Thiamine neuronal cell death, deficiency

Oxidative stress contributes to selective neuronal cell death in thiamine-deficiency 600... 

The suggestion that eNOS-derived NO is implicated in neuronal cell death mechanisms in thiamine deficiency contrasts with current views in cerebral ischemia in which increased eNOS-derived NO is thought to play a neuro-protective role by virtue of its vasodilatory potential. 

Moreover, targeted disruption (knock-down) of the eNOS gene attenuates the neuronal cell death in thiamine-deficient mice (Gibson and Zhang, 2002). eNOS knock-down but not knock-down of iNOS or nNOS leads to a reduction in protein tyrosine nitration (Beauchesne et al., 2009), suggesting a major role of eNOS as the source of nitric oxide-related nitrosative stress in thiamine deficiency. 

Thiamine deficiency results in mitochondrial dysfunction in which compromised brain energy metabolism produces oxidative stress, exci-totoxicity and inflammatory responses leading to neuronal cell death. 

We have previously demonstrated that thiamine deficiency induces ER stress or unfolded protein response (UPR) in animals and in cultured neurons (Wang et al. 2007). ER stress refers to the accumulation of unfolded or misfolded proteins in the ER lumen, resulting in an overall decrease in translation, enhanced protein degradation and increased levels of ER chaperones, which consequently increases the protein folding capacity of the ER. Sustained ER stress ultimately leads to the apoptotic death of the cell (Xu et al. 2005). A major cause of ER stress is the perturbation of calcium homeostasis (Matus et al. 2011). Therefore, it is likely that TD-induced alterations in [Ca ]i causes ER stress. 

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