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Rho-associated kinase II (ROCKII) limits axonal growth after trauma within the adult mouse spinal cord.

ABSTRACT: Rho GTPases are thought to mediate the action of several axonal growth inhibitors in the adult brain and spinal cord. RhoA has been targeted pharmacologically in both humans and animals to promote neurite outgrowth and functional recovery following CNS trauma. However, rat spinal cord injury studies suggest a complicated and partial benefit of inhibiting Rho or its downstream effector, Rho-associated kinase (ROCKII). This limited benefit may reflect inhibition of other kinases, poor access, or a minimal role of ROCKII in vivo. Therefore, we studied ROCKII mutant mice to probe this pathway genetically. ROCKII(-/-) dorsal root ganglion neurons are less sensitive to inhibition by Nogo protein or by chondroitin sulfate proteoglycan in vitro. We examined adult ROCKII(-/-) mice in two injury paradigms, cervical multilevel dorsal rhizotomy and midthoracic dorsal spinal cord hemisection. After dorsal root crush injury, the ROCKII(-/-) mice recovered use of the affected forepaw more quickly than did controls. Moreover, multiple classes of sensory axons regenerated across the dorsal root entry zone into the spinal cord of mice lacking ROCKII. After the spinal cord injury, ROCKII(-/-) mice showed enhanced local growth of raphespinal axons in the caudal spinal cord and corticospinal axons into the lesion site. Improved functional recovery was not observed by Basso Mouse Scale score following dorsal hemisection, likely due to developmental defects in the nervous system. Together, these findings demonstrate that the ROCKII gene product limits axonal growth after CNS trauma.

SUBMITTER: Duffy P

PROVIDER: S-EPMC2855556 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Rho-associated kinase II (ROCKII) limits axonal growth after trauma within the adult mouse spinal cord.

Duffy Philip P Schmandke Andre A Schmandke Antonio A Sigworth Jonathan J Narumiya Shuh S Cafferty William B J WB Strittmatter Stephen M SM

The Journal of neuroscience : the official journal of the Society for Neuroscience 20091201 48

Rho GTPases are thought to mediate the action of several axonal growth inhibitors in the adult brain and spinal cord. RhoA has been targeted pharmacologically in both humans and animals to promote neurite outgrowth and functional recovery following CNS trauma. However, rat spinal cord injury studies suggest a complicated and partial benefit of inhibiting Rho or its downstream effector, Rho-associated kinase (ROCKII). This limited benefit may reflect inhibition of other kinases, poor access, or a ...[more]

PMID: 19955379

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Project description:Spinal cord stimulation (SCS) is used clinically to limit chronic pain, but fundamental questions remain on the identity of axonal populations recruited. We developed an ex vivo adult mouse spinal cord preparation to assess recruitment following delivery of clinically analogous stimuli determined by downscaling a finite element model of clinical SCS. Analogous electric field distributions were generated with 300-µm × 300-µm electrodes positioned 200 µm above the dorsal column (DC) with stimulation between 50 and 200 µA. We compared axonal recruitment using electrodes of comparable size and stimulus amplitudes when contacting the caudal thoracic DC and at 200 or 600 ?m above. Antidromic responses recorded distally from the DC, the adjacent Lissauer tract (LT), and in dorsal roots (DRs) were found to be amplitude and site dependent. Responses in the DC included a unique component not seen in DRs, having the lowest SCS recruitment amplitude and fastest conduction velocity. At 200 ?m above, mean cathodic SCS recruitment threshold for axons in DRs and LT were 2.6 and 4.4 times higher, respectively, than DC threshold. SCS recruited primary afferents in all (up to 8) caudal segments sampled. Whereas A and C fibers could be recruited at nearby segments, only A fiber recruitment and synaptically mediated dorsal root reflexes were observed in more distant (lumbar) segments. In sum, clinically analogous SCS led to multisegmental recruitment of several somatosensory-encoding axonal populations. Most striking is the possibility that the lowest threshold recruitment of a nonprimary afferent population in the DC are postsynaptic dorsal column tract cells (PSDCs) projecting to gracile nuclei.NEW & NOTEWORTHY Spinal cord stimulation (SCS) is used clinically to control pain. To identify axonal populations recruited, finite element modeling identified scaling parameters to deliver clinically analogous SCS in an ex vivo adult mouse spinal cord preparation. Results showed that SCS first recruited an axonal population in the dorsal column at a threshold severalfold lower than primary afferents. These putative postsynaptic dorsal column tract cells may represent a previously unconsidered population responsible for SCS-induced paresthesias necessary for analgesia.

Project description:IntroductionFirearm-related spinal cord injuries are commonly missed in the initial assessment as they are often obscured by concomitant injuries and emergent trauma management. These injuries, however, have a significant health and financial impact. The objective of this study was to examine firearm-related spinal cord injuries and identify predictors of presence of such injuries in adult trauma patients.MethodsThis retrospective cohort study examined adult trauma patients (≥16 years) with injuries from firearms included in the 2015 United States National Trauma Data Bank. We performed descriptive and bivariate analyses and compared two groups: patients with no spinal cord injury (SCI) or vertebral column injury (VCI); and patients with SCI and/or VCI. Predictors of SCI and/or VCI in patients with firearm-related injuries were identified using a multivariate logistic regression analysis.ResultsThere were 34,898 patients who sustained a firearm-induced injury. SCI and/or VCI were present in 2768 (7.9%) patients. Patients with SCI and/or VCI had more frequently severe injuries, higher Injury Severity Score (ISS), lower mean systolic blood pressure, and lower Glasgow Coma Scale (GCS). The mortality rate was not significantly different between the two groups (14.7%, N = 407 in SCI and/or VCI vs 15.0%, N = 4,811 in no SCI or VCI group). Significant general positive predictors of presence of SCI and/or VCI were as follows: university hospital; assault; public or unspecified location of injury; drug use; air medical transport; and Medicaid coverage. Significant clinical positive predictors included fractures, torso injuries, blood vessel or internal organ injuries, open wounds, mild (13-15) and moderate GCS scores (9 - 12), and ISS ≥ 16.ConclusionFirearm-induced SCI and/or VCI injuries have a high burden on affected victims. The identified predictors for the presence of SCI and/or VCI injuries can help with early detection, avoiding management delays, and improving outcomes. Further studies defining the impact of each predictor are needed.

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Rho-associated kinase II (ROCKII) limits axonal growth after trauma within the adult mouse spinal cord.

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Rho-associated kinase II (ROCKII) limits axonal growth after trauma within the adult mouse spinal cord.

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