Resveratrol Prevents Toxic Buildup in Cells of Sanfilippo Mouse Model

Plant-based compound promotes autophagy, lowers heparan sulfate levels in cells

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Treatment with resveratrol, a plant-derived compound that activates a cell cleansing process called autophagy, reduced the toxic buildup of heparan sulfate and normalized behavior in a mouse model of Sanfilippo syndrome.

“Resveratrol normalized urinary [heparan sulfate] levels and attenuated abnormal behaviors in [Sanfilippo B] model mice, supporting further studies on this compound as a possible drug for treating Sanfilippo disease,” the researchers wrote.

The study, “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,” was published in the journal Neurotherapeutics.

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Autophagy — from the Greek words for “self-eating” — is a recycling process that cells use to break down large and complex molecules into simple components that can be reused by the cell.

Sanfilippo syndrome is caused by mutations that lead to the toxic accumulation of the sugar molecule heparan sulfate inside of cells. A group of researchers at the University of Gdansk, in Poland, conducted a series of tests to see whether activating autophagy could reduce this toxic accumulation.

“In this study, we asked whether pharmacological stimulation of autophagy by naturally occurring molecules can accelerate the degradation” of heparan sulfate in Sanfilippo, the scientists wrote.

“Unfortunately, most strong exogenous [externally applied] autophagy activators are deleterious to cells when used for a long time; therefore, they are not appropriate candidates for treatments against genetic diseases,” they added. “Hence, in our studies, we have focused on natural compounds that are safe for patients to use long-term and that effectively stimulate autophagy.”

The study included several naturally occurring compounds previously shown to activate autophagy: capsaicin, curcumin, resveratrol, trehalose, and calcitriol.

These compounds were first tested in cell experiments using patient-derived fibroblasts, a type of structural cell. Results showed that most of the autophagy activators were not toxic, and several lowered the accumulation of heparan sulfate within the cells.

Notably, the reduction in heparan sulfate levels was seen in cells with all four types of Sanfilippo syndrome.

Based on toxicity and efficacy data from these cell experiments, and because the effects of trehalose have been reported previously, the researchers selected resveratrol for further studies in a mouse model of Sanfilippo type B. Mice were administered either water or a solution containing resveratrol by mouth, starting at age 8 weeks and continuing until the mice were 30 weeks old.

Significant drop in heparan sulfate levels in animal’s urine reported

Results showed that resveratrol’s use significantly reduced the concentrations of heparan sulfate and related molecules in the mice’s urine. In fact, levels in resveratrol-treated Sanfilippo B mice “were indistinguishable from those measured in the urine of wild-type [healthy] mice,” the researchers wrote.

Tests of brain and liver tissue also indicated that resveratrol treatment activated autophagy as expected.

Sanfilippo B mice given resveratrol also showed fewer hyperactive and anxiety-like behaviors compared to their untreated counterparts. In these assessments, treated Sanfilippo B mice performed comparably to wild-type mice.

“These results demonstrated that resveratrol was … very efficient in correcting behavioral abnormalities in the mouse models of Sanfilippo disease used in this study,” the researchers wrote.

Overall, study findings support autophagy activation, generally — and treatment with resveratrol, specifically — as a potential therapeutic strategy in Sanfilippo syndrome, the researchers said.

The team noted that resveratrol also has shown benefit in models of other conditions characterized by the toxic accumulation of molecules in cells, such as Gaucher and Batten disease. In addition to its autophagy-promoting activity, resveratrol functions as an antioxidant, which may play a role in these effects, the scientists said.