A Natural Benzofuran from the Patagonic Aleurodiscus vitellinus Fungus has Potent Neuroprotective Properties on a Cellular Model of Amyloid-β Peptide Toxicity

Abstract

Alzheimer's disease (AD) is characterized by amyloid plaques that form due to an increase in amyloid-β peptide (Aβ) aggregation. One strategy in the search of new treatments for AD focuses on compounds that decrease Aβ accumulation. Compounds containing a benzofuran ring have been described to play an important role in decreasing Aβ-induced toxicity; however, only synthetic benzofurans have been tested thus far. The aim of the present study was to examine the in vitro neuroprotective properties of fomannoxin (Fx), a natural benzofuran isolated from cultures of the Andean-Patagonian fungi Aleurodiscus vitellinus, and evaluate its effect on Aβ peptide. We tested the effect of Fx at a wide concentration range (10-11-10-4 M) in PC-12 cells, and found the compound did not alter cellular viability. Fx also showed a concentration-dependent effect on the Aβ-induced toxicity in PC12 cells, showing viability above 100% at 10-6 M. We then measured the effect of Fx (10-7-10-5 M) on the frequency of cytosolic Ca2+ transients in rat hippocampal neurons at both acute and chronic (24 h) times. Acute incubation with Fx increased the frequency of cytosolic Ca2+ transients to values around 200%, whereas chronic incubation with Fx increased the frequency of Ca2+ transients. Finally, the Aβ-induced decrease in intracellular Ca2+ transients was prevented when Fx (10-6 M) was co-incubated with Aβ (5×10-6 M). The results suggest a potent neuroprotective effect of this naturally occurring benzofuran against Aβ peptide toxicity that could be mediated by an interference with it binding to plasma membrane, and lead Fx as new chemical entity to develop pharmacological tools against Aβ peptide neurotoxicity.

Benzofuran and Indole: Promising Scaffolds for Drug Development in Alzheimer's Disease

“…In 2018, Fuentealba and co‐workers examined the in vitro neuroprotective properties of a natural benzofuran [fomannoxin (Fx), Figure ] isolated from the cultures of Aleurodiscus vitellinus fungus and investigated its effect on Aβ peptide . Fx does not alter cellular viability over a wide concentration range (10 −11 to 10 −4 m ) and shows a concentration‐dependent effect on Aβ‐induced toxicity in PC12 cells (viability above 100 % at 10 −6 m ).…”

Exploring the Multi–Target Neuroprotective Chemical Space of Benzofuran Scaffolds: A New Strategy in Drug Development for Alzheimer’s Disease

“…This class of chemical motifs have been shown to display antibacterial, antifungal, antioxidant, antitumoral, antiinflammatory, anticonvulsant, and anti-HIV bioactivities (Hiremathad et al, 2015;Khanam, 2015;Nevagi et al, 2015). Interestingly, benzofurans have also been found to have neuroprotective activity, inhibiting the important events involved in the AD process (Howlett et al, 1999;Allsop et al, 2001;Ono et al, 2002;Ono et al, 2006;Rizzo et al, 2008;Rizzo et al, 2012;Sashidhara et al, 2014;Ha et al, 2017;González-Ramírez et al, 2018;Kumar et al, 2018). Our research group has also investigated the role of natural fungal benzofurans in synaptic failure, decay of intracellular Ca 2+ transients and synaptic disorganization (González-Ramírez et al, 2018).…”

“…Interestingly, benzofurans have also been found to have neuroprotective activity, inhibiting the important events involved in the AD process (Howlett et al, 1999;Allsop et al, 2001;Ono et al, 2002;Ono et al, 2006;Rizzo et al, 2008;Rizzo et al, 2012;Sashidhara et al, 2014;Ha et al, 2017;González-Ramírez et al, 2018;Kumar et al, 2018). Our research group has also investigated the role of natural fungal benzofurans in synaptic failure, decay of intracellular Ca 2+ transients and synaptic disorganization (González-Ramírez et al, 2018). Although several factors are involved in the development of AD, it has been established that the production of toxic Ab is crucial for the genesis of AD.…”

“…Indeed, benzofuran scaffolds have been reported to play an important role as inhibitors of Ab fibril formation ( Figure 1A). Despite the promising neuroactivity displayed by benzofuran derivatives, their bioactivity still remains singletargeted in nature and a systematic study exploring the neuroprotective chemical space of these interesting heterocycles has not been carried out (González-Ramírez et al, 2018). This investigation is essential to find the chemical fundamentals that would provide the knowledge necessary to develop multi-target AD drugs based on benzofuran scaffolds.…”

“…This investigation is essential to find the chemical fundamentals that would provide the knowledge necessary to develop multi-target AD drugs based on benzofuran scaffolds. Existing reports show that the neuroprotective bioactivity of benzofuran derivatives falls into the µM range (Howlett et al, 1999;Allsop et al, 2001;Ono et al, 2002;Ono et al, 2006;Rizzo et al, 2008;Rizzo et al, 2012;Sashidhara et al, 2014;Ha et al, 2017;González-Ramírez et al, 2018). Thus, chemical probes containing benzofuran cores have yet to become approved drugs to control AD, mainly due to their modest potency.…”