title: Loss of astrocytic glutamate transporters in Wernicke encephalopathy.
abstract: Wernicke encephalopathy (WE), a neurological disorder caused by thiamine deficiency (TD), is characterized by structural damage in brain regions that include the thalamus and cerebral cortex. The basis for these lesions is unclear, but may involve a disturbance of glutamatergic neurotransmission. We have therefore investigated levels of the astrocytic glutamate transporters EAAT1 and EAAT2 in order to evaluate their role in the pathophysiology of this disorder. Histological assessment of the frontal cortex revealed a significant loss of neurons in neuropathologically confirmed cases of WE compared with age-matched controls, concomitant with decreases in alpha-internexin and synaptophysin protein content of 67 and 52% by immunoblotting. EAAT2 levels were diminished by 71% in WE, with levels of EAAT1 also reduced by 62%. Loss of both transporter sites was confirmed by immunohistochemical methods. Development of TD in rats caused a profound loss of EAAT1 and EAAT2 in the thalamus accompanied by decreases in other astrocyte-specific proteins. Treatment of TD rats with N-acetylcysteine prevented the downregulation of EAAT2 in the medial thalamus, and ameliorated the loss of several other astrocyte proteins, concomitant with increased neuronal survival. Our results suggest that (1) loss of EAAT1 and EAAT2 glutamate transporters is associated with structural damage to the frontal cortex in patients with WE, (2) oxidative stress plays an important role in this process, and (3) TD has a profound effect on the functional integrity of astrocytes. Based on these findings, we recommend that early treatment using a combination of thiamine AND antioxidant approaches should be an important consideration in cases of WE.
authors: Department of Medicine, University of Montreal, Montreal, Quebec, Canada. alan.stewart.hazell@umontreal.ca
authors: Alan S
authors: AS
authors: Hazell
authors: Donna
authors: D
authors: Sheedy
authors: Raluca
authors: R
authors: Oanea
authors: Meghmik
authors: M
authors: Aghourian
authors: Simon
authors: S
authors: Sun
authors: Jee Yong
authors: JY
authors: Jung
authors: Dongmei
authors: D
authors: Wang
authors: Chunlei
authors: C
authors: Wang
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism*; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism*; D005625:Frontal Lobe / Q000378:metabolism; D050491:Glutamate Plasma Membrane Transport Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013788:Thalamus / Q000378:metabolism; D013832:Thiamine Deficiency / Q000188:drug therapy / Q000503:physiopathology*; D014899:Wernicke Encephalopathy / Q000503:physiopathology*
chemical_list: D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins; D018696:Neuroprotective Agents; C493397:SLC1A2 protein, human; C493394:SLC1A3 protein, human; C493395:Slc1a2 protein, rat; C493392:Slc1a3 protein, rat; D000111:Acetylcysteine