Artemisinin Prevents Glutamate-Induced Neuronal Cell Death Via Akt Pathway Activation

Lin, Shao Peng; Li, Wenjun; Winters, Ali; Liu, Ran; Yang, Shao Hua

doi:10.3389/fncel.2018.00108

Cited by 50 publications

(40 citation statements)

References 30 publications

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“…As the multifactorial nature of AD, the search for Chinese herbal compounds with a wide spectrum of neuroprotective activities, hold very encouraging future for the treatment of AD [ 46 ]. ART, widely used in the clinic as an anti-malarial drug, has exhibited neuroprotective effects in various neuronal cells [ 47 , 48 ]. However, the mechanism is still not clear and protective effects of ART on cognitive impairment and pathology in-vivo are not well known so far.…”

Section: Discussionmentioning

confidence: 99%

Artemisinin Improved Neuronal Functions in Alzheimer's Disease Animal Model 3xtg Mice and Neuronal Cells via Stimulating the ERK/CREB Signaling Pathway

Zhao¹,

Li²,

Gaur³

et al. 2020

Aging and disease

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The most common form of dementia is Alzheimer's disease which is characterized by memory loss and cognitive disorders. The pathogenesis of Alzheimer's disease is not known at present but toxicity of amyloidbeta is one of the central hypotheses. Amyloid-beta can stimulate the production of reactive oxygen species (ROS), cause oxidative stress, damage mitochondrial, cause inflammatory reactions and activate apoptosis related factors which lead to the neuronal death. In this study, we found that artemisinin, a first line antimalarial drug used in clinic for decades, improved the cognitive functions in Alzheimer's disease animal model 3xTg mice. Further study showed that artemisinin reduced the deposition of amyloid-beta and tau protein, reduced the release of inflammation factors and apoptosis factors, and thereby reduced the neuronal cell death. Western blot assay showed that artemisinin stimulated the activation of ERK/CREB signaling pathway. Consistent with these results, artemisinin concentration-dependently promoted the survival of SH-SY5Y cell against toxicity of amyloid-beta protein 1-42 induced ROS accumulation, caspase activation and apoptosis. Artemisinin also stimulated the phosphorylation of ERK1/2 and CREB in SH-SY5Y cells in time and concentration-dependent manner. Inhibition of ERK/CREB pathway attenuated the protective effect of artemisinin. These data put together suggested that artemisinin has the potential to protect neuronal cells in vitro as well as in vivo animal model 3xTg mice via, at least in part, the activation of the ERK/CREB pathway. Our findings also strongly support the potential of artemisinin as a new multi-target drug that can be used for preventing and treating the Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

Artemisinin Improved Neuronal Functions in Alzheimer's Disease Animal Model 3xtg Mice and Neuronal Cells via Stimulating the ERK/CREB Signaling Pathway

Zhao¹,

Li²,

Gaur³

et al. 2020

Aging and disease

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show abstract

“…When we compared both the compound cellular viability assay results we found that the artemisinin was better than DHA. Owing to its lipid-soluble nature, artemisinin can pass the blood brain barrier and maintain a higher concentration in the central nervous system [35], giving it advantage over other neurological drugs. Also as an FDA-approved anti-malarial drug, artemisinin has been clinically used for decades with no significant adverse effects [36].…”

Section: Discussionmentioning

confidence: 99%

Artemisinin Attenuated Hydrogen Peroxide (H2O2)-Induced Oxidative Injury in SH-SY5Y and Hippocampal Neurons via the Activation of AMPK Pathway

Zhao¹,

Fang²,

Li³

et al. 2019

IJMS

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Oxidative stress is believed to be one of the main causes of neurodegenerative diseases such as Alzheimer’s disease (AD). The pathogenesis of AD is still not elucidated clearly but oxidative stress is one of the key hypotheses. Here, we found that artemisinin, an anti-malarial Chinese medicine, possesses neuroprotective effects. However, the antioxidative effects of artemisinin remain to be explored. In this study, we found that artemisinin rescued SH-SY5Y and hippocampal neuronal cells from hydrogen peroxide (H2O2)-induced cell death at clinically relevant doses in a concentration-dependent manner. Further studies showed that artemisinin significantly restored the nuclear morphology, improved the abnormal changes in intracellular reactive oxygen species (ROS), reduced the mitochondrial membrane potential, and caspase-3 activation, thereby attenuating apoptosis. Artemisinin also stimulated the phosphorylation of the adenosine monophosphate -activated protein kinase (AMPK) pathway in SH-SY5Y cells in a time- and concentration-dependent manner. Inhibition of the AMPK pathway attenuated the protective effect of artemisinin. These data put together suggested that artemisinin has the potential to protect neuronal cells. Similar results were obtained in primary cultured hippocampal neurons. Cumulatively, these results indicated that artemisinin protected neuronal cells from oxidative damage, at least in part through the activation of AMPK. Our findings support the role of artemisinin as a potential therapeutic agent for neurodegenerative diseases.

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“…100 nM Insulin (Roche, #11376497001) was added 30 min before the hypoxia treatment and 1 mM of 4-Phenylbutyric acid (4-PBA, Sigma-Aldrich, #P21005) was added at the beginning of hypoxia exposure ( Liu et al, 2016 ). 5 μM MK2206 (Cayman #1032350-13-2) was added together with hypoxia treatment ( Lin et al, 2018 ).…”

Section: Methodsmentioning

confidence: 99%

Neuroprotective Role of Akt in Hypoxia Adaptation in Andeans

et al. 2021

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Chronic mountain sickness (CMS) is a disease that potentially threatens a large segment of high-altitude populations during extended living at altitudes above 2,500 m. Patients with CMS suffer from severe hypoxemia, excessive erythrocytosis and neurologic deficits. The cellular mechanisms underlying CMS neuropathology remain unknown. We previously showed that iPSC-derived CMS neurons have altered mitochondrial dynamics and increased susceptibility to hypoxia-induced cell death. Genome analysis from the same population identified many ER stress-related genes that play an important role in hypoxia adaptation or lack thereof. In the current study, we showed that iPSC-derived CMS neurons have increased expression of ER stress markers Grp78 and XBP1s under normoxia and hyperphosphorylation of PERK under hypoxia, alleviating ER stress does not rescue the hypoxia-induced CMS neuronal cell death. Akt is a cytosolic regulator of ER stress with PERK as a direct target of Akt. CMS neurons exhibited lack of Akt activation and lack of increased Parkin expression as compared to non-CMS neurons under hypoxia. By enhancing Akt activation and Parkin overexpression, hypoxia-induced CMS neuronal cell death was reduced. Taken together, we propose that increased Akt activation protects non-CMS from hypoxia-induced cell death. In contrast, impaired adaptive mechanisms including failure to activate Akt and increase Parkin expression render CMS neurons more susceptible to hypoxia-induced cell death.

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Artemisinin Prevents Glutamate-Induced Neuronal Cell Death Via Akt Pathway Activation

Cited by 50 publications

References 30 publications

Artemisinin Improved Neuronal Functions in Alzheimer's Disease Animal Model 3xtg Mice and Neuronal Cells via Stimulating the ERK/CREB Signaling Pathway

Artemisinin Improved Neuronal Functions in Alzheimer's Disease Animal Model 3xtg Mice and Neuronal Cells via Stimulating the ERK/CREB Signaling Pathway

Artemisinin Attenuated Hydrogen Peroxide (H2O2)-Induced Oxidative Injury in SH-SY5Y and Hippocampal Neurons via the Activation of AMPK Pathway

Neuroprotective Role of Akt in Hypoxia Adaptation in Andeans

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