Concurrent calpain and caspase-3 mediated proteolysis of aII-spectrin and tau in rat brain after methamphetamine exposure: A similar profile to traumatic brain injury Matthew W. Warren a,b, * , Firas H. Kobeissy a,b,d , Ming Cheng Liu b,e , Ronald L. Hayes a,b,f , Mark S. Gold a,b,g , Kevin K.W. Wang a,b,c a University of Florida Department of Psychiatry, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA b University of Florida Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA c Center for Neuroproteomics and Biomarkers Research, University of Florida College of Medicine, PO BOX 100256, Gainesville, FL 32610, USA d University of Florida College of Medicine, PO BOX 100215, Gainesville, FL 32610, USA e University of Florida College of Medicine, PO BOX 100244, Gainesville, FL 32610, USA f Institute for Traumatic Brain Injury Studies, University of Florida College of Medicine, PO BOX 100244, Gainesville, FL 32610, USA g Division of Addiction Medicine, PO BOX 100183, Gainesville, FL 32610, USA Received 15 November 2004; accepted 22 April 2005 Abstract Neurotoxicity in rat cortex and hippocampus following acute methamphetamine administration was characterized and compared to changes following traumatic brain injury. Doses of 10, 20, and 40 mg/kg of methamphetamine produced significant increases in calpain- and caspase- cleaved aII-spectrin and tau protein fragments, suggesting cell injury or death. Changes in proteolytic products were significantly increased over vehicle controls. Use of fragment specific biomarkers detected prominent calpain-mediated protein fragments in the cortex and hippocampus while caspase-mediated protein fragments were also detected in the hippocampus. Remarkably, proteolytic product increases at the 40 mg/kg dose after 24 h were as high as those observed in experimental traumatic brain injury. Use of calpain and caspase proteolytic inhibitors may be useful in preventing methamphetamine-induced neurotoxicity. D 2005 Elsevier Inc. All rights reserved. Keywords: Methamphetamine; Drug abuse; Traumatic brain injury; Caspases; Calpain; Alpha-spectrin; Tau protein; Cerebral cortex; Hippocampus Introduction Methamphetamine (Meth, or Speed) is now among the most popular drugs of abuse. Meth mentions in emergency depart- ments have been increasing each year since 1999, with a 19% jump in mentions between 2001 and 2002 (DAWN, 2003). A single dose of Meth can cause adverse reactions, such as clinical hyperthermia (NIDA, 1997). Meth has been shown to cause dopaminergic and, to a lesser extent, serotonergic neurite and nerve terminal degeneration of neurons in the striatum and hippocampus (Larsen et al., 2002). This striatal cell damage leads to clinical psychosis which is currently the main end point in clinical evaluation (Martin et al., 2003). It has been proposed that Meth-induced redistribution of dopamine from synaptic vesicles to cytoplasmic compartments, where dop- amine can oxidize to produce quinones and additional reactive oxygen species, may account for this selective neurotoxicity (De Vito and Wagner, 1989; Gluck et al., 2001). Furthermore, it has been reported that Meth exposure, by producing reactive oxygen species, can upregulate pro-apoptosis genes such as c- Jun , c-myc and L-myc and thus induce neuronal apoptosis directly (Stumm et al., 1999; Deng et al., 2002b; Thiriet et al., 2001). In support of those findings, Meth also induces apoptosis in both a CNS-derived catecholaminergic cell line 0024-3205/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.lfs.2005.04.058 * Corresponding author. University of Florida, College of Medicine, PO BOX 100183, Gainesville, FL 32610. Tel.: +1 352 392 3681. E-mail addresses: warren@ufl.edu (M.W. Warren), firasko@ufl.edu (F.H. Kobeissy), liumc@mbi.ufl.edu (M.C. Liu), hayes@mbi.ufl.edu (R.L. Hayes), msgold@psychiatry.ufl.edu (M.S. Gold), kwang@psychiatry.ufl.edu (K.K.W. Wang). Life Sciences 78 (2005) 301 – 309 www.elsevier.com/locate/lifescie