Rho-ROCK Inhibition in the Treatment of Spinal Cord Injury

Forgione, Nicole; Fehlings, Michael G.

doi:10.1016/j.wneu.2013.01.009

Cited by 105 publications

(57 citation statements)

References 38 publications

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“…This pathway has also been shown to play an important role in the pathophysiology of SCI [6,4,7]. For example, upregulation of RhoA was observed after SCI [8].…”

Section: Introductionmentioning

confidence: 98%

RhoA/Rho Kinase Mediates Neuronal Death Through Regulating cPLA2 Activation

Walker

et al. 2016

Mol Neurobiol

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Activation of RhoA/Rho kinase leads to growth cone collapse and neurite retraction. Although RhoA/Rho kinase inhibition has been shown to improve axon regeneration, remyelination and functional recovery, its role in neuronal cell death remains unclear. To determine whether RhoA/Rho kinase played a role in neuronal death after injury, we investigated the relationship between RhoA/Rho kinase and cytosolic phospholipase A 2 (cPLA 2 ), a lipase that mediates inflammation and cell death, using an in vitro neuronal death model and an in vivo contusive spinal cord injury model performed at the 10 th thoracic (T10) vertebral level. We found that coadministration of TNF-α and glutamate induced spinal neuron death, and activation of RhoA, Rho kinase and cPLA 2 . Inhibition of RhoA, Rho kinase and cPLA 2 significantly reduced TNF-α/glutamate-induced cell death by 33%, 52% and 43%, respectively (p < 0.001). Inhibition of RhoA and Rho kinase also significantly down-regulated cPLA 2 activation by 66% and 60%, respectively (p < 0.01). Furthermore, inhibition of RhoA and Rho kinase reduced the release of arachidonic acid, a downstream substrate of cPLA 2 . The immunofluorescence staining showed that ROCK 1 or ROCK 2, two isoforms of Rho kinase, was co-localized with cPLA 2 in neuronal cytoplasm. Interestingly, co-immunoprecipitation (Co-IP) assay showed that ROCK 1 or ROCK 2 , bonded directly with cPLA 2 and phospho-cPLA 2 . When the Rho kinase inhibitor Y27632 was applied in mice with T10 contusion injury, it significantly decreased cPLA 2 activation and expression, and reduced injury-induced apoptosis in the lesion area. Taken together, our results reveal a novel mechanism of RhoA/Rho kinase-mediated neuronal death through regulating cPLA 2 activation.

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“…This pathway has also been shown to play an important role in the pathophysiology of SCI [6,4,7]. For example, upregulation of RhoA was observed after SCI [8].…”

Section: Introductionmentioning

confidence: 98%

RhoA/Rho Kinase Mediates Neuronal Death Through Regulating cPLA2 Activation

Walker

et al. 2016

Mol Neurobiol

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“…This complex combination transduces downstream activation of the small guanine triphosphatase (GTPase) Rho and its effector kinase ROCK. The main consequence of Rho-ROCK activation is to trigger growth cone collapse, which is a significant barrier to axonal regeneration (Forgione and Fehlings, 2014). Therefore, targeting the Rho signal to promote regeneration of insulted nerves may be a feasible therapeutic strategy after brain injury.…”

mentioning

confidence: 99%

Panax notoginseng saponins provide neuroprotection by regulating NgR1/RhoA/ROCK2 pathway expression, in vitro and in vivo

Shi

Yang

et al. 2016

Journal of Ethnopharmacology

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“…These inhibitors bind their receptor complex, including NgR1, the p75 neurotrophin receptor (p75NTR), and LINGO-1 [8], and downstream signaling leads to failure of remyelination and arrest of neurite/axon growth [9]. An important downstream pathway of these myelin-associated inhibitors (MAIs) is Rho molecules, especially RhoA, and their kinases (Rho kinases (ROCKs)), whose activities are considerably increased in several neurological disorders such as stroke, MS, Alzheimer's disease (AD), and Parkinson's disease (PD) [10,11], while the blockade of Rho/ROCK is thought to inhibit inflammation, to reduce infarct size [12], and to suppress EAE [13][14][15]. On the other hand, adenosine 3′,5′-cyclic monophosphate (cAMP) plays an important role in neuronal survival and modulation of growth cone and enhancement of neurite outgrowth [16].…”

Section: Introductionmentioning

confidence: 99%

Matrine Treatment Blocks NogoA-Induced Neural Inhibitory Signaling Pathway in Ongoing Experimental Autoimmune Encephalomyelitis

Kan

Zhang

et al. 2016

Mol Neurobiol

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Myelin-associated inhibitors, such as NogoA, myelin-associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMgp), play a pivotal role in the lack of neuroregeneration in multiple sclerosis, an inflammatory demyelinating disease of the central nervous system (CNS). Matrine (MAT), a monomer that is used in traditional Chinese medicine as an anti-inflammatory agent, has shown beneficial effects in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. However, the underlying mechanisms of MAT-induced EAE amelioration are not fully understood. In the present study, we show that MAT treatment suppressed ongoing EAE, and this effect correlated with an increased expression of growth-associated protein 43, an established marker for axonal regeneration. MAT treatment significantly reduced the levels of NogoA, its receptor complex NgR/p75NTR/LINGO-1, and their downstream RhoA/ROCK signaling pathway in the CNS. In contrast, intracellular cyclic AMP (cAMP) levels and its protein kinase (protein kinase A (PKA)), which can promote axonal regrowth by inactivating the RhoA, were upregulated. Importantly, adding MAT in primary astrocytes in vitro largely induced cAMP/PKA expression, and blockade of cAMP significantly diminished MAT-induced expression of PKA and production of BDNF, a potent neurotrophic factor for neuroregeneration. Taken together, our findings demonstrate that the beneficial effects of MAT on EAE can be attributed not only to its capacity for immunomodulation, but also to its directly promoting regeneration of the injured CNS.

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Rho-ROCK Inhibition in the Treatment of Spinal Cord Injury

Cited by 105 publications

References 38 publications

RhoA/Rho Kinase Mediates Neuronal Death Through Regulating cPLA2 Activation

RhoA/Rho Kinase Mediates Neuronal Death Through Regulating cPLA2 Activation

Panax notoginseng saponins provide neuroprotection by regulating NgR1/RhoA/ROCK2 pathway expression, in vitro and in vivo

Matrine Treatment Blocks NogoA-Induced Neural Inhibitory Signaling Pathway in Ongoing Experimental Autoimmune Encephalomyelitis

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