Decreased synthesis of acetylcholine accompanying impaired oxidation of pyruvic acid in rat brain minces

Abstract

The relation between pyruvate utilization and acetylcholine synthesis was investigated in minces of adult rat brain. The flux of pyruvate to acetylcholine was less than 1% of that to CO2; nevertheless, a number of agents which inhibited conversion of [1-14C]-pyruvate or [2-14C]pyruvate into 14CO2 were associated with corresponding decreases in the conversion of [2-14C]pyruvate into acetylcholine. The amount of acetylcholine produced by minces of whole rat brain, measured by g.l.c.-mass spectrometry, decreased similarly. Among the inhibitory compounds tested were 3-bromopyruvate, an irreversible inhibitor of pyruvate dehydrogenase; 2-oxobutyrate, a competitive inhibitor of pyruvate dehydrogenase; other 2-oxo acids; and amobarbital and pentobarbital. Linear-regression equations relating CO2 production to acetylcholine synthesis gave correlation coefficients of 0.89-0.93 for the combined observations. The inhibition of acetylcholine synthesis could not be attributed to inhibition of choline acetyltransferase. Incorporation of [2-14C]pyruvate into lipids, proteins and nucleic acids was effected less than that into acetylcholine. Under these experimental conditions, it was shown that pyruvate utilization can limit acetylcholine synthesis.

Cerebrometabolic Aspects of Delirium in Relationship to Dementia

“…Cholinergic transmission turns out to be exquisitely sensitive to impairments of cerebral metabolism, despite the two to three order of magnitude differences in fluxes of carbon to CO 2 and to acetylcholine. Results were similar in vitro and in vivo, and with several different types of experimental preparations [5][6][7]. The oxygen tensions associated with decreased acetylcholine synthesis in mice are those associated with impaired judgement in humans [2,6].…”

“…A functional connection between the metabolic encephalopathies and disorders of neurotransmission was uncovered by our coworkers and us in the 1970s [4][5][6][7]. Cholinergic transmission turns out to be exquisitely sensitive to impairments of cerebral metabolism, despite the two to three order of magnitude differences in fluxes of carbon to CO 2 and to acetylcholine.…”

Causes and Consequences of Disturbances of Cerebral Glucose Metabolism in Sporadic Alzheimer Disease: Therapeutic Implications

“…The energy-rich compound acetyl-CoA is used 1. for further oxidation to ATP in the tricarboxylic acid cycle (more than 95% of acetyl-CoA), 2. for the formation of the neurotransmitter acetylcholine (1% to 2% of acetyl-CoA) (Gibson et al, 1975), and 3. for the formation of cholesterol in the 3-hydroxy-3-methylglutarly-CoA cycle (Michikawa and Yanagisawa, 1999). Cholesterol is the main sterol in membranes, and it also serves as the basic compound from which neurosteroids derive (Rupprecht and Holsboer, 1999).…”

Long-term abnormalities in brain glucose/energy metabolism after inhibition of the neuronal insulin receptor: implication of tau-protein

“…The glycolytically formed compounds 1) fructose-6-phosphate is the source of the hexosamine biosynthetic pathway synthesizing UDP-N-acetylglucosamine (UDPGlcNAc) for protein O-glycosylation (for review, Gong et al, 2006), and 2) pyruvate yields the energy-rich compound acetyl-CoA which is used a) for further oxidation in the tricarboxylic acid cycle (TCAC) to ATP (more than 95% of acetyl-CoA), b) for the formation of the neurotransmitter acetylcholine (1-2% of acetyl-CoA) (Gibson et al, 1975;Perry et al, 1980), and c) for the formation of cholesterol in the 3-hydroxy-3-methyl-glutaryl-CoA cycle (Michikawa and Yanagisawa, 1999).…”