Changes in pyruvate dehydrogenase complex (PDHc) activity and [3H]QNB-receptor binding in rat brain subsequent to intracerebroventricular injection of bromopyruvate.
Pyruvate dehydrogenase complex (PDHc), a link between carbohydrate and acetylcholine metabolism, is a regulatory enzyme for glucose and neurotransmitter metabolism in the brain and is reduced in Alzheimer-diseased brain. To study functional consequences of an inhibition of PDHc on muscarinic receptor binding, bromopyruvate, a suicide inhibitor od PDHc, was injected intracerebroventricularly (icv) in rats. Bromopyruvate caused a reduction of PDHc activity in the 3 brain regions examined, however, reaching significance only in the cerebral cortex and the hippocampus and not in the striatum, 24 h after injection. 3, 6, and 12 weeks later, there was a normalization or transiently increased activity, respectively, of PDHc in these brain regions. No changes in concentrations of energy-rich phosphates could be demonstrated in the cerebral cortex 12 weeks after brompyruvate injection. The number of muscarinic receptors was significantly reduced in the cerebral cortex 12 weeks after injection. The data indicate that a transient reduction of brain PDHc activity in vivo is associated with a long-lasting reduction in muscarinic cholinergic receptors. Because comparable changes of PDHc and muscarinic receptors are found in dementia of Alzhemier type, the model of bromopyruvate inhibition of PDHc in rats is suggested to be useful for experimental dementia research.
Frölich
L
L
Department of Psychiatry, University of Würzburg, Federal Republic of Germany.
Strauss
M
M
Kornhuber
J
J
Hoyer
S
S
Sorbi
S
S
Riederer
P
P
Amaducci
L
L
D000544:Alzheimer Disease / Q000201:enzymology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology; D007276:Injections, Intraventricular; D007700:Kinetics; D008297:Male; D011768:Pyruvate Dehydrogenase Complex / Q000037:antagonists & inhibitors*; D011773:Pyruvates / Q000008:administration & dosage / Q000494:pharmacology*; D011813:Quinuclidinyl Benzilate / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000378:metabolism*
D011768:Pyruvate Dehydrogenase Complex; D011773:Pyruvates; D011976:Receptors, Muscarinic; C028484:quinuclidinyl benzilate receptor; C017092:bromopyruvate; D011813:Quinuclidinyl Benzilate