Neuroprotection by sodium ferulate against glutamate-induced apoptosis is mediated by ERK and PI3 kinase pathways

Abstract

Aim: To investigate whether sodium ferulate (SF) can protect cortical neurons from glutamate-induced neurotoxicity and the mechanisms responsible for this protection. Methods: Cultured cortical neurons were incubated with 50 µmol/L glutamate for either 30 min or 24 h, with or without pre-incubation with SF (100, 200, and 500 µmol/L, respectively). LY294002, wortmannin, PD98059, and U0126 were added respectively to the cells 1 h prior to SF treatment. After incubation with glutamate for 24 h, neuronal apoptosis was quantified by scoring the percentage of cells with apoptotic nuclear morphology after Hoechst 33258 staining. After incubation with glutamate for either 30 min or 24 h, cellular extracts were prepared for Western blotting of active caspase-3, poly (ADP-ribose) polymerase (PARP), µ-calpain, Bcl-2, phospho-Akt, phosphorylated ribosomal protein S6 protein kinase (p70S6K), phospho-mitogen-activated protein kinase kinase (MEK1/2) and phosphorylated extracellular signal-regulated kinase (ERK) 1/2. Results: SF reduced glutamate-evoked apoptotic morphology, active caspase-3 protein expression, and PARP cleavage and inhibited the glutamate-induced upregulation of the µ-calpain protein level. The inhibition of the phosphatidylinositol 3-kinase (PI3K) and the MEK/ERK1/2 pathways partly abrogated the protective effect of SF against glutamate-induced neuronal apoptosis. SF prevented the glutamateinduced decrease in the activity of the PI3K/Akt/p70S6K and the MEK/ERK1/2 pathways. Moreover, incubation of cortical neurons with SF for 30 min inhibited the reduction of the Bcl-2 expression induced by glutamate. Conclusion: The results indicate that PI3K/Akt/p70S6K and the MEK/ERK signaling pathways play important roles in the protective effect of SF against glutamate toxicity in cortical neurons.

Ferulic acid inhibits nitric oxide-induced apoptosis by enhancing GABAB1 receptor expression in transient focal cerebral ischemia in rats

“…In vitro studies [5,12] have demonstrated that the NO-induced apoptotic signaling cascade involves mitogen-activated protein (MAP) kinase-mediated Bax translocation from the cytosol to the mitochondria and subsequent caspase-3 activation in cultured In previous studies, FA reduces cerebral ischemic injury by weakening the expression of PSD-95 in the ischemic area and provides neuroprotection against apoptosis partly via inhibiting intercellular adhesion molecule-1 (ICAM-1) mRNA expression in a transient middle cerebral artery occlusion (MCAo) model [13,14] . In addition, FA inhibits glutamate-induced apoptosis through modulation of the MAP kinase signaling pathway in cultured cortical neurons [15] . However, the precise mechanism by which FA suppresses apoptosis in transient MCAo remains unclear.…”

The Gut Microflora and its Metabolites Regulate the Molecular Crosstalk between Diabetes and Neurodegeneration

“…In neurons, FA inhibits peroxyl radical induced apoptosis and at higher doses prevented protein and lipid oxidation [90,91]. Indeed, in a glutamate toxicity model, FA completely inhibited apoptosis and the elevated caspase 3 and reduced Bcl2 levels [92]. In a rat model of cerebral ischemia, FA prevented apoptosis and iNOS induction, indicating that it is protective against external assaults.…”

“…The apoptotic activity of FA was completely inhibited in the presence of a PI3K inhibitor indicating that the anti-apoptotic effects of FA depend on the PI3K/Akt pathway. In addition, FA was shown to rescue the level of phosphorylated Akt and the downstream p70S6K in the glutamate toxicity model [92]. In terms of ERK, inhibition of ERK signaling in a model of glutamate toxicity partially abrogated the anti-apoptotic effect of FA [92].…”

“…In addition, FA was shown to rescue the level of phosphorylated Akt and the downstream p70S6K in the glutamate toxicity model [92]. In terms of ERK, inhibition of ERK signaling in a model of glutamate toxicity partially abrogated the anti-apoptotic effect of FA [92]. Nevertheless, FA could prevent the decrease of ERK phosphorylation in the glutamate toxicity model, in a MAPK dependent manner [92].…”

“…In terms of ERK, inhibition of ERK signaling in a model of glutamate toxicity partially abrogated the anti-apoptotic effect of FA [92]. Nevertheless, FA could prevent the decrease of ERK phosphorylation in the glutamate toxicity model, in a MAPK dependent manner [92]. Ultimately, through these pathways, FA effectively inhibits apoptosis activity by inhibiting caspase 3 activation and PARP cleavage.…”