Ischemia energy failure

Energy failure, an early consequence of hypoxia-ischemia, causes disruption of ionic homeostasis and accumulation of extracellular neurotransmitters 559... 

A. Lorek, Y. Takei, E. B. Cady, J. S. Wyatt, J. Penrice, A. D. Edwards, D. Peebles, M. Wylezinska, H. Owen-Reece V. Kirkbride, et al.. Delayed (secondary) cerebral energy failure after acute hypoxia-ischemia in the newborn piglet continuous 48-hour studies by phosphorus magnetic resonance spectroscopy. Pediatr. Res., 1994, 36, 699-706. 

R. C. Vannucci, J. Towfighi and S. J. Vannucci, Secondary energy failure after cerebral hypoxia-ischemia in the immature rat. J. Cereb. Blood Flow Metab., 2004, 24,1090-1097. 

Especially in models of transient cerebral ischemia, apoptotic cell death has been observed after 3-7 days post insult in selected brain regions in which basal energy metabolism has been preserved (Chen et al. 1997 Du et al. 1996). In the meantime, molecular switches have been identified that gate different populations of neurons with regard to the type of cell death they eventually undergo (Nicotera 2003). However, there is little doubt that in animal stroke the vast majority of cells would die from necrosis or, alternatively, secondary energy failure even in the presence of a pro-apop-totic genetic balance. The concept of thresholds of cerebral blood flow (CBF) for various functions of brain parenchyma (see below) explains why the infarct core suffers from pan-necrosis whereas the peri-infarct border in which function is suppressed, but structure initially preserved (the so-called ischemic penumbra), may show apoptotic cell death or a combination of both. 

Besides the variable functional outcome after ischemia in animal models, it is well established that specific neuronal populations within an individual vary substantially in ischemic tolerance. Neurons in the CA1 region of the hippocampus and other distinct cellular populations of the caudate, thalamus, neocortex and cerebellum are selectively vulnerable to relatively brief periods of ischemia (Kirino and Sano 1984 Siesjo 1988). The reasons for this phenomenon are not fully elucidated, but for example in cerebellar Purkinje cells it could be shown that a reduced level of aldolase may trigger energy failure after brief periods of anoxia (Welsh et al. 2002). Changes in microcirculation, as seen in focal stroke,... 

Busza AL, Allen KL, King MD, van Bruggen N, Williams SR, Gadian DG (1992) Diffusion-weighted imaging studies of cerebral ischemia in gerbils potential relevance to energy failure. Stroke 23 1602-1612... 

Pathophysiologically, the pronounced ADC decline during ischemia occurs at the same time as anoxic depolarization. Anoxic depolarization is the consequence of energy failure with secondary failure of ion pumps (in particular Na+/K+-ATPase), which are necessary to maintain ion gradients over cell membranes. The resulting influx of Na+-ions is accompanied by a water shift from the extra- to the intracellular space (cytotoxic edema) without a net uptake of water (Fig. 7.1). 

While this association between the ischemia-associated ADC decline and energy failure/anoxic depolarization is undisputed, it is still a matter of debate what exactly leads to the restriction in water proton diffusion. As already mentioned above, water... 

Fig. 7.1. Pathophysiology of abnormal diffusion in cerebral ischemia. Cascade of metabolic changes leading to a decrease in diffusion of water protons in cerebral ischemia. The main steps leading to significant diffusion reductions are shown, while modest changes may also be found with incomplete energy failure. [Reproduced with permission from Neumann-Haefelin and Moseley (2003)]...

Y. S. Chang, W. S. Park, M. Lee, K. S. Kim, S. M. Shin, and J. H. Choi, Near-Infrared Spectroscopic Monitoring of Secondary Cerebral Energy Failure after Transient Global Hypoxia-Ischemia in the Newborn Piglet, Neurological Res., 21(2), 216-224 (1999). 

Liposomal ATP protected human endothelial cells from energy failure in a cell culture model of sepsis (21). ATP-L increased the number of ischemic episodes tolerated before electrical silence and brain death in the rat (22,23). In a hypovolemic shock-reperfusion model in rats, the administration of ATP-L increased hepatic blood flow during shock and reperfusion of the liver (24). The addition of the ATP-L during cold storage preservation of rat liver improved its energy state and metabolism (25,26). Co-incubation of ATP-L with sperm cells improved their motility (27). Finally, biodistribution studies demonstrated significant accumulation of ATP-L in ischemia-damaged canine myocardium (28). 

Energy failure with failure of cell membrane ionic pumps, similar to ischemia Hemiplegic Migraine... 

In contrast to global ischemia, the time course of energy failure in focal ischemia is slower which, in part, is explained by the localized nature of the insult and the ability... 

Fig. 4.10 Secondary energy failure is a phenomenon that occurs during reperfusion after 2 h of ischemia when the CBF is essentially normal and the glucose levels me at or above control The left two panels represent ATP and P-creatine levels in the adult rate, whereas the right panels indicate changes in the aging brain. Note that the core values were not presented, since SEE occured independent of age. The time course for the penumbra is indicated by the dotted lines which do not show SEP over the 8 h reperfusion time-course following 2 h of ischemia even in the core...

Lust, W.D., Taylor, C., Pundik, S., Sehnan, W.R., and Ratcheson, R.A. (2002) Ischemic ceU death Dynamics of delayed secondary energy failure during reperfusion foUowing focal ischemia. Metab. Brain Dis., 17 113-121. 

In infants who have suffered perinatal hypoxic-ischaemic brain injury (birth asphyxia), P spectra obtained within a few hours of birth show no abnormalities. However, in many cases a delayed secondary energy failure (SEP) develops within 24 h. The Pi signal increases, accompanied by reduced PCr and, in severe cases, low NTP. Furthermore, in contrast to the profound acidosis seen during acute hypoxia-ischemia, an intracellular alkalosis may be detected. Additionally, localized spectroscopy shows elevated lactate levels for several weeks following SEE. Both PCr/Pi and lactate/N-acetylaspartate (Lac/NAA) ratios have proved to be extremely useful indices of the severity of hypoxic-ischaemic injury, with strong prognostic capabilities. 

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