Transthyretin Amyloidosis Therapy: A possibility in "Brahmi" (Centella asiatica and Bacopa monnieri) phytochemicals

Abstract

Transthyretin (TTR) is a 55 kDa multifunctional plasma protein. Human native TTR is a ẞ-sheet-rich homotetramer with monomers comprising of 127 amino acid residues. Its canonical functions include the transport of thyroid hormones and vitamin A, aided by retinol-binding protein within the blood and cerebrospinal fluid. Under certain conditions, TTR acquires a gain in toxic function role associated with the development of a severe disorder, transthyretin (ATTR) amyloidosis. ATTR amyloidosis are a group of progressive, debilitating and often fatal disease for which there is currently no cure. They are characterized by systemic deposition and accumulation of abnormal, misfolded/mis-aggregated TTR in vital organs leading to degeneration and dysfunction. With limited therapeutic options there is need for investigations aimed at developing safe and effective remedies for these ailments. Given that they key molecular event underlying the etiopathogenesis of TTR amyloidogenesis is the dissociation of the homotetramer into monomers only which could enter the amyloid cascade, preventing tetramer dissociation using small ligands or stabilizers which enhance the kinetic barrier for dissociation had been promoted as a pragmatic therapeutic strategy to combat ATTR amyloidosis. The primary objective of this work was to determine and elucidate the TTR amyloidogenic inhibitory activities of two popular nervines, Centella asiatica and Bacopa monnieri. Chemical characterization showed that both extracts were replete with antioxidant bioactive compounds. Tetramer stability assays by urea- and acid-mediated denaturation revealed that both extracts protected against tetramer dissociation into monomers. Aggregation-inducing assays suggest that both extracts inhibited the formation of mature amyloid fibrils from TTR. However, only B. monnieri extract prevented formation of TTR aggregates. From the ANS and NBT-redox cycling assays, it could be inferred that both extracts were able to bind at the hydrophobic thyroxine-binding sites putatively increasing dimer-dimer interactions. While the binding interactions between TTR and C. asiatica seems to be covalent, that between the protein and B. monnieri extract was weak and non-covalent. Together, these findings suggest that C. asiatica and B. monnieri inhibited TTR amyloidogenesis in vitro and highlighted the potential of these bioactives as plausible therapeutic candidates and sources for the mining of novel drug scaffolds targeted against TTR amyloidosis.