Blood-brain barrier thiamin deficiency

Haemorrhagic lesions are characteristic of experimental thiamine deficiency and WE in humans indicative of a breakdown of the blood-brain barrier (BBB). A study using immunoglobulin G (IgG) as an indicator of BBB integrity in thiamine-deficient rats revealed increased IgG immunoreactivity in the inferior colliculus and inferior olive prior to the onset of cell death in these regions (Calingasan et al.,... 

Beauchesne E, Desjardins P, HazeU AS, Butterworth RE (2009) eNOS gene deletion restores blood-brain barrier integrity and attenuates neurodegeneration in the thiamine-deficient mouse brain. J Neurochem 111 452-459... 

The nervous system consists of various cell types that are functionally interconnected so as to allow efficient signal transmission throughout the system (see Chapter 48). The cells of the central nervous system are protected from potentially toxic compounds by the blood-brain barrier, which restricts entry of compounds into the nervous system (ammonia, however, is a notable exception). The brain cells communicate with each other and with other organs, through the synthesis of neurotransmitters and neuropeptides. Many of the neurotransmitters are derived from amino acids, most of which are synthesized within the nerve cell. Because the pathways of amino acid and neurotransmitter biosynthesis require cofactors (such as pyridoxal phosphate, thiamine pyrophosphate, and vitamin BI2), deficiencies of these cofactors can lead to neuropathies (dysfunction of specific neurons within the nervous system). 

A variety of models have been developed to study TD. TD in rodents can be produced in multiple ways. Simple deprivation of thiamine will deplete thiamine and thiamine-dependent processes. However, this expands the time until the symptoms occur, and increases the variability for time of the onset of the symptoms. Injection of inhibitors of thiamine utilization in conjunction with the thiamine deficient diet shortens the time until onset of symptoms and provides a remarkably reproducible model. Pyrithiamine, which is structurally similar to thiamine, blocks the thiamine pyrophospho kinase, which catalysis the phosphorylation of thiamine to thiamine pyrophosphate (TPP) so that the production of the metabolically active form of thiamine, TPP, is impaired. Pyrithiamine readily crosses the blood brain barrier so that TD is produced in the brain and in the periphery. On the other hand, oxythiamine does not cross the BBB and only produces TD in the periphery. The precise timing of the acute and chronic changes in TD varies with the model. All the models lead to diminished food intake, so, often paired fed controls are used. These have never shown that pathology is related to TD. 

Cafingasan, N. Y., et al., 1995a. Blood-brain barrier abnormalities in vulnerable brain regions during thiamine deficiency. Exp Neurol. 134, 64—72. 

PDH deficiency results in raised blood concentrations of pyruvate, lactate and alanine. Some patients respond to supplementation with lipoic acid or thiamin (coenzymes for PDH). Treatment with a low carbohydrate, ketogenic diet has been advocated but with limited success. (The ketone bodies readily cross the blood-brain barrier and their catabolism produces acetyl CoA independently of PDH.)... 

Considerable evidence for blood-brain barrier (BBB) damage in thiamine deficiency and WE has been described, with disturbances localized to brain regions vulnerable to thiamine deficiency, including the presence of hemorrhagic lesions (Torvik 1985 Vortmeyer and Colmant 1988). Such a process may also contribute to previous reports of brain edema identified in both thiamine deficiency and in cases of WE. 

The blood-brain barrier (BBB) is disrupted in thiamine deficiency and can lead to serious damage in areas of the brain where it occurs. 

Disruption of the blood brain barrier is a major consequence of thiamine deficiency and WE. 

Beauchesne, E., Desjardins, P., Flazell, A.S., and Butterworth, R.F., 2009. Endothelial NOS mediates blood-brain barrier alterations in the thiamine-deficient mouse brain. Journal of Neurochemistry. Ill 452—459. 

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