A study on the effect of JNK inhibitor, SP600125, on the disruption of blood-brain barrier induced by methamphetamine.
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.
Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
Andres
A
Urrutia
Ana
A
Rubio-Araiz
Maria Dolores
MD
Gutierrez-Lopez
Ayman
A
ElAli
Dirk M
DM
Hermann
Esther
E
O'Shea
Maria Isabel
MI
Colado
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D015153:Blotting, Western; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007797:Laminin / Q000096:biosynthesis; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL
D000873:Anthracenes; D000697:Central Nervous System Stimulants; D004791:Enzyme Inhibitors; D007797:Laminin; C432165:pyrazolanthrone; D008694:Methamphetamine; D048670:MAP Kinase Kinase 4; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9