Therapeutic Potential of Hydroxypropyl-β-Cyclodextrin-Based Extract of Medicago sativa in the Treatment of Mucopolysaccharidoses

Abstract

Mucopolysaccharidoses are inherited metabolic disorders resulting in the dysfunction of enzymes involved in the degradation of glycosaminoglycans, leading to severe clinical symptoms and a significantly shortened life span of patients. Flavonoids are recognized as glycosaminoglycan metabolism modulators, able to correct glycosaminoglycan cell storage. Therefore, the aim of this work was the development of an efficient and eco-friendly extraction process of phytochemicals from by simultaneous use of ultrasound extraction and hydroxypropyl--cyclodextrin complexation, and investigation of the potential of such an extract as a glycosaminoglycan metabolism modulator. The Box-Behnken design and response surface methodology were used in order to optimize the extraction process, considering hydroxypropyl--cyclodextrin concentration, ultrasonic power, and extraction time as the key parameters. The dependent variables included total phenolicand total flavonoid content, DPPH radical scavenging activity, and Fe chelating activity, due to the importance of oxidative stress in the pathology of mucopolysaccharidoses. The developed technology using hydroxypropyl--cyclodextrin led to more selective flavonoid extraction from than obtained either by the use of water or ethanol. The lyophilization of extracts resulted in products with high radical scavenging activity, suitable for further use. The application of 20 mM hydroxypropyl--cyclodextrin solution, 432 W ultrasonic power, and an extraction time of 45 min resulted in an extract with both the highest total flavonoid content and the lowest radical scavenging activity IC. This extract reduced the levels of glycosaminoglycans in skin fibroblasts of mucopolysaccharidose III patient in a dose-dependent manner. At concentrations of 3 and 6 µg/mL, the observed levels of glycosaminoglycans were reduced by 41.2 and 51.1 %, respectively, clearly demonstrating the validity of the selected approach.

Development and In Vitro Evaluation of an Innovative “Dietary Flavonoid Supplement” on Osteoarthritis Process

“…This is due partially to the effect of HPBCD acting synergistically with the complexed compound. In fact, it shows moderate GAGs restoration (198  μ g·mL −1 ) for its capability to form hydrogen bonds with polysaccharides, as GAGs [19]. From this result, the potential role of HP-betaCD as a therapeutic agent also emerges for the prevention and treatment of a group of metabolic disorders in which abnormal accumulations of GAGs occur.…”

“…This behavior can lead to increased in vivo ERT release and to the improvement of its bioavailability and activity. In addition, according to the literature [19, 20], an intrinsic activity of HP-betaCD on GAGs restoration also emerges, indicating its potential function in the treatment and prevention of many diseases associated with the imbalance of GAGs.…”

“…HP-betaCD is a soluble derivative of β -cyclodextrin and was selected because in the literature it is reported that it forms inclusion complexes with flavonoids and enhances their aqueous water solubility and dissolution rate [16–18]. Moreover, HP-betaCD appears to be useful in many diseases correlated to an increase of GAGs [19, 20], with PG also involved in OA.…”

Oxidative Stress in Mucopolysaccharidoses: Pharmacological Implications

“…Moreover, Fumić et al [ 70 ] proposed a novel MPS therapy using compounds of plant origin. They developed an efficient chemical process to obtain a Medicago sativa extract using ultrasound extraction and hydroxypropyl-β-cyclodextrin complexation.…”

How close are we to therapies for Sanfilippo disease?

“…In a recent study performed by Fumić et al ( 2017 ), a highly active and purified extract of flavonoids from Medicago sativa has been obtained. These authors have confirmed that pure genistein is effective in reduction of GAG levels in MPS III cells (they did not specify what subtypes of Sanfilippo disease were studied), and demonstrated similar (but about 25% lower) activity of the flavonoids’ extract.…”