Abstract
Emerging evidence reveals that an aberrant accumulation of β-amyloid (Aβ) is the main reason of Alzheimer’s disease (AD) pathogenesis. Thus, inhibition of Aβ-induced neurotoxicity may be promising therapeutic tactics to mitigate AD onset and advance. The development of agent candidates by cultured neurons against Aβ-induced cytotoxicity is widely accepted to be an efficient strategy to explore the drug for AD patients. Previously, we have revealed that trilobatin (TLB), a small molecule monomer, derives from Lithocarpus polystachyus Rehd, possessed antioxidative activities on hydrogen peroxide-induced oxidative injury in PC12 cells. The present study was designed to investigate the effects and the underlying mechanism of TLB on Aβ-induced injury in hippocampal HT22 cells. The results demonstrated that TLB attenuated Aβ25–35-induced HT22 cell death, as evidenced by MTT assay and LDH release. Furthermore, TLB dramatically mitigated cell death after Aβ25–35 insulted via decreasing the intracellular and mitochondrial ROS overproduction and restoring antioxidant enzyme activities, as well as suppressing apoptosis. Of note, Aβ25–35 triggered increase in ratio of Bax/Bcl-2, activation of caspase-3, phosphorylation of tau, JNK, p38 MAPK, and decrease in Sirt3 expression, whereas TLB reversed these changes. Intriguingly, TLB could directly bind to p38, as evidenced by molecular docking and p38 inhibitor. Taken together, the results reveal that TLB effectively protects against Aβ25–35-induced neuronal cell death via activating ROS/p38/caspase 3-dependent pathway. Our findings afford evidence for the potential development of TLB to hinder neuronal death during AD.
Highlights
Alzheimer’s disease (AD), the extremely common type of senile dementia, which is accompanied by progressive learning and memory impairment, as well as cognitive deficits (Deng et al, 2017; Suh et al, 2019)
The results showed that TLB significantly increased cell viability and decreased LDH release than those of Ab25–35 group, as evidenced by MTT and LDH release assay, respectively (Figures 1B, C)
The results revealed that Ab25–35-treated cells led to the decrease in the number of cells and floatation than those of the control group; while, TLB reversed these change than those of Ab25–35 group (Figure 1D)
Summary
Alzheimer’s disease (AD), the extremely common type of senile dementia, which is accompanied by progressive learning and memory impairment, as well as cognitive deficits (Deng et al, 2017; Suh et al, 2019). AD is characterized by the aggregation of b-amyloid (Ab) plaques, loss of neurofibrillary tangles (NFTs) and neurons (Hashimoto et al, 2019). It is believed that Ab deposition is the major element of senile plaques discovered in the brains of AD patients (Weiner et al, 2017). Inhibition of Ab-induced neurotoxicity may be a promising therapeutic strategy to mitigate AD onset and advance. The exploit of safe and efficient treatment strategies for AD are still an urgent clinical need. It is worth noting that a lot of neuroprotectants for AD failed in clinical trials, mainly due to an encounter with the hardness in affording therapeutic proteins or drugs to the central nervous system (Yuan et al, 2019). It is reasonably assumed that small molecule monomer, primarily derive from the natural product, will be an alternative to affect neurons
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