Pharmacological Treatment of Central Nervous System Trauma

Abstract: Traumatic injuries to the brain or spinal cord cause tissue damage, in part by initiating reactive biochemical changes. Pharmacological approaches aim to modify this delayed injury response by blocking one or more components of the reactive biochemical/metabolic cascade. This minireview summarizes both historical and recent developments in experimental and clinical treatment of CNS trauma. Potential treatments include: corticosteroids; antioxidants or free radical scavengers; drugs that modify arachidonic acid metabolism, platelet-activating factor antagonists; gangliosides; modulators of monoamine actions; opioid receptor antagonists; thyrotropin-releasing hormone and thyrotropin-releasing hormone analogues; glutamate receptor antagonists; calcium channel blockers; agents that modify the inflammatory/ immune response; and trophic factors. Understanding the mechanisms of action for these compounds can permit rational drug development/application, delineation of the therapeutic window, and laying of the ground-work for evaluating potential synergistic effects of combination treatment strategies.     

The relationship of drinking and birth outcome in a US national sample of expectant mothers

Alcohol consumption by pregnant women and birth outcome were studied in 9953 livebirths, 3309 fetal deaths and 5332 infant deaths from the 1988 National Maternal and Infant Health Survey. In crude analyses, race, age, mother's education, prenatal care, parity, low birthweight, gestational age, smoking and alcohol consumption during pregnancy were significantly related to the occurrence of fetal deaths and infant deaths. Among women having livebirths, race, age, mother's education, prenatal care, prematurity, gestational age, smoking and alcohol consumption during pregnancy were significantly related to having a low birthweight baby (< 2500 g). In this group, women who drank more during pregnancy also smoked more, were younger and less educated than women who drank at lower levels or not at all. The relationship of alcohol consumption during pregnancy and infant birthweight for those women having livebirths was studied using multivariable linear regression. The results indicated that race, mother's education, baby's sex, parity, mother's height, mother's body mass index and smoking, but not alcohol consumption, were significantly related to birthweight. Multivariable logistic regressions were performed for the occurrence of low birthweight, fetal death and infant death. The effect of alcohol was significant in all these analyses. These results indicate that alcohol has an important relationship with birth outcome, but that for the drinking reported in this study, the alcohol effect on mean birthweight is small relative to that of other risk factors, accounting for the non-significant result in the multiple linear regression.     

Neuropsychological Performance and Treatment Outcome in Male Alcoholics

Commonly used neuropsychological tests were administered to 91 detoxified alcoholics at the beginning of treatment. Statistically significant relationships were observed between test scores and post treatment consumption determined 8 months after completing treatment for 72 patients. The results varied depending upon the particular measure of posttreatment consumption evaluated and the type of statistical analysis used. The most consistent relationships were often counter to the notion that increased neuropsychological performance is correlated with a more favorable treatment outcome. Neuropsychological evaluation is of limited clinical utility in predicting posttreatment alcohol consumption.     

Computerized cortical surface electroencephalography after temporary middle cerebral artery occlusion in rabbits

The sensitivity and regional specificity of intraoperative electroencephalographic (EEG) monitoring in cerebral ischemia was evaluated in a new experimental model of temporary focal cerebral ischemia in rabbits. EEG potentials were recorded directly from the cortical surface using a bipolar disc electrode grid and were analyzed by computer. Groups of 5 animals each underwent temporary occlusion of the left middle cerebral arterial trunk for 5, 10, 20, 30, 45, or 60 minutes. EEG data were recorded from the cortex proximal (temporal site) and distal (parasagittal site) to the middle cerebral arterial trunk during occlusion and 2 hours of reperfusion. EEG suppression was detected immediately after occlusion at the temporal site by analysis of power spectra in 29 of 30 rabbits (mean power, 32% of base line), by compressed spectral array (CSA) edge analysis in 23, and by analysis of the conventional EEG wave form in 24. Within 5 minutes after the start of occlusion, all 30 rabbits showed EEG power suppression and 26 showed decrease in the CSA edge frequency or in the routine EEG wave form. By the end of the occlusion period, EEG power at the temporal site had decreased to 20.5% of base line. At the parasagittal site, a lesser degree of EEG suppression was detected; 20 rabbits had an initial loss of EEG power (mean, 85.7% of base line), 13 had decrease in the CSA edge, and 7 had suppression of the EEG wave form. By the end of the occlusion period, spectral power at the parasagittal site had decreased in 25 of 30 rabbits to a mean of 86.9% of base line.(ABSTRACT TRUNCATED AT 250 WORDS)     

31P NMR characterization of graded traumatic brain injury in rats

Irreversible tissue injury following central nervous system trauma is believed to result from both mechanical disruption at the time of primary insult, and more delayed "autodestructive" processes. These delayed events are associated with various biochemical changes, including alterations in phosphate energy metabolism and intracellular pH. Using 31P NMR, we have monitored the changes in phosphorus energy metabolism and intracellular pH in a single hemisphere of the rat brain over an 8-h period following graded, traumatic, fluid percussion-induced brain injury. Following trauma the ratio of phosphocreatine to inorganic phosphate (PCr/Pi) declined in each injury group. This decline was transitory with low injury (1.0 +/- 0.5 atm), biphasic with moderate (2.1 +/- 0.4 atm) and high (3.9 +/- 0.9 atm) injury, and sustained following severe injury (5.9 +/- 0.7 atm). The initial PCr/Pi decline in the moderate and high injury groups was associated with intracellular acidosis; however, the second decline occurred in the absence of any pH changes. Alterations in ATP occurred only in severely injured animals and such changes were associated with marked acidosis and 100% mortality rate. After 4h, the posttraumatic PCr/Pi ratio correlated linearly with the severity of injury. We suggest that a reduced posttraumatic PCr/Pi ratio may be indicative of altered mitochondrial energy production and may predict a reduced capacity of the cell to recover from traumatic injury.     

Life expectancy in British Marfan syndrome populations

A total of 206 patients with Marfan syndrome were ascertained throughout genetic clinics in Wales and Scotland during the period 1970–1990. There were 45 deaths representing 22% of the cohort. Mean age at death was 45.3 ± 16.5 years. 50% median cumulative survival in the total cohort (n = 206) was 53 years for males and 72 years for females. Multivariate analysis confirmed severity as the best independent indicator of survival. These findings and survival curves will assist in the counselling of British families and individuals with Marfan syndrome.     

Distribution of immunoreactive dynorphin in discrete brain nuclei; comparison with vasopressin

The distribution of the opioid peptide, dynorphin, has been studied in discrete, microdissected hypothalamic nuclei, and compared with the distribution of vasopressin. Both peptides were found in relatively high concentration in the supraoptic and paraventricular nuclei. However, dynorphin-like immunoreactivity (DYN-LI) was much more widely distributed in the hypothalamus than vasopressin-like immunoreactivity, with highest concentrations in the anterior hypothalamic and ventromedial nuclei. DYN-LI was also observed in some extra-hypothalamic structures; concentrations which were comparable to the highest levels in the hypothalamus were found in the tractus diagonalis and the nucleus interstitialis stria terminalis. Among the three brainstem nuclei examined, DYN-LI levels were highest in the sensory nucleus of the trigeminal nerve.