Hanna M. Pappius

Effects of Steroids on Cold Injury Edema

1. Dexamethasone diminishes total edema which develops in response to a standard freezing lesion. 2. Dexamethasone does not affect the characteristics of the edema that does develop. 3. Dexamethasone drastically diminishes the EEG abnormalities which develop in response to a standard injury to the brain. This effect does not appear to be mediated by the effect of this drug on cerebral edema.

Effect of Drugs on Local Cerebral Glucose Utilization in Traumatized Brain: Mechanisms of Action of Steroids Revisited

It may seem inappropriate to include in this volume work which does not deal directly with cerebral edema. However, we make no apologies for this fact since our present studies on the mechanisms by which injury to the brain causes functional neurological disturbances have evolved from a longstanding interest of one of us in processes underlying the development of brain edema and its consequences. We believe that the implications of our findings are pertinent to consideration of any condition associated with functional disturbances which are generally, rightly or wrongly, ascribed to cerebral edema.

Effects of Steroids on Edema Associated with Injury of the Spinal Cord

Standardized spinal cord injury was produced in cats by impact. Some were untreated and others treated with dexamethasone before and up to 24 h after injury.

Cerebral Edema and the Blood-Brain Barrier

Brain edema accompanies a wide variety of pathologic processes and contributes to the morbidity and mortality of many neurologic diseases.42 The early literature on this subject, dating back more than 50 years, was both confused and confusing for two main reasons: increased intracranial pressure (ICP) was often equated with the presence of edema, and there was no appreciation that different types of edema exist with different mechanisms of formation and resolution and thus presumably open to different therapeutic approaches.

Studies on the Mechanisms of Action of Steroids in Traumatized Brain

Preliminary results of a study of distribution of sodium-24 between the brain and the blood in cats show that 1. The relative specific activity (RSA) of sodium-24 in cerebral cortex is increased in both the control and the experimental (traumatized) hemisphere 24 h after a freezing lesion, as compared with cerebral cortex from normal animals. The effect is not seen in the white matter. This finding does not contradict the hypothesis that active transport of solute by astrocytes may be involved in the resolution of cerebral edema. It does suggest, however, that astrocytes of cerebral cortex, as opposed to those in the white matter, would play the major role in such a mechanism. 2. Furosemide diminishes the relative specific activity of sodium-24 in cerebral cortex in both the intact and the traumatized brain to the same extent. Thus, it does not abolish the increase in RSA of sodium seen as a consequence of injury. 3. Acetazolamide had no effect on sodium distribution in traumatized brain indicating that carbonic anhydrase is not involved in the sodium fluxes studied under our experimental conditions. 4. While the results available at present are not definitive, dexamethasone appears to have little, if any, generalized effect on the electrolyte metabolism of traumatized brain.

Evidence Regarding the Action of Steroids in Injured Spinal Cord

1. Dexamethasone (0.25 mg/kg/day) prevents the loss of potassium from the injured spinal cord which occurs in untreated animals between the third and sixth day and persists on the ninth day. 2. The level of potassium in the spinal cord on the sixth day after injury correlates with the functional state of the animal at the same time. 3. These results indicate that in spinal cord injury, as in cerebral trauma, the benefical effects of dexamethasone do not appear to be mediated through their action on edema. In both instances, functional intergrity appears better preserved in dexamthasone-treated animals while effects on edema are not particulary impressive

Neurochemical Sequelae of Brain Damage and Their Role in Functional Disturbances

Various types of injury have been shown to produce a variety of chemical changes in brain which are thought to underly functional disturbances resulting from the particular insult. Some of the systems known to be affected in injured brain are summarized in Figure 1, but the list is by no means exhaustive. The exact mechanisms by which the chemical perturbations are related to functional disturbances are not understood in most cases and it is often difficult to distinguish between the cause and the effect in this relationship. One problem has been the difficulty in assessing neurological function in animals since normalization of neurochemical disturbances in brain cannot always be equated with normally functioning central nervous system and the available methods are not necessarily applicable in the particular experimental situation.

Neurochemical approaches to the amelioration of brain injury

The studies reported here represent a continuing search for mechanisms which may play a role in neurological disturbances resulting from brain injury. In particular, they are part of an effort to elucidate the involvement of both the serotonergic and noradrenergic neurotransmitter systems in the wide-spread decrease in cortical glucose utilization, interpreted as reflecting a functional depression, associated with a focal cortical lesion in the rat. Quinolinic acid, an endogenous metabolite of L-tryptophan, a neurotoxin and an N-methyl-D-aspartate (NMDA) receptor agonist was found to accumulate in cortical areas of a traumatized rat hemisphere in parallel with a previously demonstrated increase of 5-hydroxyindoleacetic acid. Ketanserin (20 mg/kg/day), a 5-HT2 receptor blocker ameliorated the depression of glucose utilization in traumatized brain while MK-801 (3 mg/kg, before and after lesion), an NMDA receptor blocker, had no effect. Alpha 1-adrenergic receptors, quantitated in vivo with [125I]-HEAT (iodo-2-[beta-(4-hydroxyphenyl)-ethyl-aminomethyl]tetralone), were found to be elevated in cortical areas of the lesioned hemisphere, but not in other structures.

Cerebral Water and Electrolyte Content Following Ischemia and Blood-Brain Barrier Disturbances

As part of a series of studies on the effects of carotid occlusion in the gerbil (1–3, 5), water and electrolyte contents of the affected hemisphere were determined following 1 h of unilateral occlusion and different periods of recirculation. The results were compared with effects of air embolism (6) on the same parameters to determine whether some of the observed changes were associated generally with opening of the blood-brain barrier or were a more specific consequence of ischemic insult.

Effect of Injury on α1-Adrenoreceptors in Rat Brain in Vivo

We have used a freezing lesion in the rat as a model of cerebral injury (Pappius, 1981) and the deoxyglucose method of Sokoloff et al. (1977) to assess the functional state of traumatized brain. These studies indicated that with time after a focal lesion a widespread but not uniform depression of local cerebral glucose utilization (LCGU) developed, measurable within 4 hours and persisting for at least 5 days. Quantitation of CMRgluc in various structures showed that the cortical areas throughout the lesioned hemisphere were the most affected, the average cortical glucose utilization falling to about 50% of normal 3 days following the lesion. The effect was not restricted to areas surrounding the lesion or overlying edematous white matter, but involved the whole hemisphere from frontal to visual cortex. Heat lesions had a similar effect (Pappius, 1981).