Abstract
Finding effective neuroprotective strategies to combat various neurodegenerative disorders still remain a clinically unmet need. Methyl caffeate (MC), a naturally occurring ester of caffeic acid, possesses antioxidant and anti-inflammatory activities; however, its role in neuroprotection is less investigated. In order to better characterize neuroprotective properties of MC, we tested its effectiveness in various models of neuronal cell injury in human neuroblastoma SH-SY5Y cells and in mouse primary neuronal cell cultures. MC at micromolar concentrations attenuated neuronal cell damage induced by hydrogen peroxide (H2O2) in undifferentiated and neuronal differentiated SH-SY5Y cells as well as in primary cortical neurons. This effect was associated with inhibition of both caspase-3 and cathepsin D but without involvement of the PI3-K/Akt pathway. MC was neuroprotective when given before and during but not after the induction of cell damage by H2O2. Moreover, MC was protective against 6-OHDA-evoked neurotoxicity in neuronal differentiated SH-SY5Y cells via inhibition of necrotic and apoptotic processes. On the other hand, MC was ineffective in models of excitotoxicity (induced by glutamate or oxygen–glucose deprivation) and even moderately augmented cytotoxic effects of the classical apoptotic inducer, staurosporine. Finally, in undifferentiated neuroblastoma cells MC at higher concentrations (above 50 microM) induced cell death and when combined with the chemotherapeutic agent, doxorubicin, it increased the cell damaging effects of the latter compound. Thus, neuroprotective properties of MC appear to be limited to certain models of neurotoxicity and depend on its concentrations and time of administration.
Highlights
Hydroxycinnamic acids (HCAs) belong to the family of phenolic compounds which are widespread in nature, and among them, caffeic (CA), ferulic, p-coumaric and sinapic acids are most abundant [1,2,3]
In RA-SH-SY5Y cells we did not find any attenuating effect of Methyl caffeate (MC) on the H2O2-evoked reduction in cell viability when cells were moderately damaged (H2O2 0.5 mM; ca. 50% injury) (Figure 4A) but we observed neuroprotective effects when more severe damage occurred (H2O2 0.75 mM; ca. 80% injury) (Figure 4C)
We demonstrated a significant induction of caspase-3 activity after 9 h of exposure of SH-SY5Y cells to H2O2 (0.25 and 0.75 mM for UN- and RA-SH-SY5Y cells, respectively) which was significantly attenuated by a caspase 3 inhibitor and MC caffeate at concentrations 1–10 μM and 10–50 μM for UN- and RA-SH-SY5Y cells, respectively (Figure 6A,B)
Summary
Hydroxycinnamic acids (HCAs) belong to the family of phenolic compounds which are widespread in nature, and among them, caffeic (CA), ferulic, p-coumaric and sinapic acids are most abundant [1,2,3]. According to the literature published so far CA and its derivatives seem to be the most promising candidates for neuroprotective agents since they possess relatively higher antioxidant activity and are protective against a wider range of harmful factors when compared to other HCAs [8,10,12,13] 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]
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