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RNA interference-mediated inhibition of brain-derived neurotrophic factor expression increases cocaine's cytotoxicity
Qing-Shan Yan1, Mei-Jinag Feng, Shu-E Yan
1Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61656, USA. qsy@uic.edu
Abstract:
Previous studies showed that cocaine exposure decreased brain-derived neurotrophic factor (BDNF) function and resulted in neuronal cell death. To investigate a role of BDNF in cocaine's cytotoxicity, an RNA interference (RNAi) approach was used. Transfection of neuroblastoma SK-N-AS cells or primary rat hippocampal neurons with the small double-stranded interfering RNA (siRNA) targeting BDNF mRNA, but not the scrambled siRNA, resulted in reductions in levels of BDNF mRNA and proteins by more than 70% in the transfected cells as compared with the control group, suggesting an RNAi-mediated, sequence-specific gene silencing. The results also showed that cocaine-induced cytotoxicity, assessed by the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazodium bromide) assay, was more pronounced in the cells transfected with the siRNA than in the cells transfected with the scrambled siRNA or in the cells treated with Lipofectamine 2000 alone (the control group), suggesting that inhibition of BDNF expression enhances cocaine's cytotoxicity. Together with previous studies showing that cocaine suppresses BDNF expression, the present data suggest that the drug-induced reduction of BDNF productions may make neurons more vulnerable to cocaine's toxic effects and precipitate cocaine-induced central nervous system damages.
Insights
Cocaine exposure reduces brain-derived neurotrophic factor (BDNF), increasing neuronal vulnerability. Inhibiting BDNF enhances cocaine
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Cocaine exposure is known to decrease brain-derived neurotrophic factor (BDNF) function, leading to neuronal cell death.
- The precise role of BDNF in cocaine's neurotoxicity remains to be fully elucidated.
Purpose of the Study:
- To investigate the role of BDNF in cocaine-induced cytotoxicity.
- To determine if reduced BDNF levels enhance cocaine's toxic effects on neurons.
Main Methods:
- Utilized an RNA interference (RNAi) approach using small double-stranded interfering RNA (siRNA) targeting BDNF mRNA in neuroblastoma SK-N-AS cells and primary rat hippocampal neurons.
- Assessed cocaine-induced cytotoxicity using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazodium bromide) assay.
- Confirmed sequence-specific gene silencing by measuring reductions in BDNF mRNA and protein levels.
Main Results:
- Transfection with siRNA targeting BDNF mRNA significantly reduced BDNF levels by over 70% compared to control groups.
- Cocaine-induced cytotoxicity was significantly more pronounced in cells with inhibited BDNF expression.
- This suggests that reduced BDNF levels potentiate the toxic effects of cocaine on neuronal cells.
Conclusions:
- Inhibition of BDNF expression enhances cocaine's cytotoxicity.
- The drug-induced reduction of BDNF may increase neuronal vulnerability to cocaine's toxic effects.
- This mechanism may contribute to cocaine-induced central nervous system damage.
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