Simvastatin Induces Neuroprotection in 6‐<scp>OHDA</scp>‐Lesioned <scp>PC</scp>12 via the <scp>PI</scp>3K/<scp>AKT</scp>/Caspase 3 Pathway and Anti‐Inflammatory Responses

Yu, Yinghua; Long, Ling; Yan, Jize; Wei, Lei; Pan, Mengqiu; Gao, Hong; Zhou, Peng; Liu, Mei; Zhu, Cansheng; Tang, Beisha; Wang, Qing

doi:10.1111/cns.12053

Cited by 75 publications

(53 citation statements)

References 53 publications

(63 reference statements)

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“…Cotreatment with LY294002, the inhibitor of PI3K, blocked the up-regulation of p-Akt and p-GSK-3β protein expressions as well as deregulation of NSC apoptosis by simvastatin, indicating that PI3K/Akt/GSK-3β signaling pathway is involved in the neuroprotection of simvastatin against isoflurane-induced NSC apoptosis. This is similar to the findings that simvastatin played in other models [56,57]. Whether the protective effects of simvastatin is merely due to the increase in Akt phosphorylation or the decrease in Akt and GSK-3β dephosphorylation needs to be studied further.…”

Section: Cellular Physiology and Biochemistrysupporting

confidence: 85%

Simvastatin Attenuates Neurogenetic Damage and Improves Neurocongnitive Deficits Induced by Isoflurane in Neonatal Rats

Wang¹,

Lu²,

Wang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Isoflurane inhibited neurogenesis and induced subsequent neurocognitive deficits in developing brain. Simvastatin exerts neuroprotection in a wide range of brain injury models. In the present study, we investigated whether simvastatin could attenuate neurogenetic inhibition and cognitive deficits induced by isoflurane exposure in neonatal rats. Methods: Sprague-Dawley rats at postnatal day (PND) 7 and neural stem cells (NSCs) were treated with either gas mixture, isoflurane, or simvastatin 60 min prior to isoflurane exposure, respectively. The rats were decapitated at PND 8 and PND 10 for detection of neurogenesis in the subventricular zone (SVZ) and subgranular zone (SGZ) of the hippocampus by immunostaining. NSC proliferation, viability and apoptosis were assessed by immunohistochemistry, CCK-8 and TUNEL, respectively. The protein expressions of caspase-3, p-Akt and p-GSK-3β both in vivo and vitro were assessed by western blotting. Cognitive functions were assessed by Morris Water Maze test and context fear conditioning test at the adult. Results: Isoflurane exposure inhibited neurogenesis in the SVZ and SGZ, decreased NSC proliferation and viability, promoted NSC apoptosis and led to late cognitive deficits. Furthermore, isoflurane increased caspase-3 expression and decreased protein expressions of p-Akt and p-GSK-3β both in vivo and in vitro. Pretreatment with simvastatin attenuated isoflurane-elicited changes in NSCs and cognitive function. Co-treatment with LY294002 reversed the effect of simvastatin on NSCs in vitro. Conclusion: We for the first time showed that simvastatin, by upregulating Akt/GSK-3β signaling pathway, alleviated isoflurane-induced neurogenetic damage and neurocognitive deficits in developing rat brain.

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Section: Cellular Physiology and Biochemistrysupporting

confidence: 85%

Simvastatin Attenuates Neurogenetic Damage and Improves Neurocongnitive Deficits Induced by Isoflurane in Neonatal Rats

Wang¹,

Lu²,

Wang³

et al. 2018

Cell Physiol Biochem

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“…Our previous study on simvastatin (Sim) therapy involving patients with PD confirmed that Sim is able to modulate NMDA receptors [8] and protect against dopaminergic neurodegeneration through the PI3K/Akt/caspase 3 pathway [9]. In a related study, we observed that the anti-oxidative stress function of Sim in dopaminergic neurons is very prominent.…”

Section: Introductionmentioning

confidence: 82%

Simvastatin Protects Dopaminergic Neurons Against MPP+-Induced Oxidative Stress and Regulates the Endogenous Anti-Oxidant System Through ERK

Yan

Qiao

et al. 2018

Cell Physiol Biochem

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Background/Aims: Many clinical studies have demonstrated that statins, especially simvastatin, can decrease the incidence of Parkinson’s disease (PD). However, the specific underlying mechanism remains unclear. This study aimed to investigate how simvastatin affects experimental parkinsonian models via the regulation of extracellular signal-regulated kinase 1/2 (ERK1/2)-mediated activation of the anti-oxidant system. Methods: l-Methyl-4-phenylpyridine ion (MPP⁺)-treated SH-SY5Y cells and substantia nigra neurons were used to investigate the neuroprotective effect of simvastatin. After incubation with MPP⁺ and/or simvastatin for 24 h, the MTT assay was used to assess cell viability. Reactive oxygen species (ROS) levels were measured using 2′,7′-dichlorofluorescin diacetate, while cellular superoxide dismutase (SOD) levels were determined based on the blue formazan produced by the reduction of nitroblue tetrazolium. The level of cellular grade micro-reduced glutathione (GSH) was measured with 5,5’-dithiobis-(2-nitrobenzoic acid). Meanwhile, the malondialdehyde content released from SH-SY5Y cells and substantia nigra neuronal cells exposed to different culture media was calculated based on the condensation reaction involving thiobarbituric acid. The mRNA levels of genes encoding nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase 1 (HO-1), and NAD(P)H dehydrogenase (quinone) 1 (NQO-1) were determined by a quantitative polymerase chain reaction assay, while the ERK, Nrf2, HO-1, NOX2, and NQO-1 protein levels were analyzed by western blot. Additionally, ERK small interfering RNA (siRNA) was used to investigate the mechanisms underlying MPP⁺-induced oxidative stress and the regulation of the endogenous anti-oxidant system. Results: Simvastatin (1.5 μM) enhanced the viability of SH-SY5Y cells and primary neurons treated with MPP⁺, and significantly alleviated the oxidative stress induced by MPP⁺ in SH-SY5Y cells by regulating the production of SOD, analytical grade micro-reduced GSH, and ROS, which may be associated with the activation of the Nrf2 anti-oxidant system. An analysis involving ERK1/2 siRNA revealed that simvastatin can inhibit NOX2 expression via the activation of ERK1/2 in the MPP⁺-treated PD cell model. Conclusion: Our results provide strong evidence that ERK1/2-mediated modulation of the anti-oxidant system after simvastatin treatment may partially explain the anti-oxidant activity in experimental parkinsonian models. These findings contribute to a better understanding of the critical roles of simvastatin via the ERK1/2-mediated modulation of the anti-oxidant system, which may be relevant for treating PD.

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“…In addition to lowering cholesterol, statins have gradually been used to reduce the risk of heart attack, cerebral ischemia, and have been demonstrated to exert potential beneficial effects in different neurological diseases (Wang et al, 2007;Keener & Sanossian, 2008;van der Most et al, 2009;Sugawara et al, 2011;Ayer et al, 2013). Although the precise mechanisms are unclear and contrasting results have been observed (Reiss & Wirkowski, 2007;Becker et al, 2008), additional studies have found that statins display important effects on cognitive related neurological diseases such as PD van der Most et al, 2009;Wang et al, 2011;Lee et al, 2013;Xu et al, 2013). If statins would have a potentially useful impact on impaired memory regulation in the progression of PD, this presents an interesting challenge.…”

Section: Introductionmentioning

confidence: 99%

Simvastatin reverses the downregulation of M1/4 receptor binding in 6-hydroxydopamine-induced parkinsonian rats: The association with improvements in long-term memory

et al. 2014

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. (2014). Simvastatin reverses the downregulation of M1/4 receptor binding in 6-hydroxydopamine-induced parkinsonian rats: the association with improvements in long-term memory. Neuroscience, 267 57-66.Simvastatin reverses the downregulation of M1/4 receptor binding in 6-hydroxydopamine-induced parkinsonian rats: the association with improvements in long-term memory AbstractBackground It is believed that muscarinic M1/4 receptors are closely correlated to the dopaminergic system and are strongly involved in the pathogenesis of Parkinson's disease (PD). In addition to regulating lipid metabolism and protection from stroke, statins have been used to regulate the declined cognition. We aimed to explore the regional changes in M1/4 receptors in the 6-hydroxydopamine (6-OHDA)-lesioned rat brain. Methods PD rat model was set up by injecting 6-OHDA into the unilateral medial forebrain bundle; while simvastatin (10 mg/kg/day) or saline was orally administrated for 3 weeks, respectively. Long-term memory was measured using the Morris water maze.[3H]pirenzepine binding autoradiography was applied to investigate the alterations of M1/4 receptors in the PD rat brains. Results 6-OHDA induced long-term memory deficits along with downregulation of M1/4 receptors in the hippocampus, the medial amygdala, the posteromedial cortical and the piriform cortex; simvastatin administration significantly ameliorated the impaired memory and reversed the downregulation of M1/4 receptors in the examined brain regions. Profound positive correlations were verified between the decline in long-term memory activity and the restoration of M1/4 receptors in different brain regions after simvastatin treatment. Conclusions/significance Our results provide strong evidence that M1/4 receptor modulation after simvastatin administration did, at least partially, contribute to the improvement in the long-term memory in 6-OHDA-induced PD rats. These results provide a possible mechanism for simvastatin treatment in psycho-neurological diseases such as PD via M1/4 receptors.

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Simvastatin Induces Neuroprotection in 6‐OHDA‐Lesioned PC12 via the PI3K/AKT/Caspase 3 Pathway and Anti‐Inflammatory Responses

Cited by 75 publications

References 53 publications

Simvastatin Attenuates Neurogenetic Damage and Improves Neurocongnitive Deficits Induced by Isoflurane in Neonatal Rats

Simvastatin Attenuates Neurogenetic Damage and Improves Neurocongnitive Deficits Induced by Isoflurane in Neonatal Rats

Simvastatin Protects Dopaminergic Neurons Against MPP+-Induced Oxidative Stress and Regulates the Endogenous Anti-Oxidant System Through ERK

Simvastatin reverses the downregulation of M1/4 receptor binding in 6-hydroxydopamine-induced parkinsonian rats: The association with improvements in long-term memory

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