Phase-dependent expression of matrix metalloproteinases and their inhibitors in demyelinating canine distemper encephalitis

Matrix metalloproteinases (MMPs) are zinc- and calcium-dependent enzymes that cleave molecules of the extracellular matrix, and thus are able to open the blood-brain-barrier and affect myelin. Their inhibitors (TIMPs) are important candidates for the therapy of demyelinating diseases. To establish an immunohistochemical profile of MMP and TIMP expression in plaque variants in dogs with spontaneous demyelinating distemper encephalitis, paraffin-embedded cerebella were studied employing the avidin-biotin-peroxidase complex method with a panel of nine polyclonal (anti-MMP-1, -3, -7, -9, -12, -13, -14, -TIMP-1, and -2) and two monoclonal antibodies (anti-latent MMP-2, and -MMP-11). All MMPs and TIMPs were prominently up-regulated in acute and subacute non-inflammatory lesions, and double-labeling techniques showed that they were mainly expressed by astrocytes and brain macrophages/microglia. In subacute inflammatory and chronic plaques, a moderate to strong decrease of MMP and TIMP expression compared to acute lesions was observed. In these phases MMP-11, -12, and -13 were still moderately present. In addition to astro- and microglia, invading perivascular mononuclear cells were positive for MMPs and TIMPs. In summary, there seems to be a phase-dependent expression of MMPs and TIMPs in demyelinating canine distemper encephalitis, and an MMP-TIMP imbalance might account for the lesion progression in this disease.