Mitochondrial Events Determine the Status of Hippocampal Cells in the Post-Ischemic Period

Excerpt

Understanding ischemia-induced events is important for effective protective strategies in brain pathologies. Actively functioning neuronal cells, the specialization and efficiency of which were formed evolutionarily, are resistant to minor fluctuations in the extracellular environment, maintaining cell and tissue homeostasis. If the threshold for resistance is exceeded, a molecular imbalance appears, followed by a neurodegenerative process. Although the energy-supplying function of mitochondria in cellular metabolism is well known, the contribution of mitochondrial events to cell survival in extreme situations is not yet fully understood. In conditions of oxygen-glucose deficiency, the vulnerability of the brain is not identical in different cells and regions. It is known that the pyramidal neurons of the CA1 hippocampal region are most vulnerable, while interneurons and glial cells are relatively resistant to ischemia, and contribute to neuroprotection [1, 2]. The approaches in the study of mechanisms underlying neurodegeneration and/or rehabilitation are complicated by overlapping responses of functionally and structurally connected brain cells. Often, researchers focus on one type of cell in the investigation of cerebral damage. Despite numerous studies, many aspects of neuronal and glial responses to ischemia have not yet been elucidated. Deficiency of oxygen and glucose leads to systemic changes in the brain that are initially oriented towards the restoration of cellular and tissue homeostasis (adaptation), but can also trigger delayed pathological events up to irreversible neuronal degradation. In brain diseases, along with specific pathogenic mechanisms, ischemia-induced mitochondrial dysfunction is a general factor in the neurodegenerative process [3‐5]. The reasons for delayed damage to hippocampal cells in a mild oxygen-glucose deficit, as well as the cellular aspects of this phenomenon, have not yet been fully elucidated. The energy supply of mammalian brain metabolism is mainly carried out by mitochondria through the aerobic oxidation of glucose. The cellular energy resource (production and buffering of ATP) is largely determined by mitochondrial activity (MA), as well as the number and morphology of mitochondria [6, 7]. This in vitro study presents an evaluation of the mitochondrial patterns of basic hippocampal cell types in the modeling of post-ischemic damage using slice cultures and transient oxygen-glucose deprivation (OGD) followed by normoxia. The hippocampal CA1 region that is most sensitive to OGD was analyzed. MA was determined based on a semi-quantitative analysis of mitochondrial membrane potential using a mitochondrial probe [MitoTracker Orange (MTO)] and confocal microscopy. Electron microscopic assessment of structural mitochondrial parameters was also carried out. In addition, given the standardized experimental conditions of our ischemic damage model in vitro, we extrapolated mitochondrial dynamics to relative parameters characterizing the state of hippocampal cells during the study period. …