TY - JOUR
T1 - Modulation of nigrostriatal dopaminergic transmission by antisense oligodeoxynucleotide against brain-derived neurotrophic factor
AU - Lau, Yuen Sum
AU - Hao, Ruyi
AU - Fung, Yiu K.
AU - Fu, Liu Song
AU - Bishop, John F.
AU - Pfeiffer, Ronald F.
AU - Mouradian, M. Maral
N1 - Funding Information:
This research was supported in part by grants from the University of Missouri Research Board, the National Parkinson Foundation, Inc. (YSL) and College of Dentistry, University of Nebraska Medical Center (YKF). The technical assistance of Todd Anderson and Marian Schmid is gratefully acknowledged. We thank Dr. Stanley Appel at Baylor College of Medicine, Houston, TX for providing MES 23.5 cells and Amgen, Inc., Thousand Oaks, CA for supplying BDNF antibody.
PY - 1998
Y1 - 1998
N2 - Brain-derived neurotrophic factor (BDNF) promotes the differentiation and growth of developing dopamine (DA) neurons and supports the survival of mature DA cells in culture. However, the neurotrophic role of endogenous BDNF in the adult DA system in vivo has not been well established. To investigate the hypothesis that blockade of endogenous BDNF expression results in DA dysregulation, we used an 18-mer antisense oligodeoxynucleotide (ODN) targeted to the first ATG codon of the BDNF transcript. The biological activity of the antisense ODN was initially tested in vitro. In cultured dopaminergic MES 23.5 cells, antisense BDNF (20 μM) effectively reduced BDNF protein expression and cell survival. Furthermore, in primary embryonic mesencephalic cultures, antisense BDNF reduced the number of tyrosine hydroxylase positive neurons and inhibited [3H]DA uptake in a time- and dose-dependent manner. The specificity of the antisense molecule was confirmed by comparing its effects with those of a control ODN having the same base composition but in scrambled sequence. In rats, two days following an intranigral or intrastriatal injection of antisense BDNF (0.5 μg), we observed a two-fold and five-fold increase in nigral DA levels, respectively, but no change in striatal DA content. Seven days after an intrastriatal antisense BDNF injection, DA levels were elevated in the striatum apparently due to decreased DA turnover. These observations suggest that inhibition of endogenous BDNF expression tends to augment rather than inhibit nigrostriatal DA transmission. Thus, the biological effects of endogenous BDNF on the nigrostriatal DA system in the adult organism merits further investigation.
AB - Brain-derived neurotrophic factor (BDNF) promotes the differentiation and growth of developing dopamine (DA) neurons and supports the survival of mature DA cells in culture. However, the neurotrophic role of endogenous BDNF in the adult DA system in vivo has not been well established. To investigate the hypothesis that blockade of endogenous BDNF expression results in DA dysregulation, we used an 18-mer antisense oligodeoxynucleotide (ODN) targeted to the first ATG codon of the BDNF transcript. The biological activity of the antisense ODN was initially tested in vitro. In cultured dopaminergic MES 23.5 cells, antisense BDNF (20 μM) effectively reduced BDNF protein expression and cell survival. Furthermore, in primary embryonic mesencephalic cultures, antisense BDNF reduced the number of tyrosine hydroxylase positive neurons and inhibited [3H]DA uptake in a time- and dose-dependent manner. The specificity of the antisense molecule was confirmed by comparing its effects with those of a control ODN having the same base composition but in scrambled sequence. In rats, two days following an intranigral or intrastriatal injection of antisense BDNF (0.5 μg), we observed a two-fold and five-fold increase in nigral DA levels, respectively, but no change in striatal DA content. Seven days after an intrastriatal antisense BDNF injection, DA levels were elevated in the striatum apparently due to decreased DA turnover. These observations suggest that inhibition of endogenous BDNF expression tends to augment rather than inhibit nigrostriatal DA transmission. Thus, the biological effects of endogenous BDNF on the nigrostriatal DA system in the adult organism merits further investigation.
KW - Antisense oligodeoxynucleotide
KW - Brain-derived neurotrophic factor
KW - Dopaminergic transmission
KW - Rat
KW - Striatum
KW - Susbtantia nigra pars compacta
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U2 - 10.1023/A:1022482518292
DO - 10.1023/A:1022482518292
M3 - Article
C2 - 9566587
AN - SCOPUS:0031956007
SN - 0364-3190
VL - 23
SP - 525
EP - 532
JO - Neurochemical Research
JF - Neurochemical Research
IS - 4
ER -