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.

Substantial portions of the dorsal, and almost the entire posteroventral and anteroventral (Av) cochlear nuclei were aspirated unilaterally in a chimpanzee. Axonal degeneration was studied by the Fink-Heimer method. The greatest amount of degeneration was followed medially from the region of Av into the lateral part of the trapezoid body. Degeneration also coursed around the superior surface of the restiform body and was traced into the dorsal and intermediate acoustic striae. Within the superior olivary complex, degeneration was distributed to: the ipsilateral lateral superior olive; laterally and medially oriented dendrites of the ipsilateral and contralateral medial superior olivary nuclei respectively (some perisomatic degeneration also was present bilaterally); the contralateral medial trapezoid nucleus; retro-olivary and preolivary cell groups bilaterally. Abundant degeneration passed into the contralateral lateral lemniscus and was distributed largely to its ventral nucleus. The contralateral central nucleus of the inferior colliculus was a major site of termination of ascending second order auditory fibers. The caudal tip of the ipsilateral ventral nucleus of the lateral lemniscus received abundant degeneration, but this diminished rostrally. The ipsilateral inferior colliculus contained a moderate amount of degeneration. A fair number of degenerated second order auditory fibers ascended in the contralateral brachium of the inferior colliculus and were distributed both to the principle and magnocellular divisions of the medial geniculate body. This pathway appears to represent a phylogenetic advance in the brain of the great ape.

Described here are ultrastructural changes in neurons of feline red nucleus exhibiting axon reaction after unilateral rubropsinal tratotomy at the C-2 level and surviving 2 to 65 days. Ultrastructural alterations included neurofilamentous hyperplasia; proliferation of smooth ER; temporary disappearance of organized granular ER with partial substitution by haphazardly arranged, broad cisternal profiles; loss of rosette ribosomes and occurrence of single ribonucleoprotein granules or an intercisternal amorphous density; increased numbers of subsurface cisterns and allied structures, often disposed in stacks; vesiculation and vacuolation of Golgi cisternae; prevalence of autophagic bodies derived in part from Golgi complexes; probable mitochondrial hyperplasia and various qualitative changes in these organelles; an increase in lipofuscin. Dendritic changes paralleled those of perikarya save that proliferation of subsurface cisterns and autophagic bodies was absent. Abnormalities of myelinated axons and boutons occurred and may have originated from retrograde degeneration of cortical neurons induced by lateral funiculotomy. Some perikarya were devoid of axosomatic boutons. Ultrastructural changes varied with the length of postoperative survival and were, at least partly, reversible. Chromatolysis was detectable light microscopically before ultrastructural abnormality appeared. The bearing of transneuronal mechanisms on axon reaction of central neurons and the protective effect of section of axons beyond the site of origin of collaterals are discussed.

Blunt and ischemic injuries of the brain have been shown to result in swelling that is predominantly limited to a single cell type, the astrocyte, within the complex cellular mosiac of cerebral gray matter. Evaluation of various diuretic (aryloxy)acetic acids in vitro using incubating cat brain slices and primary astrocyte cultures identified compounds with marked ability to inhibit brain tissue swelling. Some of the compounds significantly reduced the mortality and morbidity following acceleration/deceleration brain injury in anesthesized cats. A variety of (indanyloxy)alkanoic acids were synthesized which were analogous to the dually active (indanyloxy)acetic acids. Some of the 4-(indanyloxy)butanoic acids were found to be devoid of diuretic activity but to possess equal or greater activity than the dually active compounds in the in vitro and in vivo brain assays. Selected examples from both the (indanyloxy)acetic and 4-(indanyloxy)butanoic acid series showed marked chiral effects, with one enantiomer generally exhibiting a much greater activity than the other. A clinical study of severely head-injured patients treated with ethacrynic acid demonstrated a significantly improved outcome when compared to controls. These data suggest a clinical advantage for the nondiuretic (aryloxy)alkanoic acids which possess in vitro and in vivo activities in the cat brain assays that are comparable or superior to dually active compounds.