Abstract
Ischemia, and subsequent acidosis, induces neuronal death following brain injury. Oxidative stress is believed to be a key component of this neuronal degeneration. Acute chemical ischemia (azide in the absence of external glucose) and acidosis (external media buffered to pH 6.0) produce increases in intracellular calcium concentration ([Ca2+]i) and inward membrane currents in cultured rat cortical neurons. Two α-tocopherol analogues, trolox and butylated hydroxytoluene (BHT), and the spin trapping molecule α-Phenyl-N-tert-butylnitrone (PBN) were used to determine the role of free radicals in these responses. PBN and BHT inhibited the initial transient increases in [Ca2+]i, produced by ischemia, acidosis and acidic ischemia and increased steady state levels in response to acidosis and the acidic ischemia. BHT and PBN also potentiated the rate at which [Ca2+]i increased after the initial transients during acidic ischemia. Trolox inhibited peak and sustained increases in [Ca2+]i during ischemia. BHT inhibited ischemia induced initial inward currents and trolox inhibited initial inward currents activated by acidosis and acidic ischemia. Given the inconsistent results obtained using these antioxidants, it is unlikely their effects were due to elimination of free radicals. Instead, it appears these compounds have non-specific effects on the ion channels and exchangers responsible for these responses.
Highlights
Brain ischemia causes deprivation of O2 and glucose, and a switch from aerobic to anaerobic glycolysis in neurons
Acidosis and the combination of the two, acidic ischemia, produce increases in [Ca2+]i and activation of inward whole cell currents in cultured cortical neurons isolated from E18 rats
In cultured cortical neurons loaded with Fura-2, chemical ischemia produces an immediate increase in [Ca2+]i of 151 ± 5 nM, which decreases to a sustained steady state level of 109 ± 6 nM (Figure 1A)
Summary
Brain ischemia causes deprivation of O2 and glucose, and a switch from aerobic to anaerobic glycolysis in neurons. These deficiencies result in ATP depletion, and inhibition of ATP-dependent proteins required for maintaining cellular ionic homeostasis. The production of lactate via anaerobic glycolysis results in tissue acidosis This acidosis is known to activate acid-sensing ion channels (ASIC) in neurons, which results in intracellular Ca2+ ([Ca2+]i) overload and cell death [1,2,3]. One of the consequences of ischemia-evoked calcium dyshomeostasis is mitochondrial dysfunction and the production of reactive oxygen species (ROS) [5] This interplay between calcium overload, mitochondrial dysfunction and ROS production is a major cause of ischemic injury and a target for potential stroke therapy [6]
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