Thiamine deficiency results in metabolic acidosis and energy failure in cerebellar granule cells: An in vitro model for the study of cell death mechanisms in Wernicke's encephalopathy

Pierre Pannunzio, Alan S. Hazell, Marc Pannunzio, K. V. Rama Rao, Roger F. Butterworth

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

Thiamine deficiency (TD) in both humans and experimental animals results in severe compromise of mitochondrial function and leads to selective neuronal cell death in diencephalic and cerebellar structures. To examine further the influence of TD on neuronal survival in relation to metabolic changes, primary cultures of rat cerebellar granule cells were exposed to thiamine-deficient medium for up to 7 days in the absence or presence of the central thiamine antagonist pyrithiamine (Py). Exposure of cells for 7 days to thiamine-deficient medium alone resulted in no detectable cell death. On the other hand, 50 μM Py treatment led to reductions of thiamine phosphate esters, decreased activities of the thiamine-dependent enzymes α-ketoglutarate dehydrogenase and transketolase, a twofold increase in lactate release (P < 0.001), a lowering of pH, and significant (58%, P < 0.001) cell death. DNA fragmentation studies did not reveal evidence of apoptotic cell death. Addition of 50 μM α-tocopherol (vitamin E) or 100 μM of butylated hydroxyanisole (BHA) to Py-treated cells resulted in significant neuroprotection. On the other hand, addition of 10 μM MK-801, an NMDA receptor antagonist, was not neuroprotective. These results suggest that reactive oxygen species (ROS) play a major role in thiamine deficiency-induced neuronal cell death. Insofar as this experimental model recapitulates the metabolic and mitochondrial changes characteristic of thiamine deficiency in the intact animal, it might be useful in the elucidation of mechanisms involved in the neuronal cell death cascade resulting from thiamine deficiency. (C) 2000 Wiley-Liss, Inc.

Original languageEnglish (US)
Pages (from-to)286-292
Number of pages7
JournalJournal of Neuroscience Research
Volume62
Issue number2
DOIs
StatePublished - Oct 15 2000
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Cellular and Molecular Neuroscience

Keywords

  • Cell culture
  • Cell viability
  • Cerebellar granule cells
  • Energy metabolism
  • Pyrithiamine
  • Thiamine deficiency

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