Main characteristics and biological effects of martix metalloproteinases in the nervous system

Martix metalloproteinases (MMPs), one of the subgroups of the metzincins, are a large family of zinc-dependent endoproteases with multiple roles in extracellular matrix remodelling and modulation of signalling pathways. They are able to cleave all protein components of the extracellular matrix, as well as to activate or inactivate various signaling molecules, such as receptors, growth factors and adhesion molecules. MMPs are associated with many physiological functions such as embryonic development, angiogenesis and wound healing. Therefore, these proteinases are considered to be crucial mediators in many biological processes. Elevated MMP levels have also been implicated in an increasing number of injuries and disorders, such as inflammation, cancer and auto-immune diseases. Recent investigations highlight the beneficial and detrimental effects of MMPs in the nervous system in normal and pathological conditions. This review focuses on the role of MMPs as modulators of fundamental functions in the developing and adult nervous system and their potential to improve repair or regeneration after injury

Neuroinflammation after traumatic injury to the developing brain

PURPOSES: Mechanical trauma to the developing rodent brain induces a diffuse secondary neuroapoptosis associated with infiltration of immune cells, local and systemic increased levels of proinflammatory mediators. Our aim was to study their expression, cellular localization, distribution pattern and time course in various brain regions. MATERIALS AND METHODS: 7-day-old Wistar rats and C57/BL6 mice were subjected to cortical trauma. Animals were sacrificed at defined time points - from 2 h to 14 days following trauma. Brain tissues were processed for molecular analyses, single or double indirect peroxidase/fluorescence immunohistochemistry for apoptotic cell death, microglia and interleukin (IL)-1ß/IL-18. RESULTS: Apoptotic neuronal cell death detected by TUNEL was found at distant regions to trauma site mainly ipsilateral from 6 h to 5 days later. A substantial activation of ED1+ microglia occurred at the site of primary and secondary damages. It was first evident at 12 h, peaked at 36-48 h and decreased significantly after 5 days. A marked increase of mRNA, protein levels and imunohistochemical expression of two pro-inflammatory cytokines, interleukin (IL)-1ß and IL-18, was found from 2 h to 5 days following trauma. Mice deficient in IL-18 (IL-18−/−) were protected against post-traumatic brain damage. CONCLUSIONS: Brain trauma leads to neuroinflammation expressed by microglial activation and an increase in IL-1ß and IL-18. Activated microglia are one of the main cellular sources of elevated levels for both cytokines. They are probably involved in and help sustain apoptotic neurodegeneration over several days after trauma. This finding might define microglia and IL-1ß/IL-18 as potential post-traumatic therapeutic targets