Dose-dependent beneficial and detrimental effects of ROCK inhibitor Y27632 on axonal sprouting and functional recovery after rat spinal cord injury

Chan, Carmen C.M.; Khodarahmi, Kourosh; Liu, Jie; Sutherland, Darren; Oschipok, Loren W.; Steeves, John D.; Tetzlaff, Wolfram

doi:10.1016/j.expneurol.2005.08.011

Cited by 129 publications

(113 citation statements)

References 54 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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“…If translated into the human setting, these beneficial effects would greatly exceed the expected risks. Other molecules targeting the Rho pathway have also been shown to promote recovery from rodent CNS injury, including variants of the C3 exoenzyme that inactivates RhoA, and compounds that block a downstream signaling molecule, ROCK (Chan et al, 2005;Dergham et al, 2002;Fournier et al, 2003;McKerracher and Higuchi, 2006). Compounds related to ibuprofen might provide a useful starting point to screen for optimal Rho pathway inhibition and future SCI or stroke recovery therapeutics.…”

Section: ‰ Ibuprofen In Spinal Cord Injury 91mentioning

confidence: 99%

“…Downstream of RhoA, Rhoassociated kinase (ROCK) mediates, in part, the actions of RhoA (Borisoff et al, 2003;Chan et al, 2005;Fournier et al, 2003;Monnier et al, 2003;Nakagawa et al, 1996). ROCK inhibitors promote axonal growth in vitro, and improve behavioral recovery from spinal injury at certain doses when administered shortly after injury (Borisoff et al, 2003;Chan et al, 2005;Dergham et al, 2002;Fournier et al, 2003; Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, Connecticut.…”

mentioning

confidence: 99%

Ibuprofen Enhances Recovery from Spinal Cord Injury by Limiting Tissue Loss and Stimulating Axonal Growth

Wang

Budel

Baughman

et al. 2009

Journal of Neurotrauma

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The GTP-binding protein RhoA regulates microfilament dynamics in many cell types and mediates the inhibition of axonal regeneration by myelin and chondroitin sulfate proteoglycans. Unlike most other nonsteroidal anti-inflammatory drugs, ibuprofen suppresses basal RhoA activity (Zhou et al., 2003). A recent report suggested that ibuprofen promotes corticospinal axon regeneration after spinal cord injury (Fu et al., 2007). Here, we confirm that ibuprofen reduces ligand-induced Rho signaling and myelin-induced inhibition of neurite outgrowth in vitro. Following 4 weeks of subcutaneous administration of ibuprofen, beginning 3 days after spinal cord contusion, animals recovered walking function to a greater degree, with twice as many rats achieving a hind limb weight-bearing status. We examined the relative role of tissue sparing, axonal sprouting, and axonal regeneration in the action of ibuprofen. Histologically, ibuprofen-treated animals display an increase in spared tissue without an alteration in astrocytic or microglial reaction. Ibuprofen increases axonal sprouting from serotonergic raphespinal axons, and from rostral corticospinal fibers in the injured spinal cord, but does not permit caudal corticospinal regeneration after spinal contusion. Treatment of mice with complete spinal cord transection demonstrates long-distance raphespinal axon regeneration in the presence of ibuprofen. Thus, administration of ibuprofen improves the recovery of rats from a clinically relevant spinal cord trauma by protecting tissue, stimulating axonal sprouting, and allowing a minor degree of raphespinal regeneration.

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“…Fournier et al [26] report that C3 transferase has no effect on sprouting. Lastly, there were two studies that demonstrate axonal regeneration [12,20] and a single study that showed no effect on regeneration of injured axons [26]. Seven of nine studies reported on behavioral outcomes.…”

Section: Questionmentioning

confidence: 99%

“…This compound is directly applied to the dura at the time of surgery after injury. In our systematic review we identified nine preclinical studies that examined the effect of Rho antagonists in the setting of SCI [12,20,24,26,38,46,57,58,63]. These investigations made use of a combination of mouse and rat models consisting of dorsal hemisection, impactor injury, transection, and hemisection ( [63].…”

Section: Questionmentioning

confidence: 99%

Spinal Cord Injury: A Systematic Review of Current Treatment Options

Cadotte

Fehlings

2011

Clinical Orthopaedics &Amp; Related Research

116

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Background Spinal cord injury (SCI) is a devastating event often resulting in permanent neurologic deficit. Research has revealed an understanding of mechanisms that occur after the primary injury and contribute to functional loss. By targeting these secondary mechanisms of injury, clinicians may be able to offer improved recovery after SCI. Questions/purposes In this review, we highlight advances in the field of SCI by framing three questions: (1) What is the preclinical evidence for the neuroprotective agent riluzole that has allowed this agent to move into clinical trials? (2) What is the preclinical evidence for Rho antagonists that have allowed this group of compounds to move into clinical trials? (3) What is the evidence for early surgical decompression after SCI?Methods We conducted a systematic review of MEDLINE and EMBASE-cited articles related to SCI to address these questions.

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Dose-dependent beneficial and detrimental effects of ROCK inhibitor Y27632 on axonal sprouting and functional recovery after rat spinal cord injury

Cited by 129 publications

References 54 publications

The Rho Kinase Pathway Regulates Mouse Adult Neural Precursor Cell Migration

The Rho Kinase Pathway Regulates Mouse Adult Neural Precursor Cell Migration

Ibuprofen Enhances Recovery from Spinal Cord Injury by Limiting Tissue Loss and Stimulating Axonal Growth

Spinal Cord Injury: A Systematic Review of Current Treatment Options

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