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BACKGROUND AND PURPOSE Spinal muscular atrophy (SMA) is a progressive neuromuscular disease. Since disease severity is related to the amount of survival motor neuron (SMN) protein, up‐regulated functional SMN protein levels from the SMN2 gene are considered a major SMA drug‐discovery strategy. In this study, we investigated the possible effects of triptolide, a diterpene triepoxide purified from Tripterygium wilfordii Hook. F., as a new compound for increasing SMN protein. EXPERIMENTAL APPROACH The effects and mechanisms of triptolide on the production of SMA protein were determined by cell‐based assays using the motor neuronal cell line NSC34 and skin fibroblasts from SMA patients. Wild‐type (Smn+/+SMN2−/−, C57BL/6) and SMA‐like (Smn−/−SMN2) mice were injected with triptolide (0.01 or 0.1 mg·kg−1·day−1, i.p.) and their survival rate and level of change in SMN protein in neurons and muscle tissue measured. KEY RESULTS In NSC34 cells and human SMA fibroblasts, pM concentrations of triptolide significantly increased SMN protein expression and the levels of SMN complex component (Gemin2 and Gemin3). In human SMA fibroblasts, triptolide increased SMN‐containing nuclear gems and the ratio of full‐length transcripts (FL‐SMN2) to SMN2 transcripts lacking exon 7 (SMN2Δ7). Furthermore, in SMA‐like mice, triptolide significantly increased SMN protein levels in the brain, spinal cord and gastrocnemius muscle. Furthermore, triptolide treatment increased survival and reduced weight loss in SMA‐like mice. CONCLUSION AND IMPLICATIONS Triptolide enhanced SMN protein production by promoting SMN2 activation, exon 7 inclusion and increasing nuclear gems, and increased survival in SMA mice, which suggests triptolide might be a potential candidate for SMA therapy.

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