Journal
NEUROBIOLOGY OF DISEASE
Volume 50, Issue -, Pages 49-58Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2012.10.006
Keywords
Methamphetamine; JNK; Metalloproteinases; Laminin; IgG; Blood-brain barrier; Hyperthermia
Categories
Funding
- Spanish Ministerio de Economia y Competitivad (MINECO)
- Ministerio de Sanidad y Politica Social
- ISCIII y Universidad Complutense-Comunidad de Madrid [SAF2010-21529, PNSD PR47/10-17826, RedRTA (RD06/0001/0006), UCM-CAM 910258]
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Methamphetamine (METH) is a widely consumed drug with high abuse potential. Studies in animals have shown that the drug produces dopaminergic neurotoxicity following both single high-dose and repeated low-dose administration. In addition, METH produces an increase in matrix metalloproteinase expression and loss of BBB integrity. We have examined the effect of repeated low-dose METH on MMP-9/2 expression and activity and laminin expression and the role of MMPs and JNK 1/2 phosphorylation on the changes induced by the drug in BBB integrity. Mice were given METH (4 mg/kg, i.p., three times separated by 3 h) and killed at different times after the last dose. Striatal MMP-9/2 activity was determined by zymography and expression of MMPs, laminin and phosphorylated JNK 1/2 was determined by western blot. BBB integrity was determined by IgG immunoreactivity. SP600125 and BB-94 were used to inhibit JNK and MMPs respectively. METH increased striatal MMP-9 expression and activity, IgG immunoreactivity and p-JNK 1/2 expression and decreased laminin expression. Increased IgG immunoreactivity colocalized with areas of greater MMP-9 activity. JNK inhibition prevented METH-induced changes in MMP-9 activity, laminin degradation and BBB leakage. BB-94 also prevented laminin degradation and BBB leakage. The decrease in BBB integrity induced by METH is mediated by the JNK pathway which activates MMP-9 causing degradation of laminin and BBB leakage. (C) 2012 Elsevier Inc. All rights reserved.
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