Abstract
Y-27632 is known as a selective Rho-associated coiled coil-forming kinase (ROCK) inhibitor. Y-27632 has been shown to induce neurite outgrowth in several neuronal cells. However, the precise molecular mechanisms linking neurite outgrowth to Y-27632 are not completely understood. In this study, we examined the ability of Y-27632 to induce neurite outgrowth in PC12 cells and evaluated the signaling cascade. The effect of Y-27632 on the neurite outgrowth was inhibited by reactive oxygen species (ROS) scavengers such as N-acetyl cysteine (NAC) and trolox. Furthermore, Y-27632-induced neurite outgrowth was not triggered by NADPH oxidase 1 (NOX1) knockdown or diphenyleneiodonium (DPI), a NOX inhibitor. Suppression of the Rho-family GTPase Rac1, which is under the negative control of ROCK, with expression of the dominant negative Rac1 mutant (Rac1N17) prevented Y-27632-induced neurite outgrowth. Moreover, the Rac1 inhibitor NSC23766 prevented Y-27632-induced AKT and p21-activated kinase 1 (PAK1) activation. AKT inhibition with MK2206 suppressed Y-27632-induced PAK1 phosphorylation and neurite outgrowth. In conclusion, our results suggest that Rac1/NOX1-dependent ROS generation and subsequent activation of the AKT/PAK1 cascade contribute to Y-27632-induced neurite outgrowth in PC12 cells.
Highlights
Neurite outgrowth is necessary during the development of the nervous system and axonal regeneration in the injured nervous system [1]
We examined whether the prevention of reactive oxygen species (ROS) generation with ROS scavengers, such as N-acetyl cysteine (NAC) and trolox, could inhibit Y-27632-induced neurite outgrowth
nerve growth factor (NGF)-mediated neurite outgrowth and neuronal differentiation are accompanied by increased ROS levels in PC12 cells [36]
Summary
Neurite outgrowth is necessary during the development of the nervous system and axonal regeneration in the injured nervous system [1]. The small GTPase RhoA has been reported to be a critical negative regulator of neurite outgrowth in developing and regenerating neurons through its downstream effector Rho-associated coiled coil-forming kinase (ROCK) [2]. Activation of RhoA/ROCK contributes to actin cytoskeleton changes, leading to growth cone collapse, which suppresses axonal extension [1,2,3]. The ability of nerve growth factor (NGF) to induce neuronal differentiation was accompanied by ROCK1 inhibition [6,7]. Upregulation of ROCK has been reported to be associated with neural disorders and neural injury [8]
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