0000000000075271
AUTHOR
O. Kempski
Endothelial Cell Swelling and Brain Perfusion
Background: Whereas the contribution of glial swelling to no-reflow conditions in the ischemic penumbra or during reperfusion after global ischemia is widely discussed, little is known about cell volume control of endothelial cells under reperfusion conditions. Methods: The effect of extracellular acidosis-a key mediator of secondary brain damage-on cell volume was studied in the GM7373 endothelial cell line. Experiments were performed at pH = 6.0 in the presence or absence of bicarbonate, and during exposure to inhibitors of specific transport systems such as ethyl isopropyl amiloride or 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid. Results: Endothelial swelling to 111.1 ± 3.4% was f…
Glial Protection Against Neuronal Damage
Glial homeostatic mechanisms are involved in neuronal protection during the early phase of cerebral ischemia. These protective effects include, among others, glutamate uptake and the regulation of pH in the extracellular space of the brain. Uptake of glutamate goes along with glial swelling, as does the elimination of protons from the glial cytosol. Five transport systems interact in order to maintain a normal intra- and extracellular pH in the brain.
Effects of Extracellular Acidosis on Glial Cell Intracellular pH: Evidence for a Glial Spatial H+-Buffering Mechanism?
Acidosis and in particular lactacidosis from anaerobic metabolism are considered of primary significance among the consequences of cerebral ischemia, seizures,, and head injury (Siesjo 1981). A marked decrease in brain tissue pH has been demonstrated in cerebral ischemia - even more so in hyperglycemic subjects - where lactic acid may accumulate to 20–30 mM and higher concentrations (Rehncrona et al. 1980; Katsura et al. 1991). Tissue pH may drop to pH 5.5 (Chopp et al. 1988). In consequence, acidosis has since long been suspected as a mediator of brain damage (Siesjo 1981).
Neuron-Glial Interaction During Injury and Edema of the CNS
During injury and ischemia of the CNS mediator compounds are released or activated which cause secondary swelling and damage of nerve cells. Such mediators are glutamate, acidosis, free fatty acids, or high extracellular potassium. Glial homeostatic mechanisms are activated to prevent the secondary injury from these mediators. The glial clearance mechanisms have been studied in detail using in vitro systems allowing for a close control of the glial environment. Current evidence suggests glial swelling to occur together with glutamate uptake or in response to extracellular acidosis. Glial swelling, therefore, is rather the result of homeostatic mechanisms than an indication of glial demise.
Biochemical Factors and Mechanisms of Secondary Brain Damage in Cerebral Ischemia and Trauma
A distinction between primary and secondary manifestations of brain damage from acute insults, such as trauma, or ischemia is not only of scientific interest but also of the highest clinical significance. After all, prevention of secondary brain damage in patients with severe head injury or cerebral ischemia is the ultimate purpose of treatment, including the measures of emergency care. It can be assumed that the secondary sequelae of head injury are as important for the outcome as the primary insult is. Therefore, it is obvious that development of more effective forms of treatment requires a better understanding of the mechanisms underlying secondary brain damage. Manifestations of seconda…
Swelling, Intracellular Acidosis, and Damage of Glial Cells
Cerebral ischemia and severe head injury among others are associated with a limited availability of oxygen, leading to cell catabolism as well as anaerobic glycolysis. Resulting metabolites, such as arachidonic- and lactic acid, can be expected to leak into perifocal brain areas, contributing there to cytotoxic swelling and damage of neurons and glia. Since elucidation of mechanisms underlying cell swelling and damage in the brain is difficult in vivo, respective investigations were carried out in vitro using suspended glial cells. Thereby, effects of arachidonic acid (AA) and of lactacidosis on glial cell volume, intracellular pH (pHi), and cell damage were analyzed utilizing flow cytometr…
Effects of Cortical Spreading Depression on Cortical Blood Flow, Impedance, DC Potential, and Infarct Size in a Rat Venous Infarct Model
A cortical venous infarction model has been evaluated as to the degree of regional flow reduction and by studying effects of cortical spreading depression (CSD). Two adjacent cortical veins were occluded photochemically with rose bengal and fiberoptic illumination. Seven rats served to demonstrate effects on regional cortical blood flow using laser Doppler scanning. In 36 rats local CBF, DC potential, and brain tissue impedance were measured continuously for 75 min after vein occlusion. No, 3, or 10 CSD waves were induced by potassium chloride injection during the initial 75 min. Rats were compared for spontaneous CSDs; baseline local CBF, CBF, and impedance response to CSD; and infarct vol…
Novel complement C1 inhibitor BSF468248 does not improve brain damage after cortical vein occlusion
BSF468248 is a novel potent complement C1 inhibitor. To determine whether BSF468248 is effective against focal cerebral ischemia, we evaluated the change of cerebral blood flow (CBF) and infarction volume using a photochemically-induced cortical vein occlusion model in rats in blind studies. In 22 Wistar rats, two adjacent cortical veins were occluded by photochemical thrombosis and fiberoptic illumination under controlled anesthesia and ventilation. Just after the occlusion, BSF468248 or physiological saline was administrated. In the low-dose study, a treatment group (n = 7) was administered BSF468248 1 mg/kg bolus and 1 mg/kg continuously for 30 min. The same volume of saline was given to…