Region-selective permeability of the blood-brain barrier to α-aminoisobutyric acid during thiamine deficiency and following its reversal

Abstract

Thiamine deficiency (TD) results in focal lesions in several regions of the rat brain including the thalamus and inferior colliculus. Since alterations in blood-brain barrier (BBB) integrity may play a role in this damage, we have examined the influence of TD on the unidirectional blood-to-brain transfer constant (Ki) of the low molecular weight species α-aminoisobutyric acid (AIB) in vulnerable and non-vulnerable brain regions at different stages during progression of the disorder, and following its reversal with thiamine. Analysis of the regional distribution of Ki values showed early (day 10) increased transfer of [14C]-AIB across the BBB in the vulnerable medial thalamus as well as the non-vulnerable caudate and hippocampus. At the acute symptomatic stage (day 14), more widespread BBB permeability changes were detected in most areas including the lateral thalamus, inferior colliculus, and non-vulnerable cerebellum and pons. Twenty-four hours following thiamine replenishment, a heterogeneous pattern of increased BBB permeability was observed in which many structures maintained increased uptake of [14C]-AIB. No increase in the [3H]-dextran space, a marker of intravascular volume, was detected in brain regions during the progress of TD, suggesting that BBB permeability to this large tracer was unaffected. These results indicate that BBB opening i) occurs early during TD, ii) is not restricted to vulnerable areas of the brain, iii) is progressive, iv) persists for at least 24 h following treatment with thiamine, and v) is likely selective in nature, depending on the molecular species being transported.

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Acknowledgements

Financial support for this study was provided by the Canadian Institutes of Health Research.

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ASH designed and performed all experiments. Data analysis was performed by ASH. ASH and RFB jointly contributed to the writing of the manuscript.

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Correspondence to Alan S. Hazell.

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Hazell, A.S., Butterworth, R.F. Region-selective permeability of the blood-brain barrier to α-aminoisobutyric acid during thiamine deficiency and following its reversal. Metab Brain Dis 36, 239–246 (2021). https://doi.org/10.1007/s11011-020-00644-w

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Keywords

  • Thiamine
  • α-Aminoisobutyric acid
  • Neurodegeneration
  • Wernicke’s encephalopathy
  • Thiamine deficiency
  • Blood-brain barrier