Aim: To observe whether an amyloid β (Aβ)-induced increase in interleukin (IL)-1β was accompanied by an increase in the p38 mitogen-activated protein kinase (MAPK) pathway and a decrease in the cell survival pathway, and whether sodium ferulate (SF) treatment was effective in preventing these Aβ-induced changes. Methods: Rats were injected intracerebroventricularly with Aβ [25][26][27][28][29][30][31][32][33][34][35] . Seven days after injection, immunohistochemical techniques for glial fibrillary acidic protein (GFAP) were used to determine the astrocyte infiltration and activation in hippocampal CA1 areas. The expression of IL-1β, extracellular signal-regulated kinase (ERK), p38 MAPK, Akt/protein kinase B (PKB), Fas ligand and caspase-3 were determined by Western blotting. The caspase-3 activity was measured by cleavage of the caspase-3 substrate (Ac-DEVD-pNA). Reverse transcriptionpolymerase chain reaction was used to analyze the changes in IL-1βmRNA levels. Results:Intracerebroventricular injection of Aβ 25-35 elicited astrocyte activation and infiltration and caused a strong inflammatory reaction characterized by increased IL-1β production and elevated levels of IL-1β mRNA. Increased IL-1β synthesis was accompanied by increased activation of p38 MAPK and downregulation of phospho-ERK and phospho-Akt/PKB in hippocampal CA regions prepared from Aβ-treated rats, leading to cell death as assessed by activation of caspase-3. SF significantly prevented Aβ-induced increases in IL-1β and p38 MAPK activation and also Aβ-induced changes in phospho-ERK and phospho-Akt/PKB expression levels. Conclusion: SF prevents Aβ-induced neurotoxicity through suppression of p38 MAPK activation and upregulation of phospho-ERK and phospho-Akt/PKB expression.
Inflammation and oxidative stress are essential for the pathogenesis of fulminant hepatic failure (FHF). Asiatic acid (AA), which is a pentacyclic triterpene that widely occurs in various vegetables and fruits, has been reported to possess antioxidant and anti-inflammatory properties. In this study, we investigated the protective effects of AA against lipopolysaccharide (LPS) and d-galactosamine (GalN)-induced FHF and the underlying molecular mechanisms. Our findings suggested that AA treatment effectively protected against LPS/d-GalN-induced FHF by lessening the lethality; decreasing the alanine transaminase and aspartate aminotransferase levels, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α production, malondialdehyde formation, myeloperoxidase level and reactive oxygen species generation (i.e., H2O2, NO, and O2−), and increasing the glutathione and superoxide dismutase contents. Moreover, AA treatment significantly inhibited mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathway activation via the partial induction of programmed cell death 4 (PDCD4) protein expressions, which are involved in inflammatory responses. Furthermore, AA treatment dramatically induced the expression of the glutamate-cysteine ligase modifier subunit, the glutamate-cysteine ligase catalytic subunit, heme oxygenase-1, and NAD (P) H: quinoneoxidoreductase 1 (NQO1), which are largely dependent on activation of the nuclear factor-erythroid 2-related factor 2 (Nrf2) through the induction of AMP-activated protein kinase (AMPK) and glycogen synthase kinase-3β (GSK3β) phosphorylation. Accordingly, AA exhibited protective roles against LPS/d-GalN-induced FHF by inhibiting oxidative stress and inflammation. The underlying mechanism may be associated with the inhibition of MAPK and NF-κB activation via the partial induction of PDCD4 and upregulation of Nrf2 in an AMPK/GSK3β pathway activation-dependent manner.
Aim: To observe the effects of sodium ferulate (SF) on amyloid beta (Aβ) 1-40 -induced p38 mitogen-activated protein kinase (MAPK) signal transduction pathway and the neuroprotective effects of SF. Methods: Rats were injected intracerebroventricularly with Aβ 1-40 . Six hours after injection, Western blotting was used to determine the expressions of phosphorylated mitogen-activated protein kinase kinase (MKK) 3/MKK6, phospho-p38 MAPK, interleukin (IL)-1β, phospho-MAPK activating protein kinase 2 (MAPKAPK-2), the 27 kDa heat shock protein (Hsp27), procaspase-9, -3, and -7 cleavage, and poly (ADP-ribose) polymerase (PARP) cleavage. Seven days after injection, Nissl staining was used to observe the morphological change in hippocampal CA1 regions. Results: Intracerebroventricular injection of Aβ 1-40 induced an increase in phosphorylated MKK3/MKK6 and p38 MAPK expressions in hippocampal tissue. These increases, in combination with enhanced interleukin (IL)-1β protein expression and reduced phospho-MAPKAPK2 and phospho-Hsp27 expression, mediate the Aβ-induced activation of cell death events as assessed by cleavage of procaspase-9, -3, and -7 and caspase-3 substrate PARP cleavage. Pretreatment with SF (100 mg/kg and 200 mg/kg daily, 3 weeks) significantly prevented Aβ 1-40 -induced increases in phosphorylated MKK3/MKK6 and p38 MAPK expression. The Aβ 1-40 -induced increase in IL-1β protein level was attenuated by pretreatment with SF. In addition, Aβ 1-40 -induced decreases in phosphorylated MAPKAPK2 and Hsp27 expression were abrogated by administration of SF. In parallel with these findings, Aβ 1-40 -induced changes in activation of caspase-9, caspase-7, and caspase-3 were inhibited by pretreatment with SF. Conclusion: SF prevents Aβ 1-40 -induced neurotoxicity through suppression of MKK3/MKK6-p38 MAPK activity and IL-1β expression and upregulation of phospho-Hsp27 expression.
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