Review The impact of oxidative stress in thiamine deficiency: A multifactorial targeting issue Alan S. Hazell a,b,⇑ , Samantha Faim b , Guilherme Wertheimer b , Vinicius R. Silva b , Cleiton S. Marques b a Department of Medicine, University of Montreal, Montreal, Quebec, Canada b Departamento de Neurologia, Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo, Brazil article info Article history: Available online 18 January 2013 Keywords: Vitamin B1 Wernicke–Korsakoff syndrome Glutamate Astrocyte Neurodegeneration abstract Thiamine (vitamin B1) deficiency, the underlying cause of Wernicke–Korsakoff syndrome, is associated with the development of focal neuronal loss in vulnerable areas of the brain. Although the actual mech- anism(s) that lead to the selective histological lesions characteristic of this disorder remain unresolved, oxidative stress has been shown to play a major role in its pathophysiology. In this review, the multifac- torial influence of oxidative stress on a variety of processes known to take part in the development of structural lesions in TD including excitotoxicity, neuroinflammation, blood–brain barrier integrity, mito- chondrial integrity, apoptosis, nucleic acid function, and neural stem cells will be discussed, and thera- peutic strategies undertaken for treating neurodegeneration examined which may have an impact on the future treatment of this important vitamin deficiency. Ó 2013 Elsevier Ltd. All rights reserved. 1. Introduction Vitamin B1 (thiamine) deficiency is a disorder involving impair- ment of oxidative metabolism in which selective cerebral vulnera- bility is a major consequence. This is manifested in the form of Wernicke–Korsakoff syndrome (WKS), a serious and potentially life-threatening neuropsychiatric disorder (Carmichael and Stern, 1931) consisting of Wernicke’s encephalopathy (WE), the neuro- logical component of the disorder characterized by acute thiamine deficiency (TD) in association with confusion, ophthalmoplegia, and ataxia but no permanent structural damage, and Korsakoff’s psychosis, a debilitating amnesic state due to chronic TD and accompanied by irreversible diencephalic lesions. Neuropathologi- cally, the disorder is characterized by focal areas of the brain devel- oping symmetrical hemorrhagic and ischemic-like lesions, occuring most frequently in diencephalic structures, in particular the thalamus and mammillary bodies (Fig. 1), extending caudally through the midbrain (inferior colliculus) and brainstem areas that include the vestibular nuclei and inferior olivary complex (Victor et al., 1989). 2. Pathophysiology of thiamine deficiency The pathophysiological mechanisms involved in TD are com- plex. Four major enzyme systems utilize thiamine in the form of thiamine diphosphate (TDP) as a major cofactor, i.e. pyruvate dehydrogenase (EC 1.2.4.1) complex (PDHC), an organized enzyme assembly that connects glycolysis with the tricarboxylic acid (TCA) cycle, a-ketoglutarate dehydrogenase (EC 1.2.4.2) complex (KGDHC), a multicomponent enzyme complex associated with the TCA cycle, transketolase (EC 2.2.1.1) (TK), a key participant in the pentose phosphate shunt involved in nucleic acid and lipid bio- synthesis, and branched-chain a-ketoacid dehydrogenase (EC 1.2.4.4) complex (BCKDHC) involved in accumulation of the branched chain amino acids leucine, isoleucine, and valine (Wendel et al., 1983), and which is associated with a rare inborn error of metabolism, maple syrup urine disease. Chronic thiamine deprivation is accompanied by region-selective reductions in levels of thiamine-dependent enzymes in brain (Butterworth, 1986), including KGDHC and TK (Fig. 2). While the exact role of PDHC, BCKDHC and transketolase remains unclear in the development of thiamine-deficiency induced lesions, KGDHC appears to be responsible for many of the reversible changes accompanying TD (Gibson et al., 1984; Butterworth and Heroux, 1989) (see Fig. 2). During experimental TD, onset of neurological symptoms occurs when TDP concentrations fall to less than 15% of normal values, and these reductions in TDP levels are accompanied by reductions 0197-0186/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neuint.2013.01.009 Abbreviations: AD, Alzheimer’s disease; ATP, adenosine triphosphate; BBB, blood–brain barrier; eNOS, endothelial nitric oxide synthase; GFAP, glial fibrillary acidic protein; GLT-1, glutamate transporter 1; GLAST, glutamate/aspartate trans- porter; KGDHC, a-ketoglutarate dehydrogenase complex; MAO, monoamine oxi- dase; NMDA, N-methyl-D-aspartate; PD, Parkinson’s disease; ROS, reactive oxygen species; SINDEPAR, Sinemet-Deprenyl-Parlodel; TCA, tricarboxylic acid cycle; TD, thiamine deficiency; TSPO, translocator protein (18 kDa); WKS, Wernicke–Korsakoff syndrome. ⇑ Corresponding author. Address: NeuroRescue Laboratory, Hôpital Saint-Luc (CHUM), 1058 St-Denis, Montreal, Quebec, Canada H2X 3J4. Tel.: +1 (514) 890 8310x35740/58; fax: +1 (514) 412 7737. E-mail address: alan.stewart.hazell@umontreal.ca (A.S. Hazell). Neurochemistry International 62 (2013) 796–802 Contents lists available at SciVerse ScienceDirect Neurochemistry International journal homepage: www.elsevier.com/locate/nci