Correlation of enzymatic, metabolic, and behavioral deficits in thiamin deficiency and its reversal.
To clarify the enzymatic mechanisms of brain damage in thiamin deficiency, glucose oxidation, acetylcholine synthesis, and the activities of the three major thiamin pyrophosphate (TPP) dependent brain enzymes were compared in untreated controls, in symptomatic pyrithiamin-induced thiamin-deficient rats, and in animals in which the symptoms had been reversed by treatment with thiamin. Although brain slices from symptomatic animals produced 14CO2 and 14C-acetylcholine from [U-14C]glucose at rates similar to controls under resting conditions, their K+-induced-increase declined by 50 and 75%, respectively. In brain homogenates from these same animals, the activities of two TPP-dependent enzymes transketolase (EC 2.2.1.1) and 2-oxoglutarate dehydrogenase complex (EC 1.2.4.2, EC 2.3.1.61, EC 1.6.4.3) decreased 60-65% and 36%, respectively. The activity of the third TPP-dependent enzyme, pyruvate dehydrogenase complex (EC 1.2.4.1, EC 2.3.1.12, EC 1.6.4.3) did not change nor did the activity of its activator pyruvate dehydrogenase phosphate phosphatase (EC 3.1.3.43). Although treatment with thiamin for seven days reversed the neurological symptoms and restored glucose oxidation, acetylcholine synthesis and 2-oxoglutarate dehydrogenase activity to normal, transketolase activity remained 30-32% lower than controls. The activities of other TPP-independent enzymes (hexokinase, phosphofructokinase, and glutamate dehydrogenase) were normal in both deficient and reversed animals.
D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D006593:Hexokinase / Q000378:metabolism; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism; D008297:Male; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013832:Thiamine Deficiency / Q000201:enzymology / Q000378:metabolism*; D013834:Thiamine Pyrophosphatase / Q000378:metabolism; D014174:Transketolase / Q000378:metabolism
D011768:Pyruvate Dehydrogenase Complex; D007655:Ketoglutarate Dehydrogenase Complex; D014174:Transketolase; D006593:Hexokinase; D013834:Thiamine Pyrophosphatase