Ferulic acid and its water-soluble derivatives inhibit nitric oxide production and inducible nitric oxide synthase expression in rat primary astrocytes.

We recently reported that two water-soluble derivatives of ferulic acid (1-feruloyl glycerol, 1-feruloyl diglycerol) previously developed by our group exhibited protective effects against amyloid-ß-induced neurodegeneration in vitro and in vivo. In the current study, we aimed to further understand this process by examining the derivatives' ability to suppress abnormal activation of astrocytes, the key event of neurodegeneration. We investigated the effects of ferulic acid (FA) derivatives on nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression in rat primary astrocytes. The results showed that these compounds inhibited NO production and iNOS expression in a concentration-dependent manner and that the mechanism underlying these effects was the suppression of the nuclear factor-κB pathway. This evidence suggests that FA and its derivatives may be effective neuroprotective agents and could be useful in the treatment of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease.

Water-soluble ferulic acid derivatives improve amyloid-ß-induced neuronal cell death and dysmnesia through inhibition of amyloid-ß aggregation.

Ferulic acid (FA) has been reported to exhibit protective effects against amyloid-ß (Aß)-induced neurodegeneration in vitro and in vivo. Recently, we developed two water-soluble FA derivatives: 1-feruloyl glycerol and 1-feruloyl diglycerol. In this study, we examined the neuroprotective effects of these water-soluble FA derivatives on Aß-induced neurodegeneration both in vitro and in vivo. FA and water-soluble FA derivatives inhibited Aß aggregation and destabilized pre-aggregated Aß to a similar extent. Furthermore, water-soluble FA derivatives, as well as FA, inhibited Aß-induced neuronal cell death in cultured neuronal cells. In in vivo experiments, oral administration of water-soluble FA derivatives to mice improved Aß-induced dysmnesia assessed by contextual fear conditioning test and protected hippocampal neurons against Aß-induced neurotoxicity. This study provides useful evidence suggesting that water-soluble FA derivatives are expected to be effective neuroprotective agents.

Synthesis of highly water-soluble feruloyl diglycerols by esterification of an Aspergillus niger feruloyl esterase.

Ferulic acid (FA) is a component of plant cell walls that has applications in food, cosmetic, and health products, but its applications are limited by its high insolubility. We synthesized water-soluble FA derivatives by esterification of FA with diglycerol (DG) using feruloyl esterase purified from a commercial enzyme preparation produced by Aspergillus niger. The major reaction product, FA-DG1, was determined to be γ-feruloyl-α,α'-DG by NMR and electrospray ionization mass spectrometry analyses. FA-DG1 is a sticky liquid whose water solubility (>980 mg/ml) is dramatically higher than that of FA (0.69 mg/ml). Suitable conditions for esterification of FA with DG were 100 mg of FA in the presence of 1 g of DG and 0.1 ml of 1 M phosphate buffer (pH 6.0) at 50 °C under reduced pressure. Under these conditions, 168 mg of feruloyl DGs (FA-DG1, 2, and 3) was obtained, corresponding to a 95 % conversion rate of FA. We also developed a batch method which resulted in synthesis of 729 mg of feruloyl DGs and 168 mg of diferuloyl DGs from 600 mg of FA and 1 g of DG (corresponding to conversion of 69 % of the FA to feruloyl DGs and 21 % of the FA to diferuloyl DGs). As an anti-oxidant, feruloyl DGs were essentially equal to FA and butyl hydroxytoluene in scavenging 1,1-diphenyl-2-picrylhydrazyl radicals. In contrast, the scavenging abilities of diferuloyl DGs were twice those of feruloyl DGs.