Studies on chemoprotection by sulforaphane.

摘要

Oxidative stress and inflammation are common to many pathological conditions. Cellular defense mechanisms combat oxidative stress, but can become overwhelmed following injury and inflammation. Sulforaphane (SF), an isothiocyanate derived from broccoli, is a potent inducer of the Keapl/Nrf2/ARE pathway leading to upregulation of genes encoding cytoprotective proteins [e.g., NAD(P)H: quinone oxidoreductase 1 (NQO1) and GSH regulatory enzymes], which help restore redox balance. Sulforaphane also attenuates inflammation by inhibiting the NFicB pathway and the enzymatic activity of the pro-inflammatory cytokine, macrophage migration inhibitory factor (MIF). For my thesis project, I examined the protective effects of SF in two models of rodent injury, spinal cord contusion injury (SCI) and ultraviolet radiation (UVR)-induced skin damage, in which oxidative stress and inflammation play significant roles.;In the SCI study, I evaluated the therapeutic potential of SF to improve functional and anatomical recovery after SCI in a rat model. Intraperitoneal treatment was administered 16 h before or 10 min after and 72 h after injury at SF concentrations of 0, 10, and 50 mg/kg. Urinary levels of MIF enzymatic activity were highest 3 h after injury. SF treatment reduced activity by ~90%, suggesting in vivo inactivation of the enzyme. In blinded studies, 50 mg/kg SF treatment after injury enhanced hind limb motor function and increased serotonergic axon density caudal to the lesion 5 weeks after injury. Therefore, SF treatment may have cytoprotective effects and improve hind limb locomotor function and axon survival after contusion SCI.;In the UVR studies, I evaluated UVR-induced damage in skin and skin cells isolated from SKH-1 hairless mice and determined whether two inducers of the Nrf2 pathway, SF and TP-225, could protect against injury. SF treatment of primary skin cells before UVR decreased oxidative stress and increased GSH and NQOI levels. Topical treatment of mice with SF or TP-225 before UVR increased NQ01 levels and decreased edema in the skin. Sulforaphane decreased myeloperoxidase enzyme activity and protein levels, a marker of neutrophil infiltration. The ability of SF to upregulate NQ01 requires transcription factor Nrf2. Thus, inducers of the Nrf2 pathway, which possess anti-inflammatory activity, may protect against UVR-induced damage.