Glutamate thiamin deficiency

As noted in Section 6.3.1.3, brain GABA falls in thiamin deficiency, but there is increased flux through the GABA shunt. The changes in the cerebellum occur early, and asymptomatic animals are more sensitive than normal to the GABA antagonist picrotoxin. Brain concentrations of glutamate and aspartate are also reduced in thiamin deficiency, as are several other neurotransmitters. 

Page MG, Ankoma-Sey V, Coulson WF, and Bender DA (1989) Brain glutamate and gamma-amlnohutyrate (GABA) metaholism in thiamin-deficient rats. British Journal of Nutrition 62, 245-53. 

HazeU AS, Butterworth RF, Hakim AM (1993) Cerebral vulnerability is associated with selective increase in extracellular glutamate concentration in experimental thiamine deficiency. J Neurochem 61(3) 1155-1158... 

Langlais PJ, Anderson G, Guo SX, Bondy SC (1997) Increased cerebral free radical production during thiamine deficiency. Metab Brain Dis 12(2) 137-143 Langlais PJ, Mair RG (1990) Protective effects of the glutamate antagonist MK-801 on pyrithiamine-induced lesions and amino acid changes in rat brain. J Neurosd 10(5) 1664-1674... 

Hazell, A. S., et al., 2003. Thiamine deficiency results in downregulafion of the GLAST glutamate transporter in cultured astrocytes. Glia. 43, 175-184. 

Persistent net ROS formation in thiamine deficiency can also initiate a cascade of cell death pathways via intracellular messengers, e.g. intracellular cas-pase-3-mediated apoptosis. Development of oxidative stress also leads to other disturbances in brain function, including an inhibition of glutamate uptake due to transporter protein nitrosylation following peroxynitrite formation (Hazell et al. 2003 Trotti et al. 1996 Volterra et al. 1994). Under conditions of oxidative stress, levels of HO-1, cNOS, iNOS, ICAM-1 and microglial activation are increased. Thus, oxidative stress can lead to profound neuropathological consequences in thiamine deficiency and WE. 

Excitotoxic damage involving loss of astrocytic glutamate transporters is a feature of thiamine deficiency and WE. 

Oxidative stress is an important part of the pathophysiology of thiamine deficiency in which key proteins involved in processes such as nitric oxide production, apoptosis, and glutamate transport are affected. 

Thiamine deficiency and WE are associated with glutamate-mediated excitotoxicity. 

Le, O., Heroux, M., and Butterworth, R.F., 1991. Pyrithiamine-induced thiamine deficiency results in decreased Ca -dependent release of glutamate from rat hippocampal slices. Metabolic Brain Disease. 6 125-132. 

In summary, thiamine deficiency drastically increases neuronal [Ca ]i through altering GluR2 properties. TD-mediated disruption of [Ca ]i may underlie glutamate excitotoxicity or ER stress-induced neurodegeneration in selective brain structures. 

One instance is known of more or less specific patholojpcal disturbance of transamination, namely, the marked decrease in -aph and as-aph activity in all tissues of severely thiamine-deficient pigeons and rats, described by Kritzmann (118, 119) the rates of l>amino acid deamination and of re-ductive amination of PU are similarly lowered, while the activity of d-amino acid oxidase and of glutamic dehydrogenase is not impiured. Absence of these effects in starved controls and the rapid restoration of aph activity upon administration of thiamine rule out a non-specific effect of lowered protein intake. 

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