Caspase-11 plays an essential role in methamphetamine-induced dopaminergic neuron apoptosis

Toxicol Sci. 2015 May;145(1):68-79. doi: 10.1093/toxsci/kfv014. Epub 2015 Jan 27.


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 molecular mechanisms of METH-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 the midbrain of rats exposed to METH with Western 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 apoptotic markers, cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase 1 (PARP), after silencing the caspase-11 expression in rat midbrain 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 inhibited METH-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 and may be a potential gene target for therapeutics in METH-caused neurotoxicity.

Keywords: apoptosis; caspase-11; dopamine; methamphetamine; neurotoxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Caspases / genetics
  • Caspases / metabolism*
  • Cell Line, Tumor
  • Enzyme Activation
  • Gene Silencing
  • Humans
  • Male
  • Methamphetamine / toxicity*
  • Neurons / drug effects*
  • Neurons / metabolism
  • Poly(ADP-ribose) Polymerases / metabolism
  • Rats
  • Rats, Sprague-Dawley


  • Methamphetamine
  • Poly(ADP-ribose) Polymerases
  • Caspases