Fenbendazole improves pathological and functional recovery following traumatic spinal cord injury

Abstract

During a study of spinal cord injury (SCI), mice in our colony were treated with the anthelmintic fenbendazole to treat pinworms detected in other mice not involved in the study. As this was not part of the original experimental design, we subsequently compared pathological and functional outcomes of SCI in female C57BL/6 mice who received fenbendazole (150 ppm, 8 mg/kg body weight/day) for four weeks prior to moderate contusive SCI (50 kdyn force) as compared to mice on the same diet without added fenbendazole. The fenbendazole-treated mice exhibited improved locomotor function, determined using the Basso mouse scale, as well as improved tissue sparing following contusive SCI. Fenbendazole may exert protective effects through multiple possible mechanisms, one of which is inhibition of the proliferation of B lymphocytes, thereby reducing antibody responses. Autoantibodies produced following SCI contribute to the axon damage and locomotor deficits. Fenbendazole pretreatment reduced the injury-induced CD45R-positive B cell signal intensity and IgG immunoreactivity at the lesion epicenter six weeks after contusive SCI in mice, consistent with a possible effect on the immune response to the injury. Fenbendazole and related benzimadole antihelmintics are FDA approved, exhibit minimal toxicity, and represent a novel group of potential therapeutics targeting secondary mechanisms following SCI.

Intrathecal Transplantation of Autologous Adherent Bone Marrow Cells Induces Functional Neurological Recovery in a Canine Model of Spinal Cord Injury

“…In addition to these effects on macrophages, BM-derived cells also promoted sensory neurite outgrowth, induced sprouting, and increased neurite intrinsic growth capacity, further enabling axons to overcome the negative effects of inhibitory proteoglycans and M1 macrophages (6). Furthermore, it has been recently reported that the antihelmintic drug fenbendazole surprisingly reversed the effects of contusive SCI in mice (48). Immune response and autoantibodies produced after SCI contribute to axon damage, and eliminating these antibodies through the anti-inflammatory mediators secreted by ABMCs might be beneficial for regeneration.…”

Inhibition of Bruton Tyrosine Kinase Reduces Neuroimmune Cascade and Promotes Recovery after Spinal Cord Injury

“…Double immunofluorescence staining was performed as previously described [ 36 ]. Briefly, spinal cord cross-sections at the lesion site were incubated with an anti-mouse monoclonal antibody against Iba1 (GT10312, MA5-27726), 1:100; microglia/macrophage marker) or GFAP (GA5 mouse mAb #3670, CST) and a polyclonal antibody against phosphor-BTK (Tyr223, Tyr225) followed by incubation with Alexa Fluor 488 or 594-conjugated goat-anti rat secondary antibody.…”

“…Autoreactive B cell activation contributes to plasma cell formation to produce autoantibodies, causing axon/myelin damage [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. The autoimmune and inflammatory cascades exacerbate spinal tissue/axon damage, locomotor deficits and bladder dysfunction [ 12 , 16 , 17 , 24 , 32 , 33 , 34 , 35 , 36 ]. As the inflammatory/immune cascades have both pathogenic and protective roles after SCI, a challenge is to reduce the pathogenic autoimmune and pro-inflammatory cascades and promote functional recovery following SCI without creating immunodeficiency.…”

Fenbendazole Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice via Suppression of Fibroblast-to-Myofibroblast Differentiation

“…In addition, FBZ treatment reduces the production of inflammatory cytokines, such as Interferon gamma (IFN-γ), Tumor necrosis factor alpha (TNF-α), and Interleukin-1 beta (IL-1β), and thus regulates the cellular immune responses of peripheral blood lymphocytes [16,19]. In a mouse model of traumatic spinal cord injury, FBZ treatment improved pathological and functional recovery, suggesting it has a positive role in tissue damage repair [23]. As an anthelmintic commonly used on laboratory animals, FBZ has been shown to affect research outcomes through its pharmacologic mechanism of action.…”