title: 3-O-Methyldopa inhibits astrocyte-mediated dopaminergic neuroprotective effects of L-DOPA.
abstract: We evaluated the effects of 3-O-methyldopa (3-OMD), a metabolite of L-DOPA which is formed by catechol-O-methyltransferase (COMT), on the uptake, metabolism, and neuroprotective effects of L-DOPA in striatal astrocytes. We examined changes in the numbers of dopaminergic neurons after treatment with L-DOPA and 3-OMD or entacapone, a peripheral COMT inhibitor, using primary cultured mesencephalic neurons and striatal astrocytes.
  
  
  
  The number of tyrosine hydroxylase-positive dopaminergic neurons was not affected by L-DOPA treatment in mesencephalic neurons alone. However, the increase in viability of dopaminergic neurons in the presence of astrocytes was further enhanced after methyl-L-DOPA treatment (25 µM) in mixed cultured mesencephalic neurons and striatal astrocytes. The neuroprotective effect of 25 µM L-DOPA was almost completely inhibited by simultaneous treatment with 3-OMD (10 or 100 µM), and was enhanced by concomitant treatment with entacapone (0.3 µM). The uptake of L-DOPA into and the release of glutathione from striatal astrocytes after L-DOPA treatment (100 µM) were inhibited by simultaneous exposure to 3-OMD (100 µM).
  
  
  
  These data suggest that L-DOPA exerts its neuroprotective effect on dopaminergic neurons via astrocytes and that 3-OMD competes with L-DOPA by acting on target molecule(s) (possibly including glutathione) released from astrocytes. Since some amount of entacapone can cross the blood-brain barrier, this reagent may enhance L-DOPA transportation by inhibiting COMT and increase the astrocyte-mediated neuroprotective effects of L-DOPA on dopaminergic neurons.
authors.affiliation: Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan. asachan@cc.okayama-u.ac.jp.|Department of Brain Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan. asachan@cc.okayama-u.ac.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Asanuma
authors.affiliation: Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.|Department of Brain Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Miyazaki
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D065098:Catechol O-Methyltransferase Inhibitors / Q000494:pharmacology; D002396:Catechols / Q000494:pharmacology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism; D007980:Levodopa / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism; D000066829:Neuroprotection / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D014443:Tyrosine / Q000031:analogs & derivatives
chemical_list: D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D015259:Dopamine Agents; D018696:Neuroprotective Agents; D009570:Nitriles; D014443:Tyrosine; D007980:Levodopa; C071192:entacapone; D004295:Dihydroxyphenylalanine; D005978:Glutathione; C008404:3-methoxytyrosine
keywords: 3-O-Methyldopa; Astrocyte; Entacapone; Glutathione; L-DOPA