Mechanisms of neuronal cell death in Wernicke's encephalopathy.
Wernicke's Encephalopathy (WE) is a serious neurological disorder resulting from thiamine deficiency, encountered in chronic alcoholics and in patients with grossly impaired nutritional status. Neuropathologic studies as well as Magnetic Resonance Imaging reveal selective diencephalic and brainstem lesions in patients with WE. The last decade has witnessed major advances in the understanding of pathophysiologic mechanisms linking thiamine deficiency to the selective brain lesions characteristic of WE. Activities of the thiamine-dependent enzyme alpha-ketoglutarate dehydrogenase, a rate-limiting tricarboxylic acid cycle enzyme are significantly reduced in autopsied brain tissue from patients with WE and from rats treated with the central thiamine antagonist, pyrithiamine. In the animal studies, evidence suggests that such enzyme deficits result in focal lactic acidosis, cerebral energy impairment and depolarization resulting from increased release of glutamate in vulnerable brain structures. It has been proposed that this depolarization may result in N-Methyl-D-Aspartate receptor-mediated excitotoxicity as well as increased expression of immediate early genes such as c-fos and c-jun resulting in apoptotic cell death. Other mechanisms involved in thiamine deficiency-induced cell loss may involve free radicals and alterations of the blood-brain barrier. Additional studies are still required to identify the site of the initial cellular insult and to explain the predilection of diencephalic and brainstem structures due to thiamine deficiency.
Hazell
A S
AS
Neuroscience Research Unit, Centre Hospitalier de l'Université de Montréal (Campus Saint-Luc), Quebec, Canada. hazella@ere.umontreal.ca
Todd
K G
KG
Butterworth
R F
RF
D000818:Animals; D017209:Apoptosis; D001812:Blood-Brain Barrier; D004734:Energy Metabolism; D005609:Free Radicals; D006801:Humans; D009474:Neurons / Q000473:pathology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D014899:Wernicke Encephalopathy / Q000473:pathology*
D005609:Free Radicals; D016194:Receptors, N-Methyl-D-Aspartate