Calpain- and caspase-mediated alphaII-spectrin and tau proteolysis in rat cerebrocortical neuronal cultures after ecstasy or methamphetamine exposure.
Matthew W Warren, Wenrong Zheng, Firas H Kobeissy, Ming Cheng Liu, Ronald L Hayes, Mark S. Gold, Stephen F Larner, Kevin K W Wang
The International Journal of Neuropsychopharmacology August 2007 DOI: 10.1017/s1461145706007061 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro study Peer reviewed |
|---|---|
| Population | Rat primary cerebrocortical neuron cultures |
| Interventions | MDMA methamphetamine NMDA calpain inhibitor SJA6017 caspase inhibitors z-VAD-fmk and Z-D-DCB |
| Dose | 1 or 2 mM |
| Duration | 24 and 48 h |
| Measures | microscopy, lactate dehydrogenase release, immunoblot |
| Topics | MDMA |
| Key points | MDMA and methamphetamine caused dose- and time-dependent neurotoxicity in rat cortical neuron cultures, with proteolysis of alphaII-spectrin and tau by both calpain and caspase proteases. Calpain and caspase inhibitors reduced this breakdown, suggesting these protease families act together and that similar drugs might be developed to counter drug-induced neurotoxicity in vivo. |
Abstract
Abuse of 3,4-methylenedioxymethamphetamine (MDMA or Ecstasy) and methamphetamine (Meth or Speed) is a growing international problem with an estimated 250 million users of psychoactive drugs worldwide. It is important to demonstrate and understand the mechanism of neurotoxicity so potential prevention and treatment therapies can be designed. In this study rat primary cerebrocortical neuron cultures were challenged with MDMA and Meth (1 or 2 mM) for 24 and 48 h and compared to the excitotoxin N-methyl-D-aspartate (NMDA). The neurotoxicity of these drugs, as assessed by microscopy, lactate dehydrogenase release and immunoblot, was shown to be both dose- and time-dependent. Immunoblot analysis using biomarkers of cell death showed significant proteolysis of both alphaII-spectrin and tau proteins. Breakdown products of alphaII-spectrin (SBDPs) of 150, 145, and 120 kDa and tau breakdown products (TBDPs) of 45, 32, 26, and 14 kDa were observed. The use of the protease inhibitors calpain inhibitor SJA6017 and caspase inhibitors z-VAD-fmk and Z-D-DCB, attenuated drug-induced alphaII-spectrin and tau proteolysis. The calpain inhibitor reduced the calpain-induced breakdown products SBDP145 and TBDP14, but there was an offset increase in the caspase-mediated breakdown products SBDP120 and TBDP45. The caspase inhibitors, on the other hand, decreased SBDP120 and TBDP45. These data suggest that both MDMA and Meth trigger concerted proteolytic attacks of the structural proteins by both calpain and caspase family of proteases. The ability of the protease inhibitors to reduce the damage caused by these drugs suggests that the treatment arsenal could include similar drugs as possible tools to combat the drug-induced neurotoxicity in vivo.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 6
- Amphetamine toxicities Annals of the New York Academy of Sciences January 8, 2010
- PRECLINICAL STUDY: Changes in leptin, ghrelin, growth hormone and neuropeptide‐Y after an acute model of MDMA and methamphetamine exposure in rats Addiction Biology October 2, 2007
- Increased oxidative-modifications of cytosolic proteins in 3,4-methylenedioxymethamphetamine (MDMA, ecstasy)-exposed rat liver. PROTEOMICS January 2011
- The role of oxidative stress, metabolic compromise, and inflammation in neuronal injury produced by amphetamine-related drugs of abuse. Journal of Neuroimmune Pharmacology December 2008
- Neuropeptide Y protects retinal neural cells against cell death induced by ecstasy. Neuroscience March 3, 2008
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