Dual effects of TGF ‐β inhibitor in ALS ‐ inhibit contracture and neurodegeneration

We found that halofuginone inhibits contracture and neurodegeneration by blocking the TGF- β/Smad signaling in amyotrophic lateral sclerosis (ALS). Halofuginone inhibits fibrosis in fibroblasts derived from SOD1 G93A mice. In SOD1 G93A mice, excessive TGF-β-induced fibrosis of the peripheral neuromuscular system causes joint contracture and muscle degeneration, resulting in motor dysfun ction, which is suppressed by halofuginone. Halofuginone also reduces glial cell-induced neuroinflammation and neuronal apoptosis. These dual therapeutic effects on both the neuromuscular and the central nervous systems with halofuginone treatment delayed the time of symptom exacerbation in ALS mice , which led to prolonged survival. We propose TGF-β inhibitor, halofuginone, as a promising therapeutic target for ALS. Abbreviations: IL-1β, interleukin-1 beta; TNF-α, tumor necrosis factor alpha; iNOS, inducible nitric oxide synthase; CD, cluster of differentiation; IFN-α, interferon alpha; RO M, range of motion; and Arg-1, arginase-1. AbstractAs persistent elevation of transforming growth factor- β (TGF-β) promotes fibrosis of muscles and joints and accelerates disease progression in amyotrophic lateral sclerosis (ALS), we investigated whether inhibition of TGF-β would be effective against both exacerbations. The effects of TGF-β and its inhibitor on myoblasts and fibroblasts were tested in vitro and confirmed in vivo, and the dual action of a TGF-β inhibitor in ameliorating the pat...

Source: Journal of Neurochemistry - March 22, 2024 Category: Neuroscience Authors: Do ‐Yeon Lee, Young Nam Kwon, Kwangkook Lee, Sang Jeong Kim, Jung‐Joon Sung Tags: ORIGINAL ARTICLE Source Type: research