Reperfusion brain injury

Abstract

Energy production for the maintenance of brain function fails rapidly with the onset of ischemia and is reinstituted with timely reperfusion. The key bioenergetic organelle, the mitochondrion, is strongly affected by a cascade of events occurring with ischemia and reperfusion. Enhanced production of reactive oxygen species, disruption of calcium homeostasis, and an inflammatory response are induced by reperfusion and have a profound effect on cellular bioenergetics in reversible stroke. The impact of perturbed bioenergetics on cellular homeostasis/function during and after ischemia are discussed. Because mitochondrial function can be compromised by derangements at more than one of the susceptible sites on this organelle, we propose that a combination therapy is needed for the restoration and maintenance of cellular bioenergetics after reperfusion. Neurology Stroke is a complex and dynamic disease of the brain that rates fourth in mortality and first in disability in the United States. The brain has certain unique physiologic properties that make it extremely sensitive to the loss of blood flow. In general, the energy demands of the brain are high, requiring a continual supply of oxygen and its principal substrate, glucose, mainly from the blood. Occluding blood flow to the brain disrupts the delicate balance between the energy generated by glucose oxidation and energy needed for cell processes, which leads to a rapid loss of function and cell homeostasis.The imbalance of the brain bioenergetics induced by the loss of blood flow has been shown to lead to cellular infarction of all brain cells, including neurons, astrocytes, endothelial cells, oligodendrocytes, and subpopulations of these cells. Conversely, a pronounced deranged cellular milieu resulting from ischemia elicits a plethora of reactions upon re-establishment of reflow. It is increasingly evident that many of the events center on the neurovascular unit, a functional composite of microvessels, pericytes, astrocytes, neurons, axons, and other supporting cells such as microglia and oligodendrocytes. Although many of the reflow-induced events may be pathologic and their prevention potentially beneficial, it is our contention that the status of cellular bioenergetics is the major determinant of many of the pathophysiologic sequelae manifested in the neurovascular unit and therefore is fundamental to the outcome for the tissue, following reversible focal ischemia.In the past 50 years, basic science investigations first established that loss of blood flow to the brain resulted in rapid failure of cell bioenergetics, followed by an ever-increasing list of cellular perturbations. A schematic of ischemia-induced events is shown in figure 1. Rapid energy depletion reflects very low energy reserves within the brain, a high metabolic rate, and almost a total reliance on glucose oxidation for energy production. The ischemic cascade is initiated during ischemia. Ischemia depletes adenosine triphosphate (ATP) within minutes, leading to a failure of a

cGMP-Selective Phosphodiesterase Inhibitors Stimulate Mitochondrial Biogenesis and Promote Recovery from Acute Kidney Injury

“…Mitochondrial function is necessary for normal cell and tissue function, and is critical in energy-dependent repair processes. A wide array of disease states are characterized by mitochondrial dysfunction, including diabetes, neurodegenerative disease, traumatic brain injury, and acute organ injury (Lifshitz et al, 2004;Pundik et al, 2012;Cheng and Ristow, 2013;Hwang, 2013;Yan et al, 2013). I/R and drug/toxicant-induced renal injury demonstrate mitochondrial dysfunction and suppression of MB, and recovery of renal function is tightly linked to the restoration of mitochondrial number and function (Funk and Schnellmann, 2012).…”

“…Mitochondrial dysfunction is increasingly recognized as an important pathophysiological mediator of a variety of disease states, including neurodegeneration, cardiovascular disease, metabolic syndrome, and acute organ injury (Choumar et al, 2011;Pundik et al, 2012;Andreux et al, 2013;Bayeva et al, 2013;Cheng and Ristow, 2013;Cooper, 2013;Hwang, 2013;Yan et al, 2013). Mitochondrial dysfunction is an established component of the pathogenesis of acute kidney injury (AKI) and a cause of renal tubular dysfunction and cell death (Jassem et al, 2002;Jassem and Heaton, 2004;Hall and Unwin, 2007;Weinberg, 2011;Venkatachalam and Weinberg, 2012).…”

Blood—Brain Barrier Breakdown Involves Four Distinct Stages of Vascular Damage in Various Models of Experimental Focal Cerebral Ischemia

“…In fact, loss of the barrier function as indicated by hemorrhagic transformation or even intracranial bleeding is frequently observed after therapeutical recanalization via recombinant tissue plasminogen activator (rt-PA), which still represents the only FDA-approved drug-related therapy. 17,18 These complications were traditionally attributed to a reperfusion-mediated vascular damage, [19][20][21] which is commonly addressed as 'reperfusion injury'. 22,23 As clinical treatment strategies tend to apply recanalization via rt-PA more frequently and in a broader time window from ischemia onset, knowledge of the underlying mechanisms for ischemia-related BBB breakdown, especially in a clinically relevant setting of reperfusion, may be of particular interest for the development of neuroprotective strategies in combination with rt-PA.…”

Cyclosporine A, a Potential Therapy of Ischemic Reperfusion Injury. A Common History for Heart and Brain

“…Although previous randomized controlled trials [3][4][5] did not show a benefit over standard treatment, recent studies confirm the effectiveness of this strategy [6][7][8][9][10] . Endovascular methods enhancing reperfusion may expose patients to increased ischemic reperfusion injury thereby hampering the benefit of recanalization by promoting hemorrhagic transformation (HT) and severe vasogenic edema both considered as markers of reperfusion injury [11][12][13][14] .…”