RT Journal Article
SR Electronic
T1 Methamphetamine-Induced Neurotoxicity Is Attenuated in Transgenic Mice with a Null Mutation for Interleukin-6
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1247
OP 1256
DO 10.1124/mol.58.6.1247
VO 58
IS 6
A1 Bruce Ladenheim
A1 Irina N. Krasnova
A1 Xiaolin Deng
A1 Jonathan M. Oyler
A1 Aldo Polettini
A1 Timothy H. Moran
A1 Marilyn A. Huestis
A1 Jean Lud Cadet
YR 2000
UL http://molpharm.aspetjournals.org/content/58/6/1247.abstract
AB Increasing evidence implicates apoptosis as a major mechanism of cell death in methamphetamine (METH) neurotoxicity. The involvement of a neuroimmune component in apoptotic cell death after injury or chemical damage suggests that cytokines may play a role in METH effects. In the present study, we examined if the absence of IL-6 in knockout (IL-6−/−) mice could provide protection against METH-induced neurotoxicity. Administration of METH resulted in a significant reduction of [125I]RTI-121-labeled dopamine transporters in the caudate-putamen (CPu) and cortex as well as depletion of dopamine in the CPu and frontal cortex of wild-type mice. However, these METH-induced effects were significantly attenuated in IL-6−/− animals. METH also caused a decrease in serotonin levels in the CPu and hippocampus of wild-type mice, but no reduction was observed in IL-6−/− animals. Moreover, METH induced decreases in [125I]RTI-55-labeled serotonin transporters in the hippocampal CA3 region and in the substantia nigra-reticulata but increases in serotonin transporters in the CPu and cingulate cortex in wild-type animals, all of which were attenuated in IL-6−/− mice. Additionally, METH caused increased gliosis in the CPu and cortices of wild-type mice as measured by [3H]PK-11195 binding; this gliotic response was almost completely inhibited in IL-6−/− animals. There was also significant protection against METH-induced DNA fragmentation, measured by the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeled (TUNEL) cells in the cortices. The protective effects against METH toxicity observed in the IL-6−/− mice were not caused by differences in temperature elevation or in METH accumulation in wild-type and mutant animals. Therefore, these observations support the proposition that IL-6 may play an important role in the neurotoxicity of METH.