Rho kinase, a promising drug target for neurological disorders

Mueller, Bernhard K.; Mack, Helmut; Teusch, Nicole

doi:10.1038/nrd1719

Cited by 546 publications

(508 citation statements)

References 116 publications

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“…HA1077 is in clinical use for managing cerebral vasospasm associated with subarachnoid hemorrhage and is under clinical trial for acute ischemic stroke [37], among other conditions. Application of Y27632 has also been investigated for promotion of neurite outgrowth and axonal regeneration [38][39][40][41][42][43][44][45] and inactivation of Rho or ROCK signaling promoted functional recovery and/or axonal regeneration after neural injuries [46][47][48].…”

Section: Introductionmentioning

confidence: 99%

The Rho Kinase Pathway Regulates Mouse Adult Neural Precursor Cell Migration

et al. 2011

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Adult neural precursor cells (NPCs) in the subventricular zone (SVZ) normally migrate via the rostral migratory stream (RMS) to the olfactory bulb (OB). Following neural injury, they also migrate to the site of damage. This study investigated the role of Rho-dependent kinase (ROCK) on the migration of NPCs in vitro and in vivo. In vitro, using neurospheres or SVZ explants, inhibition of ROCK using Y27632 promoted cell body elongation, process protrusion, and migration, while inhibiting NPC chain formation. It had no effect on proliferation, apoptosis, or differentiation. Both isoforms of ROCK were involved. Using siRNA, knockdown of both ROCK1 and ROCK2 was required to promote NPC migration and morphological changes; knockdown of ROCK2 alone was partially effective, with little/no effect of knockdown of ROCK1 alone. In vivo, infusion of Y27632 plus Bromodeoxyuridine (BrdU) into the lateral ventricle for 1 week reduced the number of BrdU-labeled NPCs in the OB compared with BrdU infusion alone. However, ROCK inhibition did not affect the tangential-to-radial switch of NPC migration, as labeled cells were present in all OB layers. The decrease in NPC number at the OB was not attributed to a decrease in NPCs at the SVZ. However, ROCK inhibition decreased the density of BrdU-labeled cells in the RMS and increased the distribution of these cells to ectopic brain regions, such as the accessory olfactory nucleus, where the majority differentiated into neurons. These findings suggest that ROCK signaling regulates NPC migration via regulation of cell-cell contact and chain migration.

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Section: Introductionmentioning

confidence: 99%

The Rho Kinase Pathway Regulates Mouse Adult Neural Precursor Cell Migration

et al. 2011

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“…During the last decade, the Rho/ROCK signaling pathway has attracted much attention in various research fields, and more than 2,000 articles have been published; many of which focus on ROCK function in the cardiovascular system, central nervous system, cancers and embryonic development. Several excellent recent reviews have covered large aspects [11,33,51,78,94,97,113,123]. The up to date progress in the translational research has demonstrated that ROCK is an important therapeutic target for the treatment of various cardiovascular diseases and neurological disorders, cancers, etc.…”

Section: Introductionmentioning

confidence: 99%

Rho kinase in the regulation of cell death and survival

Shi

Wei

2007

Arch. Immunol. Ther. Exp.

219

183

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SummaryRho kinase (ROCK) belongs to a family of serine/threonine kinases that are activated via interaction with Rho GTPases. ROCK is involved in a wide range of fundamental cellular functions such as contraction, adhesion, migration, and proliferation. Recent studies have shown that ROCK plays an important role in the regulation of apoptosis in various cell types and animal disease models. Two ROCK isoforms, ROCK1 and ROCK2, are assumed to be function redundant, based largely on kinase construct overexpression, and chemical inhibitors (Y27632 and fasudil), which inhibit both ROCK1 and ROCK2. Gene targeting and RNA interference approaches allow further dissection of distinct cellular, physiological and patho-physiological functions of the two ROCK isoforms. This review, based on recent molecular, cellular and animal studies, focuses on the current understanding of ROCK signaling in the regulation of apoptosis and highlights the new findings from recently generated ROCK-deficient mice.

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“…neural growth cone collapse, neurite retraction, and even neuron death (Wahl et al, 2000;Mueller et al, 2005;Chan et al, 2007). Thus, inflammatory factors from inflammatory pathway up-regulation or activation were negative for neurite outgrowth (Alamdary et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…ROCK over-activation or upregulation was reported to be correlated with neural injury and most neural disorders (Mueller et al, 2005;Kubo and Yamashita, 2007). Otherwise, ROCK inhibition by Y27632 or fasudil and ROCK down-regulation by small interfering RNA (siRNA) were both able to promote neural fiber regeneration and functional recovery (Fournier et al, 2003;Hiraga et al, 2006;Impellizzeri et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Neurite outgrowth resistance to rho kinase inhibitors in PC12 Adh cell

Yin

Hou

Tao

et al. 2015

Cell Biology International

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Rho kinase (ROCK) inhibitor is a promising agent for neural injury disorders, which mechanism is associated with neurite outgrowth. However, neurite outgrowth resistance occurred when PC12 Adh cell was treated with ROCK inhibitors for a longer time. PC12 Adh cells were treated with ROCK inhibitor Y27632 or NGF for different durations. Neurite outgrowth resistance occurred when PC12 Adh cell exposed to Y27632 (33 mM) for 3 or more days, but not happen when exposed to nerve growth factor (NGF, 100 ng/mL). The gene expression in the PC12 Adh cells treated with Y27632 (33 mM) or NGF (100 ng/mL) for 2 or 4 days was assayed by gene microarray, and the reliability of the results were confirmed by real-time RT-PCR. Cluster analysis proved that the gene expression profile of PC12 Adh cell treated with Y27632 for 4 days was different from that treated with Y27632 for 2 days and those treated with NGF for 2 and 4 days, respectively. Pathway analysis hinted that the neurite outgrowth resistance could be associated with up-regulation of inflammatory pathways, especially rno04610 (complement and coagulation cascades), and down-regulation of cell cycle pathways, especially rno04110.

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Rho kinase, a promising drug target for neurological disorders

Cited by 546 publications

References 116 publications

The Rho Kinase Pathway Regulates Mouse Adult Neural Precursor Cell Migration

The Rho Kinase Pathway Regulates Mouse Adult Neural Precursor Cell Migration

Rho kinase in the regulation of cell death and survival

Neurite outgrowth resistance to rho kinase inhibitors in PC12 Adh cell

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