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Neuroscience. 2015 Sep 10;303:558-68. doi: 10.1016/j.neuroscience.2015.07.034. Epub 2015 Jul 18.

Neuroprotective effect of astaxanthin against glutamate-induced cytotoxicity in HT22 cells: Involvement of the Akt/GSK-3β pathway.

Author information

1
Department of Neurology, Guangzhou First Municipal People's Hospital, Guangzhou Medical University, Guangzhou-Birmingham University Brain and Cognition Center, No. 1 Panfu Road, Guangzhou 510180, China.
2
State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China.
3
Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
4
Department of Neurology, the Sixth Affiliated Hospital Sun Yat-sen University, Guangzhou 510440, China.
5
Department of Neurology, Guangzhou First Municipal People's Hospital, Guangzhou Medical University, Guangzhou-Birmingham University Brain and Cognition Center, No. 1 Panfu Road, Guangzhou 510180, China. Electronic address: qpanxp@163.com.
6
Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, China. Electronic address: Zhonglinliu@126.com.

Abstract

Oxidative stress (OS) mediated the pathogenesis of Alzheimer's disease (AD). Astaxanthin (ATX) has been reported to exert antioxidant activities as well as neuroprotective effects in vivo and in vitro. But it is still unknown whether the Akt/glycogen synthase kinase-3β (GSK-3β) signaling mediated the neuroprotective effect of ATX in HT22 cells. Flow cytometric analysis was used to evaluate reactive oxygen species (ROS) generation. Caspase and PARP activity was measured. The expressions of heme oxygenase-1 (HO-1), nuclear factor-E2-related factor 2 (Nrf2), Bcl-2, Bax, apoptosis-inducing factor (AIF), cytochrome-c (Cyto-c), p-Akt and p-GSK-3β were evaluated to elucidate the underlying mechanism. Our results showed that ATX significantly attenuated glutamate-induced cell viability loss and lactate dehydrogenase (LDH) release, decreased the expression of caspase-3/8/9 activity and cleaved PARP, and suppressed the intracellular accumulation of ROS in HT22 cells after exposure to glutamate. ATX also increased the mitochondrial expression of AIF, Cyto-c as well as Bax while decreased Bcl-2. Moreover, ATX also induced the HO-1 expression in a dose and time-dependent manner, increased the antioxidant-responsive element (ARE) activity and nuclear Nrf2 expression. Furthermore, treatment with ATX restored the p-Akt and p-GSK-3β (Ser9) as well as HO-1 expression reduced by glutamate. This protective effect was partially blocked by the inhibitors lithium chloride treatment in HT22, indicating the involvement of Akt/GSK-3β inactivation during the neuroprotective effect of ATX. Our results provide the first evidence that ATX can protect glutamate-induced cytotoxicity in HT22 via attenuating caspase activation and mitochondrial dysfunction and modulating the Akt/GSK-3β signaling, indicating ATX may be useful for the treatment of neurodegenerative disorders such as AD.

KEYWORDS:

Akt; GSK-3β; Nrf2; astaxanthin; oxidative stress

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