Modulation of ERK1/2 and Akt Pathways Involved in the Neurotrophic Action of Caffeic Acid Alkyl Esters

Abstract

Neurodegenerative diseases affect millions of human lives all over the world. The number of afflicted patients is rapidly growing, and disease-modifying agents are urgently needed. Caffeic acid, an important member of the hydroxycinnamic acid family of polyphenols, has considerable neurotrophic effects. We have previously shown how caffeate alkyl ester derivatives significantly promote survival and differentiation in neuronal cells. In this study, the mechanisms by which these ester derivatives exert their neurotrophic effects are examined. A series of eight caffeic acid esters with different alkyl chain lengths, ranging from methyl (CAF1) to dodecyl esters (CAF8), were synthesized and studied for their influence on neurotrophic signaling pathways. Caffeate esters did not induce tropomyosin-receptor kinase A (TrkA) phosphorylation, which was assessed by immunoblotting up to a concentration of 25 µM. NIH/3T3 cells overexpressing TrkA were generated to further examine phosphorylation of this receptor tyrosine kinase. None of the esters induced TrkA phosphorylation in these cells either. Assessment of the effect of caffeate derivatives on downstream neurotrophic pathways by immunoblotting showed that the most potent esters, decyl caffeate (CAF7) and dodecyl caffeate (CAF8) caused extracellular signal-regulated kinase (ERK1/2) and Akt serine threonine kinase phosphorylation in PC12 cells at 5 and 25 µM concentrations. In conclusion, this study shows that caffeate esters exert their neurotrophic action by modulation of ERK1/2 and Akt signaling pathways in neuronal cells, and further demonstrates the potential therapeutic implications of these derivatives for neurodegenerative diseases.

Neuroprotective Effects of Methyl Caffeate against Hydrogen Peroxide-Induced Cell Damage: Involvement of Caspase 3 and Cathepsin D Inhibition

“…Since previous reports demonstrated an involvement of inhibition of calpains and activation of PI3-K/Akt intracellular pathway in neuroprotection mediated by caffeic acid- and its derivatives [ 6 , 22 , 23 ], we verified these mechanisms in our study by using calpain (MDL28170) and PI3-K (LY294002) inhibitors. We showed that cytoprotection mediated by MC was more robust than that mediated by MDL28170 (20 μM) and has not been changed after combined treatment with both compounds ( Table 1 ).…”

“…Moreover, in the present study we found that the calpain inhibitor, MDL28170 protected cells against oxidative stress-induced cell damage to a smaller extent than MC and the protection range was not changed after administration of both compounds which suggests possible involvement of calpain inhibition in the MC-mediated neuroprotection. There are conclusive data showing the participation of activation of the pro-survival PI3-K/Akt pathway in the neuroprotective effects of CA and/or its derivatives [ 5 , 6 , 7 , 22 ]. However, in our study the inhibitor of PI3-K, LY294002 failed to block the neuroprotective effects of MC in the H 2 O 2 model of cell damage which excludes the participation of this signaling pathway in the MC-mediated neuroprotection at least in this model of neuronal injury.…”

“…Thus, much effort has been devoted to finding HCA-rich plant species for efficient extraction and isolation of active compounds. In addition, various synthetic derivatives (esters, amides) have been synthesized based on particular HCA-scaffolds [ 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. They are supposed to display a higher activity than natural compounds although their biosafety should be closely monitored to limit potential side effects.…”

“…The representatives of this class of phenolic compounds most often studied so far in pre-clinical models of neurodegeneration include caffeic acid phenyl ester (CAPE, the main active component of propolis), chlorogenic acid (CGA, present in abundance in green coffee), chicoric acid, CA and rosmarinic acid (active component of rosemary herb) [ 14 , 15 , 16 , 17 , 18 , 19 ]. These compounds are characterized by pleiotropic mechanisms of action encompassing the activation of Nrf2/ARE/HO-1 pathway and induction of phase II enzymes (SOD, GSH, NADPH oxidase, xanthine oxidase), inhibition of calpains, attenuation of apoptotic and neuroinflammatory processes, inhibition of p38 and JNK pathways, induction of autophagy, activation of pro-survival PI3-K/Akt and MAPK/ERK1/2 pathways and stimulation of production of growth factors (NGF, BDNF, GDNF, VEGF) [ 5 , 6 , 7 , 15 , 18 , 20 , 21 , 22 , 23 , 24 , 25 ].…”

Quercetin, caffeic acid and resveratrol regulate circadian clock genes and aging-related genes in young and old human lung fibroblast cells

“…Then, the cells were further cultured for 4 h in 96-well plates in mediums with or without samples (100 μM resveratrol, 2 or 20 μM quercetin, and 2.5 or 25 μM caffeic acid) under 5% CO 2 at 37 °C. The concentrations of these three compounds were determined with reference to the papers [10,[25][26][27]. Similarly, according to the experimental results of Oike and Kobori, the sample processing time was set to 4 h [10].…”