Matrix metalloproteinase expression and inhibition after sciatic nerve axotomy

Wallerian degeneration is characterized by breakdown of myelin and axons wi th subsequent macrophage infiltration and removal of the degenerating nerve components. Proteinases of the matrix metalloproteinase (MMP) family seem to play an important role in demyelinating processes, since some of their m embers have been shown to cleave myelin basic protein. In the present study we investigated the expression of MMP-2 and MMP-9 (gelatinases A and B) du ring myelin removal after peripheral nerve trauma. After transection of the sciatic nerve an upregulation of MMP-2 and MMP-9 with a first peak 12 h an d a second peak 48 h after axotomy was observed by zymography. These peaks correlate with the breakdown of the blood-nerve barrier, the accumulation o f granulocytes, and the invasion of macrophages into the damaged nerves, re spectively. Furthermore, MMP-2 was found to be upregulated in the contralat eral nontransected nerves. Immunocytochemistry for MMP-9 and in situ zymogr aphy identified MMP-reactive cells within the distal nerve stump. Chloracet ate esterase staining was used to detect granulocytes, which accumulated at the transection site and were colocalized with the in situ zymography sign al. Wallerian degeneration of the transected nerve could be delayed either by intraperitoneal injections of hydroxamate (Ro 31-9790), a nonspecific MM P inhibitor, or by local application of an MMP-9-specific antibody. Followi ng these treatment strategies, a decreased number of invading macrophages w as seen in the nerves associated with an increased amount of preserved myel in sheaths. These results suggest that the invasion of macrophages into a t ransected peripheral nerve is accompanied by an increased expression of MMP s, particularly MMP-9. Thus, MMPs may seem to play an important role in the breakdown of the blood-nerve barrier and subsequent cell recruitment from the systemic circulation into the damaged nerve.