SUMMARY1. By measurement of the rate of disappearance of injected tracer thiamine from the bloodstream, a programme for the continuous injection of thiamine at a variable rate has been devised by which a steady raised level can be achieved rapidly and maintained in the circulation. By this means the flux of radioactive thiamine across the blood-brain barrier has been measured.2. In separate experiments progressively higher levels ofthiamine were maintained in the bloodstream. Evidence was obtained that the transport of thiamine across the blood-brain barrier is a carrier-mediated process which can be saturated by raised levels of thiamine.3. The saturation of the transport process was incomplete: kinetic analysis showed that there was a non-saturable component of the transport which was probably due to passive diffusion.4. The contribution of the non-saturable component was normally small and is probably insufficient to meet the needs of the brain for the vitamin unless the concentration of the vitamin in the blood is raised considerably above normal.5. This two-component transport process had substantially similar kinetic parameters in different regions of the brain.
SUMMARY1. Rats aged from 2 to 116 weeks were studied. 2. Influx of glucose into the brain is low in suckling rats but rises after weaning, to reach its highest level in the young adult, thenceforward declining slowly as age increases.3. The blood-brain barrier for glucose is fully developed in the rat by the age of 18 days and glucose enters the brain, at this stage, by carrier-mediated transport, as in the adult.4. The results show that the low influx of glucose into the brain of the suckling animal is due to a low maximum rate of transport of glucose rather than to a low affinity of the carrier-molecule for glucose.5. In the young adult rat, efflux of glucose back from the brain into the blood is greater than in either the suckling or the old animals. Thus the margin of safety, i.e. the extent to which the blood glucose can be reduced without affecting the utilization of glucose by the brain, is highest in the young adult.6. The lower margin of safety in the suckling animals is compensated for by the high influx of the ketone bodies which provide an alternative source of energy at this age. In the old animals there is no alternative source of energy, so that the older brain is at greatest risk in hypoglycaemia.
1. Acetaldehyde has been implicated in the pathogenesis of alcohol-related liver damage by two mechanisms. Adduct formation with many tissue constituents, especially proteins, makes them immunologically foreign or reduces enzyme activity and formation of cytotoxic free radicals from acetaldehyde metabolism. Adduct formation damage to microtubule associated proteins and to hepatocyte membranes impedes protein movement into, out of and around the cell. 2. Evidence that these mechanisms also have a role in alcoholic brain damage includes raised blood acetaldehyde in alcoholics, especially in those chemically dependent, or in other abnormal states; effects of extra-hepatic free radical toxicity, including induction of superoxide dismutase activity and damaged, abnormal variants of the thiamin-dependent enzyme transketolase and extrahepatic acetaldehyde-adduct formation with haemoglobin. That acetaldehyde-mediated impairment of microtubule systems also damages the brain is suggested by its importance for the maintenance by protein transport of often greatly extended brain cell processes. 3. Oxygen-derived free radicals can damage brain tissue, the effects including cerebral oedema, neuronal loss and damage to the blood-brain barrier, all changes also reported in the brains from alcoholic patients. Alcohol-related pathology in the brain differing from that in the liver, shows sharper regional variations in vulnerability and adverse effects due to nutritional deficiencies, especially of B-group vitamins. Even though some such deficits are capable of causing encephalopathy in the non-alcoholic, the strong association between them and chronic alcoholism points to possible aggravation by metabolic interactions at various levels between acetaldehyde and thiamin or other B-vitamins. Selective regional vulnerability may reflect differences in ease of acetaldehyde access or to important metabolic differences. Alteration of animal behaviour by acetaldehyde points to a need to correlate clinical evidence of acetaldehyde central nervous cytotoxicity with the incidence of different types of cognitive defect.
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