Planta Med 2015; 81 - SL3B_03
DOI: 10.1055/s-0035-1565316

Neuroactive alkaloids from Psychotria (Rubiaceae) are SIRT inhibitors

CA Simoes-Pires 1, CS Passos 1, L Ryckewaert 1, L Sacconnay 1, MC Guerra 2, L Kato 3, CMA Oliveira 4, A Nurisso 1
  • 1School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland
  • 2Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
  • 3Laboratório de Bioatividade Molecular, Instituto de Química, Universidade Federal de Goiás, Goiânia, Brazil
  • 4Laboratório Farmacognosia, Departamento de Produção de Matéria-Prima, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

Epigenetic enzymes such as histone deacetylases (HDACs) play a crucial role in the development of aging-related diseases. Among human HDAC isoforms, class III HDACs, also known as sirtuins (SIRTs), have been considered as promising targets for treating neurodegenerative conditions [1]. Psychotria alkaloids have been reported for their inhibitory properties against central nervous system (CNS) cholinesterases and monoamine oxidases [2]. Given the multifunctional profile of these alkaloids in the CNS, we hypothesized that they could also interact with SIRTs. Here, we show the SIRT inhibition by alkaloids previously isolated from Psychotria spp. first by in silico methods, followed by enzymatic and cell assays. Five alkaloids, namely, vallesiachotamine lactone, E-vallesiachotamine, Z-vallesiachotamine, prunifoleine, and 14-oxoprunifoleine showed an inhibitory profile comparable to that of sirtinol, used as reference compound, in a dose response manner from 10 to 150 µM (Figure 1). The cytotoxicity on rat astrocytes and human cells was also evaluated and correlated to the pharmacokinetic profile of tested compounds.

Fig. 1: Enzymatic SIRT1 activity measured for Psychotria alkaloids and sirtinol. *Significantly different (p ≤0.05) in the post hoc Dunnett's test.

References:

[1] Green et al. Journal of Neurosciences 2008 28: 11500 – 11510.

[2] Passos CS et al. Phytochemistry 2013 86: 8 – 20.