival by activating HIF1α to enhance glycolysis; preventing the dysregulations of extracellular matrix remodeling, cell cycle and division, and antioxidant and detoxification; as well as attenuating inflammatory reaction response, protein synthesis and neurotransmission activity. Our results demonstrated that this established cell-based system could mimic penumbral conditions and can be used for molecular studies.
Highlights
Stroke is the second leading cause of death and the third biggest cause of disability worldwide, with ischemic stroke accounting to 87% of the cases (Feigin et al, 2017; Puig et al, 2018)
Occlusion of a Proteomic Changes of Ischemic Penumbra cerebral artery causes decreased blood flow and impaired delivery of oxygen, glucose, and nutrients to brain tissues, which lead to the formation of ischemic core, ischemic penumbra and non-ischemic regions based on cerebral blood flow (CBF) gradient (Figure 1; Olsen, 2009; Robbins and Swanson, 2014; McCabe et al, 2018)
To ensure that the treated cells could potentially recover from the hypoxia without glucose (H−G) treatment, the 17.5 h with ∼20% reduced cell viability, and 45% viable cell numbers (VCNs) was selected as a suitable time point to study the impact of glucose on cell survival
Summary
Stroke is the second leading cause of death and the third biggest cause of disability worldwide, with ischemic stroke accounting to 87% of the cases (Feigin et al, 2017; Puig et al, 2018). The ischemic penumbra is an area around the ischemic core at which cells are absent of induced electrical potentials but metabolically viable and potentially salvageable (Astrup et al, 1977; Symon et al, 1977; Fisher and Bastan, 2012). These cells could die if not rescued promptly. Enhanced understanding of the cellular and molecular events associated with ischemic penumbra is essential to identify the therapeutic target(s) and develop therapeutic strategies
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