Semagacestat, a γ-secretase inhibitor, activates the growth hormone secretagogue (GHS-R1a) receptor.

ABSTRACT

OBJECTIVES: Semagacestat, is a γ-secretase inhibitor, which belongs to a class of drugs that are being developed as therapeutic agents for Alzheimer's disease (AD). This study aims to evaluate another potential effect of semagacestat, namely its ability to stimulate the growth hormone secretagogue receptor (GHS-R1a), which may also contribute to its therapeutic efficacy. METHODS: The GHS-R1a-activating potential of semagacestat and its synthetic precursor was assessed in an in vitro calcium mobilization assay in cells expressing the GHS-R1a receptor and compared with that of the endogenous peptide GHS-R1a agonist, acyl-ghrelin, as well as the non-peptidyl synthetic GHS-R1a agonist, MK0677. In addition, semagacestat-mediated cellular trafficking of the GHS-R1a receptor, expressed as an enhanced green fluorescent protein tagged fusion protein, was analysed. KEY FINDINGS: Semagacestat and its precursor were shown to activate the GHS-R1a receptor, as demonstrated by an increased GHS-R1a-mediated intracellular calcium influx. Moreover, a synergistic GHS-R1a receptor activation was shown following a combined exposure to ghrelin and semagacestat. In addition, GHS-R1a receptor internalization was observed upon exposure to semagacestat and its precursor. CONCLUSION: These data suggest a novel molecular mechanism of action for semagacestat via modest GHS-R1a receptor activation. Studies focusing on the relative functional consequence of such effects in vivo are now warranted.