Y-27632 Induces Neurite Outgrowth by Activating the NOX1-Mediated AKT and PAK1 Phosphorylation Cascades in PC12 Cells

Park, So Yeong; An, Jeung Hee; Seo, Jeong Taeg; Seo, Su Ryeon

doi:10.3390/ijms21207679

Cited by 9 publications

(6 citation statements)

References 49 publications

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“…To evaluate the role of Akt in neurite growth modulated by ROS, we inhibited the Akt activity with LY294002, a PI3K inhibitor (Vlahos et al., 1994) at 1 or 2 DIV and we measured the neurite outgrowth after 24 h. As mentioned previously, the antioxidant treatments increased the p‐Akt and decreased the neurite growth, suggesting a negative effect of Akt in neurite growth as reported as reported in other models (Bang et al., 2001; Miyamoto et al., 2013). On the other hand, contrary to what was found in DGR neurons (Hervera et al., 2018) and PC12 cells (Park et al., 2020), in the present study the inhibition of Akt activity did not alter the inhibitory effect of antioxidants on the neurite growth in cells treated at 1 or 2 DIV and enhanced the effect of antioxidants at 1 DIV on the number of branches per cell. We therefore found opposite results between the effect of antioxidants on Akt activation (measured by an increase in p‐Akt) and the effect of Akt activation on neurite growth.…”

Section: Discussioncontrasting

confidence: 99%

ROS produced by NOX promote the neurite growth in a PI3K/Akt independent manner

Mora‐Zenil,

Morán

2023

J of Neuroscience Research

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Reactive oxygen species (ROS) function as signaling molecules in several physiologic and pathologic processes. In central nervous system, ROS are critical for differentiation, migration, polarization, and neurite growth. These actions are mediated by reversible oxidation of target proteins. On the other hand, PI3K/Akt signaling pathway is susceptible to be modulated by ROS and it has been implicated in neurite growth. In this study, we evaluated the participation of ROS in the neurite growth of cultured rat cerebellar granule neurons (CGN), as well as the possible regulation of the PI3K/Akt pathway by ROS during neurite outgrowth. For this purpose, CGN were treated with cellular or mitochondrial antioxidants, or an NOX inhibitor and neurite growth was evaluated. Moreover, to assess the participation Akt in this process, the p‐Akt levels were measured in CGN treated with antioxidants or a NOX inhibitor. The effect of antioxidants on the neurite growth in the presence of a PI3K inhibitor was also measured. We found that cellular antioxidants and the NOX inhibitor decreased the neurite growth, but not the mitochondrial antioxidant. Interestingly, the antioxidants increased the p‐Akt levels; however, the effect of antioxidants on neurite growth was no dependent on the Akt activity since the inhibitor of PI3K did not modify the antioxidant action on neurite growth. Our results show that the PI3K/Akt pathway participates in neurite growth and that ROS produced by NOX could function as signals in this process; however, this action is not mediated by a redox regulation of Akt activity.

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Section: Discussioncontrasting

confidence: 99%

ROS produced by NOX promote the neurite growth in a PI3K/Akt independent manner

Mora‐Zenil,

Morán

2023

J of Neuroscience Research

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“…In studies with Fasudil, a ROCK inhibitor, the authors observed an in vitro induction of neurogenesis in mouse neural stem cells [ 61 ], and also protection against oxygen–glucose deprivation in primary neurons of the hippocampus of mouse embryos [ 62 ]. Similar results were also observed for another ROCK inhibitor, Y-27632, which induced neurite outgrowth in PC12 cells by activating AKT phosphorylation cascades [ 63 ]. In another study, a benzofuran derivative (MBPTA), a ROCK inhibitor, protected SH-SY5Y cells against induced-oxidative stress, possibly through PI3K/Akt activation [ 64 ].…”

Section: Discussionsupporting

confidence: 82%

Novel Dual AChE and ROCK2 Inhibitor Induces Neurogenesis via PTEN/AKT Pathway in Alzheimer’s Disease Model

Moreira

Tamarozzi

Lima

et al. 2022

IJMS

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Alzheimer’s disease (AD) is a progressive and complex neurodegenerative disease. Acetylcholinesterase inhibitors (AChEIs) are a major class of drugs used in AD therapy. ROCK2, another promising target for AD, has been associated with the induction of neurogenesis via PTEN/AKT. This study aimed to characterize the therapeutic potential of a novel donepezil–tacrine hybrid compound (TA8Amino) to inhibit AChE and ROCK2 protein, leading to the induction of neurogenesis in SH-SY5Y cells. Experiments were carried out with undifferentiated and neuron-differentiated SH-SY5Y cells submitted to treatments with AChEIs (TA8Amino, donepezil, and tacrine) for 24 h or 7 days. TA8Amino was capable of inhibiting AChE at non-cytotoxic concentrations after 24 h. Following neuronal differentiation for 7 days, TA8Amino and donepezil increased the percentage of neurodifferentiated cells and the length of neurites, as confirmed by β-III-tubulin and MAP2 protein expression. TA8Amino was found to participate in the activation of PTEN/AKT signaling. In silico analysis showed that TA8Amino can stably bind to the active site of ROCK2, and in vitro experiments in SH-SY5Y cells demonstrate that TA8Amino significantly reduced the expression of ROCK2 protein, contrasting with donepezil and tacrine. Therefore, these results provide important information on the mechanism underlying the action of TA8Amino with regard to multi-target activities.

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“… 49 Similarly, in PC12 cells, neurite outgrowth increased after 2 or 3 h of treatment with Y-27632. 50 In the peripheral nervous system, activation of ROCK results in contractility and growth cone retraction. 51 Although tension has not been directly connected to ROCK inhibition, neurite outgrowth and vinculin distribution were studied in rat hippocampal neurons.…”

Section: Discussionmentioning

confidence: 99%

Förster resonance energy transfer efficiency of the vinculin tension sensor in cultured primary cortical neuronal growth cones

et al. 2022

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. Significance : Interaction of neurons with their extracellular environment and the mechanical forces at focal adhesions and synaptic junctions play important roles in neuronal development. Aim : To advance studies of mechanotransduction, we demonstrate the use of the vinculin tension sensor (VinTS) in primary cultures of cortical neurons. VinTS consists of TS module (TSMod), a Förster resonance energy transfer (FRET)-based tension sensor, inserted between vinculin’s head and tail. FRET efficiency decreases with increased tension across vinculin. Approach : Primary cortical neurons cultured on glass coverslips coated with poly- d -lysine and laminin were transfected with plasmids encoding untargeted TSMod, VinTS, or tail-less vinculinTS (VinTL) lacking the actin-binding domain. The neurons were imaged between day in vitro (DIV) 5 to 8. We detail the image processing steps for calculation of FRET efficiency and use this system to investigate the expression and FRET efficiency of VinTS in growth cones. Results : The distribution of fluorescent constructs was similar within growth cones at DIV 5 to 8. The mean FRET efficiency of TSMod ( ) in growth cones was higher than the mean FRET efficiency of VinTS ( ) and VinTL ( ) ( ). While small, the difference between the FRET efficiency of VinTS and VinTL was statistically significant ( ), suggesting that vinculin is under low tension in growth cones. Two-hour treatment with the Rho-associated kinase inhibitor Y-27632 did not affect the mean FRET efficiency. Growth cones exhibited dynamic changes in morphology as observed by time-lapse imaging. VinTS FRET efficiency showed greater variance than TSMod FRET efficiency as a function of time, suggesting a greater dependence of VinTS FRET efficiency on growth cone dynamics compared with TSMod. Conclusions : The results demonstrate the feasibility of using VinTS to probe the function of vinculin in neuronal growth cones and provide a foundation for studies of mechanotransduction in neurons using this tension probe.

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Y-27632 Induces Neurite Outgrowth by Activating the NOX1-Mediated AKT and PAK1 Phosphorylation Cascades in PC12 Cells

Cited by 9 publications

References 49 publications

ROS produced by NOX promote the neurite growth in a PI3K/Akt independent manner

ROS produced by NOX promote the neurite growth in a PI3K/Akt independent manner

Novel Dual AChE and ROCK2 Inhibitor Induces Neurogenesis via PTEN/AKT Pathway in Alzheimer’s Disease Model

Förster resonance energy transfer efficiency of the vinculin tension sensor in cultured primary cortical neuronal growth cones

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