Astrocyte-Targeted Transporter-Utilizing Derivatives of Ferulic Acid Can Have Multifunctional Effects Ameliorating Inflammation and Oxidative Stress in the Brain

Abstract

Ferulic acid (FA) is a natural phenolic antioxidant, which can exert also several other beneficial effects to combat neuroinflammation and neurodegenerative diseases, such as Alzheimer's disease. One of these properties is the inhibition of several enzymes and factors, such as β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1), cyclooxygenases (COXs), lipoxygenases (LOXs), mammalian (or mechanistic) target for rapamycin (mTOR), and transcription factor NF-κB. We have previously synthesized three L-type amino acid transporter 1- (LAT1-) utilizing FA-derivatives with the aim to develop brain-targeted prodrugs of FA. In the present study, the cellular uptake and bioavailability of these FA-derivatives were evaluated in mouse primary astrocytic cell cultures together with their inhibitory effects towards BACE1, COX/LOX, mTOR, NF-κB, acetylcholinesterase (AChE), and oxidative stress. According to the results, all three FA-derivatives were taken up 200–600 times more effectively at 10 μM concentration into the astrocytes than FA, with one derivative having a high intracellular bioavailability (Kp,uu), particularly at low concentrations. Moreover, all of the derivatives were able to inhibit BACE1, COX/LOX, AChE, and oxidative stress measured as decreased cellular lipid peroxidation. Furthermore, one of the derivatives modified the total mTOR amount. Therefore, these derivatives have the potential to act as multifunctional compounds preventing β-amyloid accumulation as well as combating inflammation and reducing oxidative stress in the brain. Thus, this study shows that converting a parent drug into a transporter-utilizing derivative not only may increase its brain and cellular uptake, and bioavailability but can also broaden the spectrum of pharmacological effects elicited by the derivative.

L-type Amino Acid Transporter 1 Utilizing Ferulic Acid Derivatives Show Increased Drug Delivery in the Mouse Pancreas Along with Decreased Lipid Peroxidation and Prostaglandin Production

“…One possible reason for high kidney accumulation is another transportation mechanism, which is more prominent for D2. The cellular uptake mechanisms have previously been studied with these two derivatives in vitro . There, we observed that D2 also utilized another non-validated transport mechanism, especially with high concentrations, although the LAT1 was the main transport mechanism for both derivatives with higher affinity.…”

“…17,41 The previous uptake mechanism studies with the FA derivatives have shown that the affinity of D2 toward LAT1 is over 20-times higher when compared to the secondary mechanism, while the overall uptake speed of D2 is 1.5-times faster when compared to D1. 18,42 However, in the present study, with a single high-dose administration, it is possible that other low-affinity transporters along LAT1 are also affecting the distribution of the compounds.…”

“…We have previously reported that amino acid derivatives of FA have increased delivery across the blood–brain barrier (BBB) as well as cellular uptake into neurons and glial cells compared to FA. , These derivatives can also alleviate oxidative stress in astrocytes, as lipid peroxidation was significantly reduced after treatment in vitro . Derivatives 1 and 2 (D1 and D2) (Figure ) have been designed to utilize an L-type amino acid transporter 1 (LAT1), which is a solute carrier protein consisting of two dimers, a light chain (LAT1; SLC7A5 ) and a heavy chain (4F2hc; SLC3A2 ) .…”

Targeting of Perforin Inhibitor into the Brain Parenchyma Via a Prodrug Approach Can Decrease Oxidative Stress and Neuroinflammation and Improve Cell Survival

“…We have also previously reported that LAT1-utilizing derivatives of ferulic acid have multifunctional properties that can ameliorate neuroinflammation and oxidative stress [52]. These included inhibition of BACE1 activity.…”

Aminopeptidase B can bioconvert L-type amino acid transporter 1 (LAT1)-utilizing amide prodrugs in the brain

“…Therefore, the aim of the present study was to identify the possible enzymes responsible for bioconversion of LAT1-utilizing amide prodrugs, particularly in the brain. We have reported that many LAT1-utilizing amide prodrugs are very stable when studied in vitro in tissue homogenates, but they have released their parent drugs in vivo in mice, and curiously some of them selectively in the brain ( Table 1 ) ( Puris et al, 2017 ; Montaser et al, 2019 ; Puris et al, 2019 ). Therefore, it has been hypothesized that the used in vitro assays may lack some essential co-factors required for the optimal function of the bioconverting enzymes.…”