Increased blood-brain transfer in a rabbit model of acute liver failure.
The blood-to-brain transfer of [14C]alpha-aminoisobutyric acid was investigated by quantitative autoradiography in normal rabbits and rabbits with acute liver failure induced by the selective hepatotoxin galactosamine. The blood-to-brain transfer of alpha-aminoisobutyric acid was similar in control animals and animals 2 and 7 h after galactosamine injections, but was increased five- to tenfold in certain gray-matter areas of the brain in animals 11 and 18 h after galactosamine treatment. No detectable differences in white-matter uptake of [14C]alpha-aminoisobutyric acid were found between the control and treated groups. The increase in alpha-aminoisobutyric acid transfer within the gray-matter areas suggested that a general or nonspecific increase in brain capillary permeability occurred in these areas. No clinical signs of early hepatic encephalopathy were observed in the treated rabbits, except for 1 animal from the 18-h postgalactosamine group. Thus, enhanced blood-brain transfer of alpha-aminoisobutyric acid preceded the development of overt hepatic encephalopathy. The distribution of radioactivity after the intravenous administration of [14C]galactosamine showed that virtually none of the hepatotoxin localized in the brain, suggesting that the drug itself does not have a direct effect upon the blood-brain barrier or the brain. The increased uptake of alpha-aminoisobutyric acid at 11 and 18 h implies that the transfer of other solutes would also be enhanced, that central nervous system homeostasis would be compromised, and that the resulting changes in brain fluid composition could contribute to or cause hepatic encephalopathy.
D000621:Aminoisobutyric Acids / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D001693:Biological Transport, Active; D001812:Blood-Brain Barrier; D002199:Capillary Permeability; D002250:Carbon Radioisotopes; D056486:Chemical and Drug Induced Liver Injury; D005688:Galactosamine; D006501:Hepatic Encephalopathy / Q000209:etiology; D008107:Liver Diseases / Q000378:metabolism*; D011817:Rabbits
D000621:Aminoisobutyric Acids; D002250:Carbon Radioisotopes; C100049:2-aminoisobutyric acid; D005688:Galactosamine