gms | German Medical Science

Objective: Introduction:The recurrence of malignant glioma is one of the major obstacles in glioma therapy and the reason for poor survival of the patients. Glioma cells infiltrate healthy brain and become inaccessible to surgical resection. Microglia supports glioma infiltration of the brain by increased expression and activation of extracellularmatrix (ECM)-degrading proteases such as MMP-2, MMP-9 and MMP-14 which are the major ECM degrading proteases in gliomas. The tetracycline-derived antibiotics (e.g. minocycline and doxycycline) are known blockers of MMP's in various cancers. Here, we tested the effect of p38MAPK blockade on MMP-9 expression. We assessed the treatment with p38MAPK inhibition as a potential therapy for experimental glioma.

Objective:Analysis of MMP-9 regulation in microglia treated with p38MAPK blockers (minocycline and SB202190) and evaluation of minocycline treatment on glioma-bearing mice survival.

Method: We determined MMP-9 regulation by RT-PCR, qPCR, westernblotting (WB) and gelatinase zymography in a mouse microglia cell culture. We stimulated the microglia cell cultures with the GL261 conditioned medium (GCM) with or without minocycline or SB202190. In addition we used the mouse in vivo glioma model where we implanted GL261 into mouse basal ganglia. These glioma-bearing mice were treated for two weeks with minocycline or vehicle. We characterized the MMP-9 distribution in and around gliomas by immunohistochemistry and confocal microscopy.

Results: Stimulation of microglia with GCM-induced MMP-9 expression as assayed by PCR. The treatment of microglia with minocycline and SB202190 led to a decrease of MMP-9 in microglia as shown by WB and gelatine zymography. Mice treated with minocycline had a statistically significant longer survival time than the control mice.

Conclusions: Minocycline is a candidate for concomitant adjuvant malignant glioma therapy.