Artemisinin protects PC12 cells against β-amyloid-induced apoptosis through activation of the ERK1/2 signaling pathway

Abstract

Accumulating evidence displays that an abnormal deposition of amyloid beta-peptide (Aβ) is the primary cause of the pathogenesis of Alzheimer's disease (AD). And therefore the elimination of Aβ is regarded as an important strategy for AD treatment. The discovery of drug candidates using culture neuronal cells against Aβ peptide toxicity is believed to be an effective approach to develop drug for the treatment of AD patients. We have previously showed that artemisinin, a FDA-approved anti-malaria drug, has neuroprotective effects recently. In the present study, we aimed to investigate the effects and potential mechanism of artemisinin in protecting neuronal PC12 cells from toxicity of β amyloid peptide. Our studies revealed that artemisinin, in clinical relevant concentration, protected and rescued PC12 cells from Aβ25–35-induced cell death. Further study showed that artemisinin significantly ameliorated cell death due to Aβ25–35 insult by restoring abnormal changes in nuclear morphology, lactate dehydrogenase, intracellular ROS, mitochondrial membrane potential and activity of apoptotic caspase. Western blotting analysis demonstrated that artemisinin activated extracellular regulated kinase ERK1/2 but not Akt survival signaling. Consistent with the role of ERK1/2, preincubation of cells with ERK1/2 pathway inhibitor PD98059 blocked the effect of artemisinin while PI3K inhibitor LY294002 has no effect. Moreover, Aβ1-42 also caused cells death of PC12 cells while artemisinin suppressed Aβ1-42 cytotoxicity in PC12 cells. Taken together, these results, at the first time, suggest that artemisinin is a potential protectant against β amyloid insult through activation of the ERK1/2 pathway. Our finding provides a potential application of artemisinin in prevention and treatment of AD.

The p38-MAPK Pathway Is Involved in Neuroprotection of Artemisinin against H2O2-induced Apoptosis in PC12 Cells

“…One of the attractive pharmacological activities of artemisinin is its super antioxidant effects. Previous research by our group has well proved that artemisinin was able to inhibit ROS production and also conferred neuroprotection against various insults in cultured cells [18,19,21,35]. Our present study here further supported the antioxidant effects of artemisinin and indicated the possibility that artemisinin administration might be a potential therapeutic strategy for the treatment of AD.…”

“…Beside these effects, previous studies including some from our group, have shown that artemisinin and its derivatives have neuroprotective effects suggesting that artemisinin might be potential candidate for AD therapy [16][17][18][19]. It has been recognized that artemisinin-mediated neuroprotection against neuronal apoptosis from various insults is regulated by ERK1/2 survival/apoptotic signaling pathway rather than the Akt pathway [16,18,19]. In addition, researchers also found that artemisinin was able to stimulate the p38MAPK pathway [16,20].…”

“…In clinical relevance, artemisinin is among the most effective therapies for malaria with great safety and the preferred first-line treatment for the disease [15]. Beside these effects, previous studies including some from our group, have shown that artemisinin and its derivatives have neuroprotective effects suggesting that artemisinin might be potential candidate for AD therapy [16][17][18][19]. It has been recognized that artemisinin-mediated neuroprotection against neuronal apoptosis from various insults is regulated by ERK1/2 survival/apoptotic signaling pathway rather than the Akt pathway [16,18,19].…”

“…In addition, researchers also found that artemisinin was able to stimulate the p38MAPK pathway [16,20]. Furthermore, our group have recently reported that artemisinin can successful protect PC12 and primary neurons from β-amyloid insult [18]. Different studies have shown that artemisinin inhibited superoxide anions and had radical scavenging activity against the highly reactive hydroxyl radicals, while the understanding of mechanisms that participated in its antioxidant effects is still very limited [19,21].…”

“…Different studies have shown that artemisinin inhibited superoxide anions and had radical scavenging activity against the highly reactive hydroxyl radicals, while the understanding of mechanisms that participated in its antioxidant effects is still very limited [19,21]. PC12 cell line with most of the typical features of primary neuron, originally derived from rat pheochromocytoma, is a useful neuronal model for the study of AD as well as other neurodegenerative disease, and was also widely used to investigate free ROS biochemical pathways related to cell apoptosis and neuroprotection [18,22,23]. Therefore, this cell line is a suitable model for studying oxidative stress-induced neuronal injury.…”