The role of thiamine deficiency in alcoholic brain disease

Abstract

A deficiency in the essential nutrient thiamine resulting from chronic alcohol consumption is one factor underlying alcohol-induced brain damage. Thiamine is a helper molecule (i.e., a cofactor) required by three enzymes involved in two pathways of carbohydrate metabolism. Because intermediate products of these pathways are needed for the generation of other essential molecules in the cells (e.g., building blocks of proteins and DNA as well as brain chemicals), a reduction in thiamine can interfere with numerous cellular functions, leading to serious brain disorders, including Wernicke-Korsakoff syndrome, which is found predominantly in alcoholics. Chronic alcohol consumption can result in thiamine deficiency by causing inadequate nutritional thiamine intake, decreased absorption of thiamine from the gastrointestinal tract, and impaired thiamine utilization in the cells. People differ in their susceptibility to thiamine deficiency, however, and different brain regions also may be more or less sensitive to this condition.

Figure 1

Brain regions affected by thiamine deficiency include the cerebellum, mamillary bodies, thalamus, hypothalamus, and brain stem.

Figure 2

The thiamine-dependent enzyme transketolase is an important enzyme in the breakdown of glucose through a biochemical pathway called the pentose phosphate pathway. Glucose is first converted to a molecule called glucose-6-phosphate, which enters the pentose phosphate pathway where it is further modified by transketolase. During that reaction, two products are formed—the sugar ribose-5-phosphate and a molecule called reduced nicotinamide adenine dinucleotide phosphate (NADPH). Ribose-5-phosphate is needed for the synthesis of nucleic acids, complex sugar molecules, and other compounds called coenzymes that are essential for the functioning of various enzymes. NADPH provides hydrogen atoms for chemical reactions that result in the production of coenzymes, steroids, fatty acids, amino acids, and neurotransmitters. In addition, NADPH plays an important role in the synthesis of glutathione, a compound that is essential to the body’s defense against damage from oxidative stress. Reduced transketolase activity interferes with all these essential biochemical processes.

Figure 3

The thiamine-dependent enzymes pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (α–KGDH) participate in the metabolism of glucose through two biochemical reactions, glycolysis and the citric acid cycle. The main function of these two sets of reactions is to generate adenosine triphosphate (ATP), which provides energy for the cells. Reduced PDH and α–KGDH activity resulting from thiamine deficiency can lead to less ATP synthesis, which in turn can contribute to cell damage and even cell death. In addition, PDH is needed to produce the neurotransmitter acetylcholine and to generate myelin, a compound that forms a sheath around the extensions (i.e., axons) of many neurons, thereby ensuring proper neuronal functioning. The citric acid cycle and α–KGDH play a role in maintaining the levels of the neurotransmitters glutamate, gamma-aminobutyric acid (GABA), and aspartate, as well as in protein synthesis.