Different characteristics of cell volume and intracellular calcium ion concentration dynamics between the hippocampal CA1 and lateral cerebral cortex of male mouse brain slices during exposure to hypotonic stress

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Brain edema is frequently observed in clinical practice, and is induced by traumatic injury, ischemic insult, epilepsy, blood ion imbalance (after infusion), and abnormal liver and kidney functions (Rungta et al., 2015; Butterworth, 2015). As the brain is housed in a limited space surrounded by hard cranial bones, an increase in the brain volume, due to edema, causes an increase in the intra‐cranial pressure. As a result, small vessels in the brain are compressed, leading to a decrease in blood flow, which in turn causes an irreversible impairment of nerve function and, at worst, death (Michinaga & Koyama, 2015). It is therefore important to have evidence on the pathophysiological features and mechanisms of the brain edema to establish proper medical treatments for patients suffering from edema.
Although edema appears to be a simple physicochemical phenomenon that is induced by a dyscontrol of water balance in cells, it involves complex movements of various ions and the activation of regulatory volume change (RVC), which is a homeostatic control mechanism of living cells (Okada, 2006; Pasantes‐Morales, Lezama, Ramos‐Mandujano, & Tuz, 2006; Hoffmann, Lambert, & Pedersen, 2009; Jiang & Sun, 2013). In the early pathophysiological studies, many researchers found a concomitant increase in [Ca2+]i, which has been considered to be the chief messenger for RVC (cf. review: McCarty & O'Neil, 1992). However, the role of the increased [Ca2+]i in RVC was demonstrated to be limited (Altamirano, Brodwick, & Alvarez‐Leefmans, 1998; Somjen 1999; Borgdorff, Somjen, & Wadman, 2000; Pasantes‐Morales et al. 2006). Recent studies demonstrated the involvement of many important volume sensitive components in the process of cell edema and subsequent RVC, such as two‐P K+ channels, the leak K+ channel (TASK‐1; Kanjhan, Pow, Noakes, & Bellingham, 2010) and back ground K+ channels (TREK1; Heurteaux et al. 2004; Honoré et al. 2007), stretch sensitive Ca2+ channel (TRPV4; Mizuno, Matsumoto, Imai, & Suzuki, 2003; Nilius, Vriens, Prenen, Droogmans, & Voets, 2004), and volume regulated anion channel (VRAC; Inoue et al. 2005; Okada, 2006, Pasantes‐Morales et al. 2006). However, almost all of these studies were carried out using single cell preparations or hippocampal slices.
In the present study, we measured changes in cell volume and [Ca2+]i simultaneously using fura‐2 fluorometry, which was applied to murine neuronal cell lines by Altamirano et al. (1998). We modified this method for application to mouse brain slices, and analyzed the pathophysiological and pharmacological characteristic responses of brain cells in the lateral cerebral cortex (LCC) and hippocampal CA1 (CA1) regions during exposure to hypotonic stress. Since the slice preparation preserves neurons, astrocytes and vasculatures, which may participate in the occurrence and regulation of edema during exposure to hypotonic stress, the results obtained here will provide better information about brain cell edema than those obtained by single cell experiments.
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