The immunosuppressant mycophenolate mofetil attenuates neuronal damage after excitotoxic injury in hippocampal slice cultures.

Abstract

In this study we investigated whether treatment with the immunosuppressant mycophenolate mofetil (MMF) has beneficial effects on neuronal damage after excitotoxic injury. Organotypic hippocampal slice culture (OHSC), lesioned by the application of N-methyl-d-aspartate (NMDA) after 6 days in vitro, showed an improved preservation of the hippocampal cytoarchitecture after continuous treatment with MMF for 3 further days (10 or 100 micro g/mL). Treatment with NMDA and MMF (100 microg/mL) reduced the number of damaged propidium iodide (PI)+ neurons by 50.7% and the number of microglial cells by 52%. Continuous treatment of lesioned OHSCs with MMF for 3 days almost abrogated the glial proliferative response, reflected by the 91.5% reduction in the number of bromo-desoxy-uridine (BrdU)-labelled microglial cells and astrocytes. Microglial cells in MMF-treated OHSCs contained fragmented nuclei, indicating apoptotic cell death, an effect which was also found in isolated microglial cells treated with MMF. The beneficial effect of MMF on neuronal survival apparently does not reflect a direct antiexcitotoxic effect, as short-term treatment of OHSCs with NMDA and MMF for 4 h did not reduce the number of PI+ neurons. In conclusion, MMF inhibits proliferation and activation of microglia and astrocytes and protects neurons after excitotoxic injury.