Reversal of motor impairments in parkinsonian rats by continuous intrastriatal delivery of L-dopa using rAAV-mediated gene transfer.

Kirik Deniz; Georgievska Biljana; Burger CorinnaWinkler ChristianMuzyczka NicholasMandel RonaldJBjorklund Anders

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Reversal of motor impairments in parkinsonian rats by continuous intrastriatal delivery of L-dopa using rAAV-mediated gene transfer.

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Intrastriatal delivery of the tyrosine hydroxylase gene by viral vectors is being explored as a tool for local delivery of L-dopa in animals with lesions of the nigrostriatal pathway. The functional effects reported using this approach have been disappointing, probably because the striatal L-dopa levels attained have been too low. In the present study, we have defined a critical threshold level of L-dopa, 1.5 pmol/mg of tissue, that has to be reached to induce any significant functional effects. Using new generation high-titer recombinant adeno-associated virus vectors, we show that levels of striatal L-dopa production exceeding this threshold can be obtained provided that tyrosine hydroxylase is coexpressed with the cofactor synthetic enzyme, GTP-cyclohydrolase-1. After striatal transduction with this combination of vectors, substantial functional improvement in both drug-induced and spontaneous behavior was observed in rats with either complete or partial 6-hydroxydopamine lesions of the nigrostriatal pathway. However, complete reversal of motor deficits occurred only in animals in which part of the striatal dopamine innervation was left intact. Spared nigrostriatal fibers thus may convert L-dopa to dopamine and store and release dopamine in a more physiologically relevant manner in the denervated striatum to mediate better striatal output-dependent motor function. We conclude that intrastriatal L-dopa delivery may be a viable strategy for treatment and control of adverse side effects associated with oral L-dopa therapy such as on-off fluctuations and drug-induced dyskinesias in patients with Parkinson's disease.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2002年第7期|4708-4713|共6页
作者
Kirik Deniz; Georgievska Biljana; Burger CorinnaWinkler ChristianMuzyczka NicholasMandel RonaldJBjorklund Anders;
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作者单位

Wallenberg Neuroscience Center, Department of Physiological Sciences, Division of Neurobiology, Lund University, BMC A11, S-221 84, Lund, Sweden.;

ublic.wh.hb.cn;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
Dependovirus; GTP Cyclohydrolase; Gene Therapy; Levodopa; Parkinson Disease; 依赖病毒; GTP环化水解酶; 基因疗法; 左旋多巴; 帕金森病; 酪氨酸单氧化酶;

Reversal of motor impairments in parkinsonian rats by continuous intrastriatal delivery of L-dopa using rAAV-mediated gene transfer.

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