Our previous study has demonstrated that hippocampal neurogenesis is vulnerable to thiamine (vitamin B1) deficiency (TD), and furthermore impaired hippocampal neurogenesis is associated with cognitive dysfunction induced by TD at the early pre-pathological stage of TD9 and TD14 (9 and 14 days after TD respectively) (Zhao et al. 2008). The mechanism through which TD impairs hippocampal neurogenesis remains to be clarified.Thiamine exerts its in vivo physiological function as thiamine pyrophosphate (TPP), the active form of thiamine. TPP is an important cofactor for three key enzymes involved in both the Krebs cycle and pentose-phosphate pathway (PPP): pyruvate dehydrogenase (PDH), a-ketoglutamate dehydrogenase (KGDH), and transketolase (TK). PDH and KGDH are key mitochondrial enzymes that regulate glucose oxidative metabolism and energy production. TK is a key enzyme of the non-oxidative branch of PPP, which is a dominant pathway responsible for synthesizing ribose-5-phosphate and the reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH). Previous biochemical studies have showed that brain PDH activity is unchanged in TD (Elnageh and Gaitonde 1988;Munujos et al. 1996). Some studies have revealed that the failure of energy metabolism and oxidative stress induced by decreased KGDH activity may be related to the pathogenesis of TD.
AbstractThiamine deficiency (TD) impairs hippocampal neurogenesis. However, the mechanisms involved are not identified. In this work, TD mouse model was generated using a thiamine-depleted diet at two time points, TD9 and TD14 for 9 and 14 days of TD respectively. The activities of pyruvate dehydrogenase (PDH), a-ketoglutamate dehydrogenase (KGDH), glucose-6-phosphate dehydrogenase (G6PD), and transketolase (TK), as well as on the contents of NADP + and NADPH were determined in whole mouse brain, isolated cortex, and hippocampus of TD mice model. The effects of TK silencing on the growth and migratory ability of cultured hippocampal progenitor cells (HPC), as well as on neuritogenesis of hippocampal neurons were explored. The results showed that TD specifically reduced TK activity in both cortex and hippocampus, without significantly affecting the activities of PDH, KGDH, and G6PD in TD9 and TD14 groups. The level of whole brain and hippocampal NADPH in TD14 group were significantly lower than that of control group. TK silencing significantly inhibited the proliferation, growth, and migratory abilities of cultured HPC, without affecting neuritogenesis of cultured hippocampal neurons. Taken together, these results demonstrate that decreased TK activity leads to pentosephosphate pathway dysfunction and contributes to impaired hippocampal neurogenesis induced by TD. TK and pentosephosphate pathway may be considered new targets to investigate hippocampal neurogenesis.