title: Molecular mechanisms of acidosis-mediated damage.
abstract: The present article is concerned with mechanisms which are responsible for the exaggerated brain damage observed in hyperglycemic animals subjected to transient global or forebrain ischemia. Since hyperglycemia enchances the production of lactate plus H+ during ischemia, it seems likely that aggravation of damage is due to exaggerated intra- and extracellular acidosis. This contention is supported by results showing a detrimental effect of extreme hypercapnia in normoglycemic rats subjected to transient ischemia or to hypoglycemic coma. Enhanced acidosis may exaggerate ischemic damage by one of three mechanisms: (i) accelerating free radical production via H(+)-dependent reactions, some of which are catalyzed by iron released from protein bindings by a lowering of pH, (ii) by perturbing the intracellular signal transduction pathway, leading to changes in gene expression or protein synthesis, or (iii) by activating endonucleases which cause DNA fragmentation. While activation of endonucleases must affect the nucleus, the targets of free radical attack are not known. Microvessels are considered likely targets of such attack in sustained ischemia and in trauma; however, enhanced acidosis is not known to aggravate microvascular dysfunction, or to induce inflammatory responses at the endothelial-blood interface. A more likely target is the mitochondrion. Thus, if the ischemia is of long duration (30 min) hyperglycemia triggers rapidly developing mitochondrial failure. It is speculated that this is because free radicals damage components of the respiratory chain, leading to a secondary deterioration of oxidative phosphorylation.
authors.affiliation: Laboratory for Experimental Brain Research, University of Lund, Sweden.
authors.forename: B K
authors.initials: BK
authors.lastname: Siesjö
authors.forename: K I
authors.initials: KI
authors.lastname: Katsura
authors.forename: T
authors.initials: T
authors.lastname: Kristián
authors.forename: P A
authors.initials: PA
authors.lastname: Li
authors.forename: P
authors.initials: P
authors.lastname: Siesjö
mesh_terms: D000136:Acid-Base Equilibrium / Q000235:genetics*; D000818:Animals; D001812:Blood-Brain Barrier / Q000235:genetics; D001925:Brain Damage, Chronic / Q000235:genetics*; D002545:Brain Ischemia / Q000235:genetics*; D053938:DNA Fragmentation / Q000235:genetics; D016883:Diabetic Ketoacidosis / Q000235:genetics*; D004579:Electron Transport / Q000235:genetics; D005609:Free Radicals; D008928:Mitochondria / Q000235:genetics; D016548:Prosencephalon / Q000098:blood supply*; D051381:Rats; D015398:Signal Transduction / Q000235:genetics
chemical_list: D005609:Free Radicals