Redox chemistry of cerebral extracellular fluid associated with brain injury.

摘要

The purpose of these studies was to determine if redox-active constituents in brain extracellular fluid are altered during brain injury. Two examples of rat brain injury were studied: (1) cerebral penetration trauma induced by insertion of an object (i.e. a microdialysis probe) into the brain, and (2) systemic administration of kainic acid, a neurotoxin.; Immediately after microdialysis probe insertion into the brain, ascorbate is present at high concentrations in microdialysates. At the same time, microdialysates produce high levels of catalase-resistant chemiluminescence. When ascorbate levels are high, catalase-sensitive (i.e. hydrogen peroxide-dependent) chemiluminescence is low in microdialysates, as well as in solutions of ascorbate. In addition to this apparent antioxidant effect, ascorbate has pro-oxidant effects in brain microdialysates; ascorbate contributes to catalase-resistant chemiluminescence and forms hydrogen peroxide in samples with time. Thus, ascorbate functions both as an antioxidant and as a pro-oxidant in brain microdialysates.; Within two hours of systemic kainic acid administration to rats (16 mg/kg ip), intracerebral microdialysates from the piriform cortex contain a 5-6 fold greater ascorbate concentration than control samples, and 100% higher urate concentrations. Chemiluminescence produced by catalase-resistant oxidant species in microdialysates increases over 100% within two hours of systemic kainic acid administration. When midazolam (5 mg/kg im) is coadministered with kainic acid, seizures do not occur. Brain extracellular fluid urate levels increase over the first hour after coadministration of kainic acid and midazolam, but decrease during the second hour to levels comparable to those observed with midazolam alone. Ascorbate levels increase even in the absence of seizure activity when midazolam is coadministered with kainic acid. When the N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovaleric acid (APV) is included in microdialysis perfusion media, there is a concentration-dependent decrease in basal ascorbate levels. In addition, microdialysis perfusion with APV (10 mM) attenuates the kainic acid-induced increase in ascorbate levels, but not urate levels, in intracerebral microdialysates. Thus, ascorbate levels increase in brain extracellular fluid after systemic administration of kainic acid, and may be associated with activity at the glutamate-NMDA receptor. In contrast, urate levels may increase as the result of changes that occur in the brain during kainic acid-induced seizures.; In conclusion, ascorbate and urate increase in brain extracellular fluid after brain insults. The redox roles of these molecules in brain extracellular fluid remains to be elucidated. Brain microdialysates produce a greater amount of oxidative chemiluminescence after cerebral penetration trauma and after systemic kainic acid administration; however, the source of the oxidant species may have been ascorbate, a constituent of the sample. Changes in brain extracellular fluid redox substances appear to be associated with brain insults and may relate to glutamatergic neuronal activity. (Abstract shortened by UMI.)