Chronic elevation of brain-derived neurotrophic factor by ampakines

被引:113
作者
Lauterborn, JC
Truong, GS
Baudry, M
Bi, XN
Lynch, G
Gall, CM
机构
[1] Univ Calif Irvine, Dept Anat & Neurobiol, Irvine, CA 92697 USA
[2] Univ Calif Irvine, Dept Neurobiol & Behav, Irvine, CA USA
[3] Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92717 USA
[4] Univ So Calif, Neurosci Program, Los Angeles, CA 90089 USA
关键词
D O I
10.1124/jpet.103.053694
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The ampakine CX614 positively modulates alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-gated currents and increases brain-derived neurotrophic factor (BDNF) expression. In rat hippocampal slice cultures, CX614 rapidly increases BDNF gene expression but with time, mRNA levels fall despite the continued presence of active drug. The present study examined this apparent refractory period and the possibility that spaced ampakine treatments could sustain elevated BDNF protein levels. In cultured hippocampal slices, CX614, a second ampakine CX546, and the cholinergic agonist carbachol each increased BDNF mRNA levels with acute (3-h) treatment. After 4-day pretreatment with CX614, fresh ampakine (CX614 or CX546) did not induce BDNF mRNA, whereas carbachol did. Western blots confirmed that after an extended period of ampakine treatment, AMPA receptor protein levels are indeed reduced, suggesting that with longer treatments receptor down-regulation mediates ampakine insensitivity. Finally, using a "24-h on/24-h off" CX614 treatment protocol, the ampakine refractory state was circumvented, BDNF mRNA was induced with each ampakine application, and elevated BDNF protein levels were maintained through 5 days in vitro. These results suggest that spaced ampakine treatments can be used to sustain elevated neurotrophin levels and to test the utility of this manipulation for neuroprotection by endogenous neurotrophins.
引用
收藏
页码:297 / 305
页数:9
相关论文
共 40 条
[31]   MAPPING PATTERNS OF C-FOS EXPRESSION IN THE CENTRAL-NERVOUS-SYSTEM AFTER SEIZURE [J].
MORGAN, JI ;
COHEN, DR ;
HEMPSTEAD, JL ;
CURRAN, T .
SCIENCE, 1987, 237 (4811) :192-197
[32]   BDNF gene can be activated by Ca2+ signals without involvement of de Novo AP-1 synthesis [J].
Sano, K ;
Nanba, H ;
Tabuchi, A ;
Tsuchiya, T ;
Tsuda, M .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1996, 229 (03) :788-793
[33]   Neurotrophic factors in Alzheimer's and Parkinson's disease brain [J].
Siegel, GJ ;
Chauhan, NB .
BRAIN RESEARCH REVIEWS, 2000, 33 (2-3) :199-227
[34]   CENTRALLY ACTIVE MODULATORS OF GLUTAMATE RECEPTORS FACILITATE THE INDUCTION OF LONG-TERM POTENTIATION IN-VIVO [J].
STAUBLI, U ;
PEREZ, Y ;
XU, FB ;
ROGERS, G ;
INGVAR, M ;
STONEELANDER, S ;
LYNCH, G .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (23) :11158-11162
[35]   FACILITATION OF GLUTAMATE RECEPTORS ENHANCES MEMORY [J].
STAUBLI, U ;
ROGERS, G ;
LYNCH, G .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (02) :777-781
[36]   Neurotrophins: from enthusiastic expectations through sobering experiences to rational therapeutic approaches [J].
Thoenen, H ;
Sendtner, M .
NATURE NEUROSCIENCE, 2002, 5 (Suppl 11) :1046-1050
[37]  
Timmusk T, 1999, J BIOL CHEM, V274, P1078
[38]   Anterograde axonal transport, transcytosis, and recycling of neurotrophic factors - The concept of trophic currencies in neural networks [J].
von Bartheld, CS ;
Wang, XX ;
Butowt, R .
MOLECULAR NEUROBIOLOGY, 2001, 24 (1-3) :1-28
[39]   Expression of cerebellar long-term depression requires postsynaptic clathrin-mediated endocytosis [J].
Wang, YT ;
Linden, DJ .
NEURON, 2000, 25 (03) :635-647
[40]   ACTIVITY DEPENDENT REGULATION OF BDNF AND NGF MESSENGER-RNAS IN THE RAT HIPPOCAMPUS IS MEDIATED BY NON-NMDA GLUTAMATE RECEPTORS [J].
ZAFRA, F ;
HENGERER, B ;
LEIBROCK, J ;
THOENEN, H ;
LINDHOLM, D .
EMBO JOURNAL, 1990, 9 (11) :3545-3550