QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (28) Citing Articles via Google Scholar Google Scholar Articles by Lee, W. Y. Articles by Kang, U. J. Search for Related Content PubMed PubMed Citation Articles by Lee, W. Y. Articles by Kang, U. J.

 Previous Article  |  Next Article 

The Journal of Neuroscience, April 15, 1999, 19(8):3266-3274

Vesicular Monoamine Transporter-2 and Aromatic L-Amino Acid Decarboxylase Enhance Dopamine Delivery after L-3,4-Dihydroxyphenylalanine Administration in Parkinsonian Rats

Won Yong Lee¹, Jin Woo Chang¹, Nicole L. Nemeth¹, and Un Jung Kang^{1, 2, 3}

Departments of ¹ Neurology and ² Pharmacological and Physiological Sciences, and ³ Committee on Neurobiology, The University of Chicago, Chicago, Illinois 60637

Medical therapy in Parkinson's disease (PD) is limited by the short-duration response and development of dyskinesia that result from chronic L-3,4-dihydroxyphenylalanine (L-DOPA) therapy. These problems occur partly because the loss of dopamine storage sites leads to erratic dopamine delivery. Vesicular monoamine transporter-2 (VMAT-2) plays a critical role in dopamine storage by packaging dopamine into synaptic vesicles and regulating sustained release of dopamine. To restore the capacity to produce and store dopamine in parkinsonian rats, primary skin fibroblast cells (PF) were genetically modified with aromatic L-amino acid decarboxylase (AADC) and VMAT-2 genes. After incubation with L-DOPA in culture, the doubly transduced fibroblast cells (PFVMAA) produced and stored dopamine at a much higher level than the cells with either gene alone. PFVMAA cells in culture released dopamine gradually in a constitutive manner. Genetically modified fibroblast cells were grafted in parkinsonian rat striata, and L-DOPA was systemically administered. Higher dopamine levels were sustained for a longer duration in rats grafted with PFVMAA cells than in those grafted with either control cells or cells with AADC alone. These findings underscore the importance of dopamine storage capacity in determining the efficacy of L-DOPA therapy and illustrate a novel method of gene therapy combined with precursor administration to overcome the major obstacles of PD treatment.

Key words: short duration response; wearing-off; gene therapy; Parkinson's disease; dopamine; L-DOPA; AADC; VMAT

---

Copyright © 1999 Society for Neuroscience  0270-6474/99/1983266-09$05.00/0

This article has been cited by other articles:

				M. Mata, J. C. Glorioso, and D. J. Fink Gene Transfer to the Nervous System: Prospects for Novel Treatments Directed at Diseases of the Aging Nervous System J. Gerontol. A Biol. Sci. Med. Sci., December 1, 2003; 58(12): M1111 - 1118. [Abstract] [Full Text] [PDF]

				J. M. Brown, G. R. Hanson, and A. E. Fleckenstein Regulation of the Vesicular Monoamine Transporter-2: A Novel Mechanism for Cocaine and Other Psychostimulants J. Pharmacol. Exp. Ther., March 1, 2001; 296(3): 762 - 767. [Abstract] [Full Text]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help