Effects of Nicorandil in Neuroprotective Activation of PI3K/AKT Pathways in a Cellular Model of Alzheimer's Disease

Kong, Jianyi; Ren, Guiru; Jia, Ning; Yan, Wang; Zhang, Hua; Zhang, Wei; Chen, Bingkun; Cao, Yunpeng

doi:10.1159/000351247

Cited by 42 publications

(20 citation statements)

References 78 publications

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“…For instance, Cuie et al has shown that the level of pAkt is decreased in the APP/PS1 transgenic model of AD (Cui et al 2013). Similarly, the reduced level of activated Akt is also reported in a cellular model of AD (neurotoxicity in SH-SY5Y cells overexpressing the Swedish mutant APP) (Kong et al 2013). Our results support the latter as the amount of pAkt was decreased in Aβ-treated cells.…”

Section: Discussionsupporting

confidence: 89%

The Interplay of Akt and ERK in Aβ Toxicity and Insulin-Mediated Protection in Primary Hippocampal Cell Culture

et al. 2015

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It is not known if insulin prevents Aβ-induced cell death, MAPK, and Akt activity in isolated hippocampal cell culture. This study was aimed to explore the effect of insulin on Aβ-induced cell death and ERK and Akt signaling alteration in isolated hippocampal cell culture. Additionally, it was desirable to assess if there is any interaction between these two pathways. The hippocampal cells were derived from fetuses at the embryonic day 18-19. The cells were treated with different drugs, and MTT assay, morphological assessments, and Western blot were done. Insulin prevented Aβ-induced cell death and caspase-3 cleavage. Aβ-induced toxicity was aligned with decrement of the phosphorylated Akt (pAkt) which was prevented by insulin. The PI3 kinase inhibitor, LY294002, decreased pAkt and abolished the protective effect of insulin. Aβ exposure increased phosphorylated ERK (pERK) in parallel with cell death and apoptosis. Insulin-inhibited ERK activation (phosphorylation) induced by Aβ and PD98059 (as ERK inhibitor) did not affect the protective effect of insulin. One of the interesting finding of this study was the interplay of Akt and ERK in Aβ toxicity and insulin-mediated protection; meaning that there is an inverse relation between pERK and pAkt, in a way that PI3-Akt pathway inhibition leads to pERK increment while ERK inhibition causes Akt phosphorylation (activation). This study showed, for the first time, that insulin protects against Aβ toxicity in isolated hippocampal cell culture via modulating Akt and ERK phosphorylation and also revealed an interaction between those signals in Aβ toxicity and insulin-mediated protection.

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Section: Discussionsupporting

confidence: 89%

The Interplay of Akt and ERK in Aβ Toxicity and Insulin-Mediated Protection in Primary Hippocampal Cell Culture

et al. 2015

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“…It has been welldocumented that the Akt signaling pathway is essential for neuronal survival in cortical neurons in vitro. Evidence from other studies has also demonstrated a decrease in Akt activity in animals and cellular models of AD [49,50]. Our results demonstrate that maintenance of high megalin expression levels prevents Ab42induced disruption of Akt phosphorylation.…”

Section: Discussionsupporting

confidence: 82%

MicroRNA‐146a represses LRP2 translation and leads to cell apoptosis in Alzheimer's disease

et al. 2016

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MicroRNA regulation of transcript expression has been reported in patients with Alzheimer's disease (AD). Here, we investigate the role of microRNA‐146a (miRNA‐146a), a brain‐enriched miRNA, which is upregulated in AD patients. Through analysis of predicted targets of miRNA‐146a, low‐density lipoprotein receptor‐related protein‐2 (Lrp2), a member of the LDLR family that is known to play a protective role in AD, was identified. Overexpression of miRNA‐146a in SH‐SY5Y cells significantly decreased Lrp2 expression, resulting in a reduction of Akt activation and induction of proapoptotic caspase‐3, thereby increasing cell apoptosis. Thus, specific miRNA‐146a regulation may contribute to AD by downregulating the Lrp2/Akt pathway.

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“…Bcl2 protects neuronal cells by inhibiting the activation of caspase-3 81,82. Previously, Bcl-2 expression was shown to be upregulated, while Bax and caspase-3 were down regulated in AD models 83. Bax also plays an essential role in oligomeric Aβ-induced neuronal cell death 84.…”

Section: Discussionmentioning

confidence: 99%

Agmatine Improves Cognitive Dysfunction and Prevents Cell Death in a Streptozotocin-Induced Alzheimer Rat Model

et al. 2014

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PurposeAlzheimer's disease (AD) results in memory impairment and neuronal cell death in the brain. Previous studies demonstrated that intracerebroventricular administration of streptozotocin (STZ) induces pathological and behavioral alterations similar to those observed in AD. Agmatine (Agm) has been shown to exert neuroprotective effects in central nervous system disorders. In this study, we investigated whether Agm treatment could attenuate apoptosis and improve cognitive decline in a STZ-induced Alzheimer rat model.Materials and MethodsWe studied the effect of Agm on AD pathology using a STZ-induced Alzheimer rat model. For each experiment, rats were given anesthesia (chloral hydrate 300 mg/kg, ip), followed by a single injection of STZ (1.5 mg/kg) bilaterally into each lateral ventricle (5 µL/ventricle). Rats were injected with Agm (100 mg/kg) daily up to two weeks from the surgery day.ResultsAgm suppressed the accumulation of amyloid beta and enhanced insulin signal transduction in STZ-induced Alzheimer rats [experimetal control (EC) group]. Upon evaluation of cognitive function by Morris water maze testing, significant improvement of learning and memory dysfunction in the STZ-Agm group was observed compared with the EC group. Western blot results revealed significant attenuation of the protein expressions of cleaved caspase-3 and Bax, as well as increases in the protein expressions of Bcl2, PI3K, Nrf2, and γ-glutamyl cysteine synthetase, in the STZ-Agm group.ConclusionOur results showed that Agm is involved in the activation of antioxidant signaling pathways and activation of insulin signal transduction. Accordingly, Agm may be a promising therapeutic agent for improving cognitive decline and attenuating apoptosis in AD.

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Effects of Nicorandil in Neuroprotective Activation of PI3K/AKT Pathways in a Cellular Model of Alzheimer's Disease

Cited by 42 publications

References 78 publications

The Interplay of Akt and ERK in Aβ Toxicity and Insulin-Mediated Protection in Primary Hippocampal Cell Culture

The Interplay of Akt and ERK in Aβ Toxicity and Insulin-Mediated Protection in Primary Hippocampal Cell Culture

MicroRNA‐146a represses LRP2 translation and leads to cell apoptosis in Alzheimer's disease

Agmatine Improves Cognitive Dysfunction and Prevents Cell Death in a Streptozotocin-Induced Alzheimer Rat Model

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