Triptolide increases SMN transcript and protein levels in human SMA fibroblasts and improves survival in SMA-like mice.

Abstract
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 is considered a major SMA drug-discovery strategy. In this study, we explore triptolide, a diterpene triepoxide purified from Tripterygium wilfordiiHook. F., as a new target increasing SMN protein. Experimental approach:? The effects and mechanisms of triptolide on the production of SMA protein were determined by cell-based assays using motor neuronal cell line NSC34 and skin fibroblasts from SMA patients. Wild-type (Smn(+/+) SMN2(-/-) , C57BL/6) and SMA-like (Smn(-/- ) SMN2) mice received triptolide (0.01 or 0.1 mg kg(-1)day(-1) ) by intraperitoneal injection to examine the survival rate and the level of change in SMN protein in neurons and muscle tissue. Key results:? In NSC34 cells and human SMA fibroblasts, triptolide at picromolar concentration significantly increased SMN protein expression and SMN complex component (Gemin2 and Gemin3) amounts. In human SMA fibroblasts, triptolide increased SMN-containing nuclear gems and the ratio of full length transcripts (FL-SMN2) to transcripts lacking exon 7 (SMN2?7). Furthermore, in SMA-like mice, triptolide significantly increased SMN protein levels of brain, spinal cord and gastrocnemius muscle. Furthermore, triptolide treatment increased survival and reduced weight loss in SMA-like mice. Conclusions and implications:? Triptolide enhances SMN protein production by promoting SMN2 activation, exon 7 inclusion and increasing nuclear gems, and extends survival in SMA mice, which suggests triptolide might be a potential target for SMA therapy.

Source : http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?tmpl=NoSidebarfile&db=PubMed&cmd=Retrieve&list_uids=22220673&dopt=Abstract

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