Atorvastatin prevents amyloid-β peptide oligomer-induced synaptotoxicity and memory dysfunction in rats through a p38 MAPK-dependent pathway

Abstract

Aim: To investigate whether atorvastatin treatment could prevent Aβ 1-42 oligomer (AβO)-induced synaptotoxicity and memory dysfunction in rats, and to elucidate the mechanisms involved in the neuroprotective actions of atorvastatin. Methods: SD rats were injected with AβOs (5 nmol, icv). The rats were administrated with atorvastatin (10 mg·kg -1 ·d -1 , po) for 2 consecutive weeks (the first dose was given 5 d before AβOs injection). The memory impairments were evaluated with Morris water maze task. The expression of inflammatory cytokines in the hippocampus was determined using ELISA assays. The levels of PSD-95 and p38MAPK proteins in rat hippocampus were evaluated using Western blot analysis. For in vitro experiments, cultured rat hippocampal neurons were treated with AβOs (50 nmol/L) for 48 h. The expression of MAP-2 and synaptophysin in the neurons was detected with immunofluorescence. Results: The AβO-treated rats displayed severe memory impairments in Morris water maze tests, and markedly reduced levels of synaptic proteins synaptophysin and PSD-95, increased levels of inflammatory cytokines (IL-1β, IL-6 and TNF-α) and p38MAPK activation in the hippocampus. All these effects were prevented or substantially attenuated by atorvastatin administration. Pretreatment of cultured hippocampal neurons with atorvastatin (1 and 5 µmol/L) concentration-dependently attenuated the AβO-induced synaptotoxicity, including the loss of dendritic marker MAP-2, and synaptic proteins synaptophysin and PSD-95. Pretreatment of the cultured hippocampal neurons with the p38MAPK inhibitor SB203580 (5 µmol/L) blocked the AβO-induced loss of synaptophysin and PSD-95. Conclusion: Atorvastatin prevents AβO-induced synaptotoxicity and memory dysfunction through a p38MAPK-dependent pathway.

Atorvastatin prevents Aβ oligomer-induced neurotoxicity in cultured rat hippocampal neurons by inhibiting Tau cleavage

“…AβOs were prepared from Aβ . This preparation contains a mixture of AβOs plus some monomers [17] . We assessed the effects of atorvastatin on hippocampal neurons that were acutely exposed to AβOs.…”

“…Clarke et al demonstrated that rats treated with atorvastatin for 3 weeks were protected against a deficiency in LTP caused by the acute injection of Aβ 1-42 [20] . Our previous results revealed that atorvastatin prevented AβO-induced synaptotoxicity, which leads to memory dysfunction through a p38MAPK-dependent pathway [17] . However, the mechanisms underlying the neuroprotective effects of statins have not been fully elucidated.…”

“…Western blot analysis was performed as previously describ ed [17] . Whole-cell lysates were prepared from hippocampal neurons cultured in 6-well dishes using radioimmune precipitation assay lysis buffer.…”

“…A recent meta-analysis by Wong et al also showed that statins have preventive effects on AD [13] . Evidence from cell culture experiments and animal studies has suggested that statins have many pleiotropic effects, such as reducing Aβ production, suppressing inflammatory responses, protecting neurons from Aβ-induced neurotoxicity, apoptosis and oxidative stress, and promoting synaptogenesis [14][15][16][17] . Recently, a transgenic mouse model of tauopathy showed a reduction in NFTs in response to statin treatment in both early and late stages of disease progression [18] .…”

Hyperoside induces both autophagy and apoptosis in non-small cell lung cancer cells in vitro

“…Western blot analysis was performed as previously described [29] . Whole cell lysates were prepared from A549 cells or BEAS-2B cells cultured in 6-well dishes using radioim-www.chinaphar.com Fu T et al Acta Pharmacologica Sinica npg munoprecipitation assay (RIPA) lysis buffer in the presence of protease inhibitors.…”