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- Title
Caspase-11 Plays an Essential Role in Methamphetamine-Induced Dopaminergic Neuron Apoptosis.
- Authors
Weiye Huang; Wei-Bing Xie; Dongfang Qiao; Pingming Qiu; Enping Huang; Bing Li; Chuanxiang Chen; Chao Liu; Qi Wang; Zhoumeng Lin; Huijun Wang
- Abstract
Methamphetamine (METH) is an extremely addictive stimulant drug that is widely used with high potential of abuse. Previous studies have shown that METH exposure damages the nervous system, especially dopaminergic neurons. However, the exact molecularmechanisms ofMETH-induced neurotoxicity remain unclear. We hypothesized that caspase-11 is involved in METH-induced neuronal apoptosis. We tested our hypothesis by examining the change of caspase-11 protein expression in dopaminergic neurons (PC12 and SH-SY5Y) and in themidbrain of rats exposed to METH withWestern blotting. We also determined the effects of blocking caspase-11 expression with wedelolactone (a specific inhibitor of caspase-11) or siRNA on METH-induced apoptosis in PC12 cells and SH-SY5Y cells using Annexin V and TUNEL staining. Furthermore, we observed the protein expression changes of the apoptoticmarkers, cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase 1 (PARP), after silencing the caspase-11 expression in ratmidbrain by injecting LV-shcasp11 lentivirus using a stereotaxic positioning system. Results showed that METH exposure increased caspase-11 expression both in vitro and in vivo, with the effects in vitro being dose- and time-dependent. Inhibition of caspase-11 expression with either wedelolactone or siRNAs reduced the number of METH-induced apoptotic cells. In addition, blocking caspase-11 expression inhibitedMETH-induced activation of caspase-3 and PARP in vitro and in vivo, suggesting that caspase-11/caspase-3 signal pathway is involved in METH-induced neurotoxicity. These results indicate that caspase-11 plays an essential role in METH-induced neuronal apoptosis andmay be a potential gene target for therapeutics inMETH-caused neurotoxicity.
- Subjects
CASPASES; METHAMPHETAMINE; DOPAMINERGIC neurons; APOPTOSIS; NEUROTOXICOLOGY; PROTEIN expression
- Publication
Toxicological Sciences, 2015, Vol 145, Issue 1, p68
- ISSN
1096-6080
- Publication type
Article
- DOI
10.1093/toxsci/kfv014