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Activation of catechol‐O‐methyltransferase in astrocytes stimulates homocysteine synthesis and export to neurons
Author(s) -
Huang Guowei,
Dragan Magdalena,
Freeman David,
Wilson John X.
Publication year - 2005
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.20185
Subject(s) - catechol o methyl transferase , neurodegeneration , biology , astrocyte , biochemistry , extracellular , glutathione , endocrinology , medicine , enzyme , central nervous system , disease , allele , gene
Elevation of the total homocysteine (tHcy) concentration in plasma has been implicated in neurodegeneration in patients with stroke, dementia, Alzheimer disease, and Parkinson disease. Because the mechanisms controlling brain tHcy are unknown, the present study investigated its synthesis and transport in primary rat brain cell cultures. We found that the catechol‐O‐methyltransferase (COMT) substrate 3,4‐dihydroxybenzoic acid (DHB) increased export of tHcy in astrocytes, but not in neurons. The export mechanism was selective for tHcy over cyst(e)ine, total glutathione (tGSH) or cysteinylglycine (Cys‐Gly). tHcy export from astrocytes was also induced by the COMT substrates levodopa ( L ‐DOPA), dopamine and quercetin, and it was blocked by the COMT inhibitors tropolone and entacapone. This export was associated with increased synthesis of tHcy because both intracellular and extracellular tHcy concentrations rose during COMT activation. Incubation in cyst(e)ine‐deficient medium inhibited the tHcy export response to COMT activation. Exogenous tHcy (100 μM) was accumulated into neurons, but not into astrocytes. We conclude that activation of COMT causes sustained synthesis of Hcy in astrocytes and transport of this amino acid to neurons.© 2005 Wiley‐Liss, Inc.