((5-6-dichloro-2-3-9-9a-tetrahydro-3-oxo-9a-propyl-1h-fluoren-7-yl)oxy)acetic-acid and Brain-Injuries

Topics: Animals; Astrocytes; Brain; Brain Injuries; Cats; Cell Size; Edema; Fluorenes; Glutamic Acid; Ion Channel Gating; Ion Channels; Microdialysis; Neuroprotective Agents; Rats; Stroke; Survival Analysis; Tamoxifen

Swelling of brain slices is shown to occur in response to elevated potassium levels or glutamate, which is accompanied by astrocytic swelling. Cl-/HCO3- anion exchange inhibitors, such as SITS (4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid) or furosemide, but not the specific cotransport inhibitor bumetanide, inhibit swelling or increased ion uptake in rat brain slices caused by elevated potassium although there were marked species differences in sensitivity. A novel anion exchange inhibitor, L-644,711, inhibits swelling and increased ion uptake caused by glutamate in rat and cat brain slices, as well as inhibiting [3H]glutamate uptake in primary rat astrocyte cultures. Possible mechanisms of action of the inhibitors are discussed. L-644,711 was also found to be effective in promoting recovery from a trauma plus hypoxia head injury model in cats. Marked perivascular astrocytic swelling is associated with this head injury model, and L-644,711 also inhibited such astroglial swelling as determined ultrastructurally. The significance of these findings in relation to possible connections between astrocytic swelling and brain pathology is discussed.

Topics: 4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid; Animals; Astrocytes; Biological Transport; Brain; Brain Injuries; Cats; Cells, Cultured; Chlorides; Disease Models, Animal; Fluorenes; Glutamates; Glutamic Acid; Hypoxia, Brain; Ouabain; Potassium; Rats

We present qualitative and quantitative ultrastructural observations on the changes induced in neuroglia and blood vessels of gray matter of cat brain by an experimental acceleration-deceleration injury which, when used alone, causes negligible morbidity and mortality, but, when combined with systemic hypoxia, leads to coma and delayed death in approximately 50% of experimental subjects. An increase in the proportion of neuropil occupied by astrocytic cytoplasm is detectable qualitatively in layer Vb of pericruciate cortex 20 min after injury without hypoxia, and is maximal (22%, as measured morphometrically, vs 11.4% in controls) 40 min afterward. Near-normal values (14.1%) are obtained 100 min following the insult. If trauma is succeeded 40 min later by a 60-min period of hypoxia, there is prolongation of astrocytic edema and other neuroglial accompaniments of the traumatic lesion, such as aggregation of nuclear nucleoprotein granules and, in astrocytes, fusion of rosette ribosomes and enlargement of mitochondria. A decrease in luminal area occurs in capillaries 40 min after trauma applied alone. Hypoxia without trauma leads to a significant increase in capillary luminal area, which, however, is abolished when trauma precedes the hypoxic interlude. Intravenous injection of a non-diuretic, fluorenyl derivative (L-644,711) of (aryloxy)alkanoic acid loop diuretics, completely prevents the astrocytic swelling ordinarily present 40 min after acceleration-deceleration injury. Also, L-644,711 improves mortality and morbidity scores in cats subjected to trauma with hypoxia. We suggest that astroglial swelling may be a critical step in the evolving pathology of this head injury model and its prevention, as by L-644,711 administration, may have relevance to the treatment of cerebral edema in human head injury and other clinical disorders accompanied by astrocytic swelling.

Topics: Animals; Brain; Brain Diseases; Brain Injuries; Cats; Disease Models, Animal; Edema; Fluorenes; Hypoxia; Microscopy, Electron; Neuroglia

Cats, injured by a mechanical plus hypoxic model of traumatic brain injury, were treated by intracisternal injection of a modified loop diuretic (L-644,711). This drug inhibits the chloride/bicarbonate anion exchange transport system. The treatment resulted in a significant decrease in mortality from 61 to 21%, and an improvement in both neurological status and EEG activity of the surviving animals. The dose of drug given intracisternally was at least 175 times less than the dosage we previously found was needed to achieve a comparable effect when the drug was given intravenously. The present results suggest that certain types of head injury can be treated by drugs which affect cellular anion transport processes in the brain.

Topics: Animals; Brain Diseases; Brain Injuries; Cats; Cisterna Magna; Electroencephalography; Fluorenes; Hypoxia; Injections; Nervous System