RhoA/Rho Kinase Mediates Neuronal Death Through Regulating cPLA2 Activation

Wu, Xiangbing; Walker, Chandler L.; Lu, Qingbo; Wu, Wei; Eddelman, Daniel B.; Parish, Jonathan; Xu, Xiao Ming

doi:10.1007/s12035-016-0187-6

Cited by 27 publications

(17 citation statements)

References 59 publications

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“…Our previous study indicated that RhoA is a direct target of miR-133b ( Lu et al, 2015 ). Moreover, RhoA has been shown to be involved in the death of neuronal cells in the spinal cord ( Wu et al, 2016 ). To assess the effect of miR-133b exosomes on the expression of RhoA after SCI, we detected the levels of RhoA expression by using western blot.…”

Section: Resultsmentioning

confidence: 99%

“…RhoA, a member of the Rho family, has been shown to be upregulated after SCI in rats and acts on its direct downstream effector Rho-associated kinase (ROCK) ( Schwab et al, 2005 ). Since a recent study demonstrated that the RhoA/ROCK signaling pathway plays a critical role in the death of spinal cord neurons after acute SCI ( Wu et al, 2016 ), we next tested whether the survival of neurons was enhanced in vivo after miR-133b exosome injection. After SCI, neuronal death occurs at the lesion site within 24 h and is attributed to the primary mechanical force and later secondary factors such as inflammation, oxidation, and apoptosis ( Liu et al, 1997 ; Esposito et al, 2012 ; Sonmez et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

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Exosomes Derived From miR-133b-Modified Mesenchymal Stem Cells Promote Recovery After Spinal Cord Injury

et al. 2018

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Dysregulation of microRNAs (miRNAs) has been found in injured spinal cords after spinal cord injury (SCI). Previous studies have shown that miR-133b plays an important role in the differentiation of neurons and the outgrowth of neurites. Recently, exosomes have been used as novel biological vehicles to transfer miRNAs locally or systemically, but little is known about the effect of the delivery of exosome-mediated miRNAs on the treatment of SCI. In the present study, we observed that mesenchymal stem cells, the most common cell types known to produce exosomes, could package miR-133b into secreted exosomes. After SCI, tail vein injection of miR-133b exosomes into rats significantly improved the recovery of hindlimb function when compared to control groups. Additionally, treatment with miR-133b exosomes reduced the volume of the lesion, preserved neuronal cells, and promoted the regeneration of axons after SCI. We next observed that the expression of RhoA, a direct target of miR-133b, was decreased in the miR-133b exosome group. Moreover, we showed that miR-133b exosomes activated ERK1/2, STAT3, and CREB, which are signaling pathway proteins involved in the survival of neurons and the regeneration of axons. In summary, these findings demonstrated that systemically injecting miR-133b exosomes preserved neurons, promoted the regeneration of axons, and improved the recovery of hindlimb locomotor function following SCI, suggesting that the transfer of exosome-mediated miRNAs represents a novel therapeutic approach for the treatment of SCI.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Exosomes Derived From miR-133b-Modified Mesenchymal Stem Cells Promote Recovery After Spinal Cord Injury

et al. 2018

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“…Primary spinal cord neurons were obtained from Sprague-Dawley (SD) rat embryonic day 15 (E15) pups according to a previously established protocol ( Jiang et al, 2006 ). In brief, E15 rat spinal cords were isolated and placed in L15 medium ( Wu et al, 2017 ). Meninges were carefully removed and spinal cords were cut into small pieces, dissociated by incubation in 0.05% trypsin/EDTA 15 min at 37°C and triturated every 5 min.…”

Section: Methodsmentioning

confidence: 99%

Remodeling of lumbar motor circuitry remote to a thoracic spinal cord injury promotes locomotor recovery

Wang

et al. 2018

eLife

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Retrogradely-transported neurotrophin signaling plays an important role in regulating neural circuit specificity. Here we investigated whether targeted delivery of neurotrophin-3 (NT-3) to lumbar motoneurons (MNs) caudal to a thoracic (T10) contusive spinal cord injury (SCI) could modulate dendritic patterning and synapse formation of the lumbar MNs. In vitro, Adeno-associated virus serotype two overexpressing NT-3 (AAV-NT-3) induced NT-3 expression and neurite outgrowth in cultured spinal cord neurons. In vivo, targeted delivery of AAV-NT-3 into transiently demyelinated adult mouse sciatic nerves led to the retrograde transportation of NT-3 to the lumbar MNs, significantly attenuating SCI-induced lumbar MN dendritic atrophy. NT-3 enhanced sprouting and synaptic formation of descending serotonergic, dopaminergic, and propriospinal axons on lumbar MNs, parallel to improved behavioral recovery. Thus, retrogradely transported NT-3 stimulated remodeling of lumbar neural circuitry and synaptic connectivity remote to a thoracic SCI, supporting a role for retrograde transport of NT-3 as a potential therapeutic strategy for SCI.

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“…Studies have shown that the Rho/ROCK signaling pathway can also regulate cytoplasmic phospholipase A2 (cPLA2) and promote the inflammatory response, which could lead to neurocyte damage and apoptosis. 48,49 Acupuncture is used to treat diseases through multiple targets and multiple pathways. Based on the Nogo/NgR and Rho/ROCK signaling pathway, this study offers a research direction for further exploration of EA.…”

Section: Figurementioning

confidence: 99%

<p>Electroacupuncture Promoting Axonal Regeneration in Spinal Cord Injury Rats via Suppression of Nogo/NgR and Rho/ROCK Signaling Pathway</p>

Xiao¹,

Ding²,

Min³

et al. 2019

NDT

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To observe the changes of Nogo/NgR and Rho/ROCK signaling pathway-related gene and protein expression in rats with spinal cord injury (SCI) treated with electroacupuncture (EA) and to further investigate the possible mechanism of EA for treating SCI. Methods: Allen's method was used to create the SCI rat model. Sixty-four model rats were further subdivided into four subgroups, namely, the SCI model group (SCI), EA treatment group (EA), blocking agent Y27632 treatment group (Y27632) and EA+blocking agent Y27632 treatment group (EA+Y), according to the treatment received. The rats were subjected to EA and/or blocking agent Y27632 treatment. After 14 days, injured spinal cord tissue was extracted for analysis. The mRNA and protein expression levels were determined by real-time fluorescence quantitative PCR and Western blotting, respectively. Cell apoptosis changes in the spinal cord were evaluated by in situ hybridization. Hindlimb motor function in the rats was evaluated by Basso-Beattie-Bresnahan assessment methods. Results: Except for RhoA protein expression, compared with the SCI model group, EA, blocking agent Y27632 and EA+blocking agent Y27632 treatment groups had significantly reduced mRNA and protein expression of Nogo-A, NgR, LINGO-1, RhoA and ROCK II in spinal cord tissues, increased mRNA and protein expression of MLCP, decreased p-MYPT1 protein expression and p-MYPT1/MYPT1 ratio, and caspase3 expression, and improved lower limb movement function after treatment for 14 days (P<0.01 or <0.05). The combination of EA and the blocking agent Y27632 was superior to EA or blocking agent Y27632 treatment alone (P < 0.01 or <0.05). Conclusion: EA may have an obvious inhibitory effect on the Nogo/NgR and Rho/ROCK signaling pathway after SCI, thereby reducing the inhibition of axonal growth, which may be a key mechanism of EA treatment for SCI.

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RhoA/Rho Kinase Mediates Neuronal Death Through Regulating cPLA2 Activation

Cited by 27 publications

References 59 publications

Exosomes Derived From miR-133b-Modified Mesenchymal Stem Cells Promote Recovery After Spinal Cord Injury

Exosomes Derived From miR-133b-Modified Mesenchymal Stem Cells Promote Recovery After Spinal Cord Injury

Remodeling of lumbar motor circuitry remote to a thoracic spinal cord injury promotes locomotor recovery

<p>Electroacupuncture Promoting Axonal Regeneration in Spinal Cord Injury Rats via Suppression of Nogo/NgR and Rho/ROCK Signaling Pathway</p>

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