Ischemic Cerebral Damage

Abstract

Abstract-In the human brain, Ϸ30% of the energy is spent on synaptic transmission. Disappearance of synaptic activity is the earliest consequence of cerebral ischemia. The changes of synaptic function are generally assumed to be reversible and persistent damage is associated with membrane failure and neuronal death. However, there is overwhelming experimental evidence of isolated, but persistent, synaptic failure resulting from mild or moderate cerebral ischemia. Early failure results from presynaptic damage with impaired transmitter release. Proposed mechanisms include dysfunction of adenosine triphosphate-dependent calcium channels and a disturbed docking of glutamate-containing vesicles resulting from impaired phosphorylation. We review energy distribution among neuronal functions, focusing on energy usage of synaptic transmission. We summarize the effect of ischemia on neurotransmission and the evidence of long-lasting synaptic failure as a cause of persistent symptoms in patients with cerebral ischemia. Finally, we discuss the implications of synaptic failure in the diagnosis of cerebral ischemia, including the limited sensitivity of diffusion-weighted MRI in those cases in which damage is presumably limited to the synapses. (Stroke. 2012;43:607-615.)Key Words: brain metabolism Ⅲ cerebral ischemia Ⅲ synaptic failure T he human brain is metabolically expensive. Although it represents only 2% of the body weight, it accounts for 20% of oxygen consumption and 25% of glucose utilization. 1,2 Cerebral ischemia is a pathological condition in which blood flow to the brain is insufficient to meet these metabolic demands, causing a loss of neuronal function and viability. Ischemia may be focal if a brain artery is occluded or global, for example, after cardiac arrest.In the 1950s, the concept of perfusion thresholds was introduced. 3 It was shown that functional activity became impaired with moderately reduced perfusion (14 -35 mL/100 g/min), along with electroencephalographic and evoked potential disturbances, whereas loss of ion gradients across the plasma membrane and subsequent cell swelling occur at lower perfusion levels Ϸ4.8 to 8.4 mL/100 g/min (Figure 1). [3][4][5] In focal brain ischemia, the brain tissue that is perfused in the flow range between these 2 levels is now called the penumbra. 6 The penumbra is considered structurally intact and viable, but functionally silent. The dysfunction is, in principle, reversible by restoration of blood flow. However, if oxygen and glucose are not resupplied in time, irreversible damage occurs.Knowledge on the distribution of energy usage among different neuronal activities may contribute to understanding the successive loss of cell function and cell damage in cerebral ischemia. In the human brain, Ϸ30% of the energy is spent on synaptic transmission. 7 Disappearance of synaptic activity is the earliest consequence of cerebral ischemia 8 and failure of synaptic transmission has been proposed to account for electric silence in the penumbra. 3,6,8 -10 The changes of syna...

Molecular Alterations in the Hippocampus after Experimental Subarachnoid Hemorrhage

“…Experimental evidence showed that persistent synaptic failure may result from mild or moderate cerebral ischemia involving both pre-and postsynaptic components of the hippocampus. 34 Although there was an acute decrease in CBF at the time of blood or saline injection, we did not find differences between CBF or glucose À ) analysis. Significantly increased NO was found in the hippocampus (A), Pp0.001, Student's t-test) but not cerebral cortex (B) in subarachnoid hemorrhage (SAH) group as compared with saline controls.…”

Optogenetic Analysis of Neuronal Excitability during Global Ischemia Reveals Selective Deficits in Sensory Processing following Reperfusion in Mouse Cortex

“…The global ischemia model used here is clinically related to cardiac arrest or cardiac surgery (Hofmeijer and van Putten, 2012). Although this model does not recapitulate more clinically relevant middle cerebral artery occlusion models (Dirnagl et al, 1999), we can precisely control the duration of ischemia to within seconds and can rapidly alternate between the initiation of ischemia or reperfusion.…”

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

“…In this condition, the region of the brain that is most damaged, the ischemic core, fully depends on oxygen and glucose provided by the affected blood vessel, while the penumbra region, the area surrounding the infarcted core, is not as compromised due to a limited supply of components required for the metabolism derived from the collateral circulation. Glucose is the main substrate for cerebral energy production (Hofmeijer and van Putten, 2012) and during stroke the oxygen carried by the blood is much less than that required for complete oxidation of its content of glucose. Under these conditions, glycolysis may persist after oxygen has been depleted, but the reduction of oxidative metabolism of glucose leads to decreased ATP levels, while ADP and AMP levels increase (Hertz, 2008), causing a disruption of ionic homeostasis (Hansen, 1985), opening of anion channels (Kimelberg and Mongin, 1998), plasma membrane depolarization (Lipton, 1999), release of glutamate through astrocytic hemichannels (Ye et al, 2003) and downregulation of glutamate transporters (Harvey et al, 2011).…”