Amisulpride

Pathological aggregation of tau is a common feature of a group of neurodegenerative disorders known as tauopathies. Hyperphosphorylation of tau is a major cause of tau aggregation which in turn leads to defects in axonal transport, synaptic malfunction, and neuronal cell death. It has recently been reported that constitutive activity of the serotonin receptor 7 (5-HT7R) contributes to the tau-mediated pathology. Amisulpride, an inverse agonist of 5-HT7R, has been shown to decrease 5-HT7R-induced tau aggregation, as well as multiple aspects of tau pathology such as tau hyperphosphorylation, tangle formation, apoptosis, and memory deficits.

Fig. 1 Amisulpride reduces hyperphosphorylation and formation of insoluble tau aggregates in HEK293 tau-BiFC cells. (Jahreis K.; et al. 2023)

Rheumatoid arthritis (RA) is a chronic inflammatory disease that involves joint swelling and destruction. One of the major cell types which expand excessively in the course of the disease is the synovial fibroblasts (SFs), which secrete inflammatory cytokines/chemokines to degrade the metalloproteinases, gradually leading to joint inflammation, stiffness and pain. Using a gene expression–based repurposing approach, it was validated that amisulpride can robustly downregulate chemokines/adhesiveness of arthritic synovial fibroblasts and can relieve fibroblast-dependent polyarthritis in hTNFtg mice. The mode of action was, however, not mediated by the drugs' official targets, dopamine receptors D2 and D3 (DRD2 and DRD3) and serotonin receptor 7 (HTR7). Its putative targets were Ascc3 and Sec62.

Fig. 2 A drug repurposing pipeline identifies amisulpride as a modulator of arthritic synovial fibroblast activity. (Papadopoulou D.; et al. 2023)