Effects of Microencapsulated Ferulic Acid or Its Prodrug Methyl Ferulate on Neuroinflammation Induced by Muramyl Dipeptide

Abstract

Ferulic acid (Fer) is known for its antioxidant and anti-inflammatory activities, which are possibly useful against neurodegenerative diseases. Despite the ability of Fer to permeate the brain, its fast elimination from the body does not allow its therapeutic use to be optimized. The present study proposes the preparation and characterization of tristearin- or stearic acid-based solid lipid microparticles (SLMs) as sustained delivery and targeting systems for Fer. The microparticles were produced by conventional hot emulsion techniques. The synthesis of the methyl ester of Fer (Fer-Me) allowed its encapsulation in the SLMs to increase. Fer-Me was hydrolyzed to Fer in rat whole blood and liver homogenate, evidencing its prodrug behavior. Furthermore, Fer-Me displayed antioxidant and anti-inflammatory properties. The amount of encapsulated Fer-Me was 0.719 ± 0.005% or 1.507 ± 0.014% in tristearin or stearic acid SLMs, respectively. The tristearin SLMs were able to control the prodrug release, while the stearic acid SLMs induced a significant increase of its dissolution rate in water. Jointly, the present results suggest that the tristearin SLMs loaded with Fer-Me could be a potential formulation against peripheral neuropathic pain; conversely, the stearic acid SLMs could be useful for Fer-Me uptake in the brain after nasal administration of the formulation.

Characterization and Hydrolysis Studies of a Prodrug Obtained as Ester Conjugate of Geraniol and Ferulic Acid by Enzymatic Way

“…Interestingly, the ester methylation of the prodrug Fer-Fer on the carboxylic moiety, which allowed to obtain a further Fer prodrug (Fer-Fer-Me), induced a strong increase in hydrolysis rate in rat brain homogenates (half-life value of about 14 min [ 26 ]). Surprisingly, a very simple prodrug of Fer, obtained by its esterification with methanol (Fer-Me), evidenced the same behavior of Fer-Ger in rat brain homogenates, i.e., the total absence of hydrolysis processes [ 25 ]. Overall, these results evidence that the hydrolysis rate of ester conjugates in physiologic environments is not dependent on their molecular size, but it is subject to sensibly changing based on the choice of molecules to conjugate.…”

“…We have recently proposed the prodrug strategy for both Ger and Fer to increase their encapsulation efficiency in polymeric or lipid particulate systems, promoting their controlled release [ 25 ] or brain targeting [ 26 , 27 ]. In this regard, the prodrug synthesis appeared particularly useful to prevent the high Ger volatility that normally hampers its encapsulation [ 27 ].…”

Conjugation, Prodrug, and Co-Administration Strategies in Support of Nanotechnologies to Improve the Therapeutic Efficacy of Phytochemicals in the Central Nervous System

“…For this reason, the rat PC12 cell line is commonly used in neurobiology, including studies of neurotoxicity, neuroprotection, neurosecretion, neuroinflammation, and synaptogenesis, and as a leading dopaminergic model in molecular neuroscience [ 66 ]. Therefore, PC12 cells represent a suitable model to study the pathogenesis of PD and AD disorders and ischemia, also providing the opportunity to measure the production of proinflammatory cytokines, such as tumour necrosis factor (TNF)-α, which underlie the onset of these pathologies [ 71 ]. On the other hand, the rat origin and the mandatory NGF-induced neuronal differentiation of PC12 cells causes the results obtained with this cellular model to be confirmed in more translational neuronal cell lines, such as the immortal cell line SH-SY5Y, derived from a human neuroblastoma [ 66 ].…”

“…The methyl ester derivative of ferulic acid (Fer-Me) is a ferulic acid prodrug able to preserve the antioxidant properties of the parent drug and its anti-inflammatory behaviour, as evaluated in vitro on PC12 cells chosen as a model for neural differentiation [ 71 ]. Solid lipid microparticles (SLMs) based on tristearin or stearic acid were loaded with ferulic acid or Fer-Me, evidencing the aptitude of the prodrug to increase loading in SLMs in comparison to ferulic acid.…”

“…Tristearin-based SLMs were able to increase the dissolution rate of Fer-Me in water, also inducing a control of the release of both ferulic acid and Fer-Me; their intramuscular administration was therefore proposed to counter neuroinflammation related to peripheral neuropathic pain. Stearic acid-based SLMs were able to induce a very fast dissolution of Fer-Me within a few minutes; their nasal administration was therefore proposed with the aim of inducing derivative brain uptake [ 71 ].…”