5‐Fluorouracil reduces the fibrotic scar via inhibiting matrix metalloproteinase 9 and stabilizing microtubules after spinal cord injury

AIMS: Fibrotic scars composed of a dense extracellular matrix are the major obstacles for axonal regeneration. Previous studies have reported that antitumor drugs promote neurofunctional recovery. METHODS: We investigated the effects of 5‐fluorouracil (5‐FU), a classical antitumor drug with a high therapeutic index, on fibrotic scar formation, axonal regeneration, and functional recovery after spinal cord injury (SCI). RESULTS: 5‐FU administration after hemisection SCI improved hind limb sensorimotor function of the ipsilateral hind paws. 5‐FU application also significantly reduced the fibrotic scar formation labeled with aggrecan and fibronectin‐positive components, Iba1(+)/CD11b(+) macrophages/microglia, vimentin, chondroitin sulfate proteoglycan 4 (NG2/CSPG4), and platelet‐derived growth factor receptor beta (PDGFRβ)(+) pericytes. Moreover, 5‐FU treatment promoted stromal cells apoptosis and inhibited fibroblast proliferation and migration by abrogating the polarity of these cells and reducing matrix metalloproteinase 9 expression and promoted axonal growth of spinal neurons via the neuron‐specific protein doublecortin‐like kinase 1 (DCLK1). Therefore, 5‐FU administration impedes the formation of fibrotic scars and promotes axonal regeneration to further restore sensorimotor function after SCI.