Discovery of neurotrophic agents based on hydroxycinnamic acid scaffold

Abstract

The number of people affected by neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease is rapidly increasing owing to the global increase in life expectancy. Small molecules with neurotrophic effects have great potential for management of these neurological disorders. In this study, different (C1-C12) alkyl ester derivatives of hydroxycinnamic acids (HCAs) were synthesized (a total of 30 compounds). The neurotrophic capacity of the test compounds was examined by measuring promotion of survival in serum-deprived conditions and enhancement of nerve growth factor (NGF)-induced neurite outgrowth in PC12 neuronal cells. p-Coumaric, ferulic, and sinapic acids and their esters did not alter cell survival, while caffeic acid and all its alkyl esters, especially decyl and dodecyl caffeate, significantly promoted neuronal survival at 25 μm. Methyl, ethyl, propyl, and butyl caffeate esters also significantly enhanced NGF-induced neurite outgrowth, among which the most effective ones were propyl and butyl esters, which at 5 μm led to 25- and 22-fold increases in the number of neurites, respectively. The findings of the docking study suggested phosphatidylinositol 3-kinase (PI3K) as the potential molecular target. In conclusion, our findings demonstrate that alkyl esters of caffeic acid can be useful as scaffolds for the discovery of therapeutic agents for neurodegenerative diseases.

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

“…These results suggest involvement of inhibition of apoptotic and necrotic processes in the neuroprotective action of MC. It should be noted that previous studies demonstrated that CA or its derivatives inhibited apoptotic processes in neuronal cells which were induced by various factors (e.g., low potassium level, H 2 O 2 , serum deprivation) [ 5 , 8 , 13 , 19 , 40 ] and our present results extend these data by showing the effects of MC in the oxidative stress-based model. It is also in line with previous data from non-neuronal cells (kidney epithelium cell line LLC-PK) where MC (100 μM) reduced the contrast-induced caspase-3 activity and increased cell survival [ 54 ].…”

“…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 ].…”

“…Garrido et al [ 8 ] has shown that only esters of CA, including also MC, but not CA, ferulic acid or ferulate esters were able to attenuate the hydrogen peroxide (H 2 O 2 )-induced cell damage in rat PC12 neuronal-like cells. Moreover, in the model of serum deprived PC12 cells, of all tested various HCAs and their esters only CA and its esters (including also MC) have been shown to promote cell survival and to enhance the NGF-induced neurite outgrowth in PC12 cells [ 5 ]. It could be hypothesized that MC could be an efficient neuroprotective compound due to its wide distribution in plants and increased lipophilicity when compared to CA [ 8 , 10 , 12 ].…”