Modulation of nigrostriatal dopaminergic transmission by antisense oligodeoxynucleotide against brain-derived neurotrophic factor

Yuen Sum Lau, Ruyi Hao, Yiu K. Fung, Liu Song Fu, John F. Bishop, Ronald Pfeiffer, M. Maral Mouradian

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)525-532
Number of pages8
JournalNeurochemical Research
Volume23
Issue number4
DOIs
StatePublished - 1998
Externally publishedYes

Fingerprint

Oligodeoxyribonucleotides
Brain-Derived Neurotrophic Factor
Dopamine
Modulation
Neurons
Corpus Striatum
Injections
Dopaminergic Neurons
Nerve Growth Factors
Base Composition
Tyrosine 3-Monooxygenase
Substantia Nigra
Bioactivity
Cell culture
Codon
Rats
Cell Survival
Cell Culture Techniques
Cells

Keywords

  • Antisense oligodeoxynucleotide
  • Brain-derived neurotrophic factor
  • Dopaminergic transmission
  • Rat
  • Striatum
  • Susbtantia nigra pars compacta

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry

Cite this

Modulation of nigrostriatal dopaminergic transmission by antisense oligodeoxynucleotide against brain-derived neurotrophic factor. / Lau, Yuen Sum; Hao, Ruyi; Fung, Yiu K.; Fu, Liu Song; Bishop, John F.; Pfeiffer, Ronald; Mouradian, M. Maral.

In: Neurochemical Research, Vol. 23, No. 4, 1998, p. 525-532.

Research output: Contribution to journalArticle

Lau, Yuen Sum ; Hao, Ruyi ; Fung, Yiu K. ; Fu, Liu Song ; Bishop, John F. ; Pfeiffer, Ronald ; Mouradian, M. Maral. / Modulation of nigrostriatal dopaminergic transmission by antisense oligodeoxynucleotide against brain-derived neurotrophic factor. In: Neurochemical Research. 1998 ; Vol. 23, No. 4. pp. 525-532.
@article{a44305e354484b88b6f1533472cb9c52,
title = "Modulation of nigrostriatal dopaminergic transmission by antisense oligodeoxynucleotide against brain-derived neurotrophic factor",
abstract = "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.",
keywords = "Antisense oligodeoxynucleotide, Brain-derived neurotrophic factor, Dopaminergic transmission, Rat, Striatum, Susbtantia nigra pars compacta",
author = "Lau, {Yuen Sum} and Ruyi Hao and Fung, {Yiu K.} and Fu, {Liu Song} and Bishop, {John F.} and Ronald Pfeiffer and Mouradian, {M. Maral}",
year = "1998",
doi = "10.1023/A:1022482518292",
language = "English (US)",
volume = "23",
pages = "525--532",
journal = "Neurochemical Research",
issn = "0364-3190",
publisher = "Springer New York",
number = "4",

}

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

AU - Mouradian, M. Maral

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

UR - http://www.scopus.com/inward/record.url?scp=0031956007&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031956007&partnerID=8YFLogxK

U2 - 10.1023/A:1022482518292

DO - 10.1023/A:1022482518292

M3 - Article

VL - 23

SP - 525

EP - 532

JO - Neurochemical Research

JF - Neurochemical Research

SN - 0364-3190

IS - 4

ER -