Activities of (Poly)phenolic Antioxidants and Other Natural Autophagy Modulators in the Treatment of Sanfilippo Disease: Remarkable Efficacy of Resveratrol in Cellular and Animal Models

Abstract

Sanfilippo disease, caused by mutations in the genes encoding heparan sulfate (HS) (a glycosaminoglycan; GAG) degradation enzymes, is a mucopolysaccharidosis (MPS), which is also known as MPS type III, and is characterized by subtypes A, B, C, and D, depending on identity of the dysfunctional enzyme. The lack of activity or low residual activity of an HS-degrading enzyme leads to excess HS in the cells, impairing the functions of different types of cells, including neurons. The disease usually leads to serious psychomotor dysfunction and death before adulthood. In this work, we show that the use of molecules known as dietary (poly)phenolic antioxidants and other natural compounds known as autophagy activators (genistein, capsaicin, curcumin, resveratrol, trehalose, and calcitriol) leads to accelerated degradation of accumulated HS in the fibroblasts of all subtypes of MPS III. Both the cytotoxicity tests we performed and the available literature data indicated that the use of selected autophagy inducers was safe. Since it showed the highest effectivity in cellular models, resveratrol efficacy was tested in experiments with a mouse model of MPS IIIB. Urinary GAG levels were normalized in MPS IIIB mice treated with 50 mg/kg/day resveratrol for 12 weeks or longer. Behavioral tests indicated complete correction of hyperactivity and anxiety in these animals. Biochemical analyses indicated that administration of resveratrol caused autophagy stimulation through an mTOR-independent pathway in the brains and livers of the MPS IIIB mice. These results indicate the potential use of resveratrol (and possibly other autophagy stimulators) in the treatment of Sanfilippo disease.

Molecular Mechanisms in Pathophysiology of Mucopolysaccharidosis and Prospects for Innovative Therapy

“…The likelihood of potential adverse effects is deemed minimal [334]. Rintz et al demonstrated that the administration of 50 mg/kg/day of resveratrol for 12 weeks or longer improved neurological symptoms, autophagy in the brain and liver, and decreased urinary GAG levels in an MPS IIIB mouse model [336]. Given the evidence that oxidative stress and compromised autophagy are implicated in the augmentation of inflammatory processes in a spectrum of lysosomal disorders, it would be prudent to investigate the efficacy of resveratrol in various forms of MPS.…”

New insights on resveratrol supported by magnesium dihydroxide (Revifast®)

“…Antiviral activity inhibiting virus entrance in cells and viral replication through different mechanisms was observed as well as an adjuvant in the anti-COVID-19 therapy (Domi et al, 2022). Interestingly, the use of resveratrol on lysosomal storage diseases (LSDs), such as Sanfilippo disease (mucopolysaccharidosis type III [MPS III]), was proposed as a novel therapeutic approach in pathology (Paciotti et al, 2017;Rintz et al, 2023).…”