Screening of the Anti-Neurodegenerative Activity of Caffeic Acid after Introduction into Inorganic Metal Delivery Systems to Increase Its Solubility as the Result of a Mechanosynthetic Approach

The proven anti-neurodegenerative properties of caffeic acid in vivo are limited due to its poor solubility, which limits bioavailability. Therefore, caffeic acid delivery systems have been developed to improve caffeic acid solubility. Solid dispersions of caffeic acid and magnesium aluminometasilicate (Neusilin US2-Neu) were prepared using the ball milling and freeze-drying techniques. The solid dispersions of caffeic acid:Neu obtained by ball milling in a 1:1 mass ratio turned out to be the most effective. The identity of the studied system in comparison to the physical mixture was confirmed using the X-Ray Powder Diffractionand Fourier-transform infrared spectroscopy techniques. For caffeic acid with improved solubility, screening tests were carried out to assess its anti-neurodegenerative effect. The obtained results on the inhibition of acetylcholinesterase, butyrylcholinesterase, tyrosinase, and antioxidant potential provide evidence for improvement of caffeic acid's anti-neurodegenerative activity. As a result of in silico studies, we estimated which caffeic acid domains were involved in interactions with enzymes showing expression relevant to the neuroprotective activity. Importantly, the confirmed improvement in permeability of the soluble version of caffeic acid through membranes simulating the walls of the gastrointestinal tract and blood-brain barrier further strengthen the credibility of the results of in vivo anti-neurodegenerative screening tests.

Automated summary

To improve the bioavailability of caffeic acid, delivery systems were developed using ball milling and freeze-drying techniques to prepare solid dispersions of caffeic acid and magnesium aluminometasilicate. The 1:1 mass ratio solid dispersion obtained from ball milling was the most effective, and its identity was confirmed using X-ray powder diffraction and Fourier-transform infrared spectroscopy techniques. Screening tests demonstrated the improved anti-neurodegenerative activity of caffeic acid with enhanced solubility, inhibiting acetylcholinesterase, butyrylcholinesterase, tyrosinase, and showing antioxidant potential. In silico studies identified the domains of caffeic acid that interacted with enzymes relevant to neuroprotective activity. Furthermore, improved permeability through gastrointestinal tract and blood-brain barrier mimicking membranes validated the in vivo screening tests for anti-neurodegenerative activity.