The interplay among reactive oxygen species (ROS) formation, elevated intracellular calcium concentration and mitochondrial demise is a recurring theme in research focusing on brain pathology, both for acute and chronic neurodegenerative states. However, causality, extent of contribution or the sequence of these events prior to cell death is not yet firmly established. Here we review the role of the alpha-ketoglutarate dehydrogenase complex as a newly identified source of mitochondrial ROS production. Furthermore, based on contemporary reports we examine novel concepts as potential mediators of neuronal injury connecting mitochondria, increased [Ca2+]c and ROS/reactive nitrogen species (RNS) formation; specifically: (a) the possibility that plasmalemmal nonselective cationic channels contribute to the latent [Ca2+]c rise in the context of glutamate-induced delayed calcium deregulation; (b) the likelihood of the involvement of the channels in the phenomenon of 'Ca2+ paradox' that might be implicated in ischemia/reperfusion injury; and (c) how ROS/RNS and mitochondrial status could influence the activity of these channels leading to loss of ionic homeostasis and cell death.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1742-4658.2005.05103.x

Calcium, mitochondria and oxidative stress in neuronal pathology

https://www.gastrojournal.org/article/0016-5085(95)90216-3/pdf

Hepatic free radical production after cold storage: Kupffer cell-dependent and -independent mechanisms in rats.

Novel aspects of an enduring theme

It has been proposed that xanthine oxidase-derived superoxide mediates reperfusion injury in the liver; however, there is a little direct evidence to support this hypothesis. In this paper we describe a model system to directly and noninvasively measure oxyradical formation and hepatic injury in isolated perfused rat liver. Using this sensitive chemiluminescent technique, we clearly demonstrate the theorized burst in oxygen radical production upon reperfusion of previously ischemic liver, without perturbing the system with chemical luminescence enhancers. This increase in chemiluminescence (CL) upon reperfusion was diminished by the free radical scavengers trolox and ascorbate, as well as N-2-mercaptoproprionyl-glycine (MPG), thereby confirming the oxyradical nature of this signal. Additionally, superoxide dismutase and the xanthine oxidase inhibitor allopurinol, but not catalase, attenuated the reperfusion effect, providing the most direct evidence so far that XOD derived superoxide anion is formed during liver reperfusion. Hepatic injury (AST release) did not appear to relate to increased CL, supporting the notion that the oxyradical flux may serve as a signal for other events leading to tissue injury. Further studies using this sensitive chemiluminescent technique should aid in delineating the detailed mechanism(s) of reperfusion injury.

Chemiluminescent measurement of increased free radical formation after ischemia/reperfusion : mechanisms of free radical formation in the liver

Using the model of the isolated perfused rat liver, we investigated the influence of the two pharmacologically different calcium channel blockers, verapamil and flunarizine, on changes of ion homeostasis, liver weights, pH deviations and enzyme activities during warm ischemia (37°C) and reperfusion. The LDH and GLDH activities were determined and the calcium, potassium, and sodium concentrations were measured in the effluent. Warm ischemia (180 min) caused an increased enzyme release, a high influx of calcium and sodium into the liver and a massive potassium efflux current. Normoxic reperfusion led to a further increase in hepatic enzyme release and although the loss of potassium ceased, the calcium influx into the liver continued. By the end of reperfusion the liver weight had increased significantly (P<0.01) in the control group. The two calcium entry blockers were added to the perfusate in various concentrations. Both substances protected the liver against warm ischemia and normoxic reperfusion damage, but they did not inhibit calcium inflow. However, the potassium efflux was significantly reduced by all concentration tasted (P<0.001). After reperfusion the liver weights were significantly lower in the treated groups (P<0.001) than in control animals. Thus, the calcium entry blockers verapamil and flunarizine protect liver cells against damage caused by warm ischemia and reperfusion. Furthermore, they prevent the disruption of intracellular potassium homeostasis, which seems to be related to improved volume regulation of liver cells.

Verapamil and flunarizine protect the isolated perfused rat liver against warm ischemia and reperfusion injury.

Depletion and repletion of Ca2+ in the perfused rat liver.

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Depletion and repletion of Ca2+ in the perfused rat liver.