The role of mTOR signaling pathway in spinal cord injury

Kanno, Haruo; Ozawa, Hiroshi; Sekiguchi, Akira; Yamaya, Seiji; Tateda, Satoshi; Yahata, Kenichiro; Itoi, Eiji

doi:10.4161/cc.21262

Cited by 87 publications

(64 citation statements)

References 75 publications

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“…The mTOR inhibitors have been used as immunosuppressants in patients undergoing transplantation surgery, and have also been used as anticancer agents . In addition, many previous experimental studies using CNS injury models have demonstrated promising effects of mTOR inhibition to reduce neural tissue damage . The present study suggests that the inhibition of mTOR has a significant therapeutic effect that can improve locomotor function and neuropathic pain condition following SCI.…”

Section: Discussionmentioning

confidence: 52%

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Rapamycin suppresses microglial activation and reduces the development of neuropathic pain after spinal cord injury

Tateda

Kanno

Ozawa

et al. 2016

Journal Orthopaedic Research

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Rapamycin is an inhibitor of the mammalian target of rapamycin (mTOR) signaling pathway, plays an important role in multiple cellular functions. Our previous study showed rapamycin treatment in acute phase reduced the neural tissue damage and locomotor impairment after spinal cord injury (SCI). However, there has been no study to investigate the therapeutic effect of rapamycin on neuropathic pain after SCI. In this study, we examined whether rapamycin reduces neuropathic pain following SCI in mice. We used a mouse model of thoracic spinal cord contusion injury, and divided the mice into the rapamycin-treated and the vehicletreated groups. The rapamycin-treated mice were intraperitoneally injected with rapamycin (1 mg/kg) 4 h after SCI. The rapamycin treatment suppressed phosphorylated-p70S6K in the injured spinal cord that indicated inhibition of mTOR. The rapamycin treatment significantly improved not only locomotor function, but also mechanical and thermal hypersensitivity in the hindpaws after SCI. In an immunohistochemical analysis, Iba-1-stained microglia in the lumbar spinal cord was significantly decreased in the rapamycin-treated mice. In addition, the activity of p38 MAPK in the lumbar spinal cord was significantly attenuated by rapamycin treatment. Furthermore, phosphorylated-p38 MAPK-positive microglia was relatively decreased in the rapamycin-treated mice. These results indicated rapamycin administration in acute phase to reduce secondary neural tissue damage can contribute to the suppression of the microglial activation in the lumbar spinal cord and attenuate the development of neuropathic pain after SCI. The present study first demonstrated that rapamycin has significant therapeutic potential to reduce the development of neuropathic pain following SCI.

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Section: Discussionmentioning

confidence: 52%

“…The mTOR pathway also regulates the immune function and autophagy . In addition, many previous studies have shown that mTOR regulates both neuroprotective and neuroregenerative functions in trauma and various diseases of the central nervous system (CNS) …”

mentioning

confidence: 99%

Rapamycin suppresses microglial activation and reduces the development of neuropathic pain after spinal cord injury

Tateda

Kanno

Ozawa

et al. 2016

Journal Orthopaedic Research

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“…Several recent studies have focused on the usefulness of autophagy as a therapy for inflammation‐induced disease . Increases in the expression levels of autophagic markers have been detected following ischaemia/reperfusion or inflammation injury, indicating that injury or stress can trigger cell self‐protective mechanisms by activating autophagy . In contrast, other studies have shown that autophagy has pernicious effects .…”

Section: Discussionmentioning

confidence: 99%

Salidroside attenuates neuroinflammation and improves functional recovery after spinal cord injury through microglia polarization regulation

Wang

Lou

et al. 2017

J Cellular Molecular Medi

148

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Spinal cord injury (SCI) is a severe neurological disease; however, few drugs have been proved to treat SCI effectively. Neuroinflammation is the major pathogenesis of SCI secondary injury and considered to be the therapeutic target of SCI. Salidroside (Sal) has been reported to exert anti‐inflammatory effects in airway, adipose and myocardial tissue; however, the role of Sal in SCI therapeutics has not been clarified. In this study, we showed that Sal could improve the functional recovery of spinal cord in rats as revealed by increased BBB locomotor rating scale, angle of incline, and decreased cavity of spinal cord injury and apoptosis of neurons in vivo. Immunofluorescence double staining of microglia marker and M1/M2 marker demonstrated that Sal could suppress M1 microglia polarization and activate M2 microglia polarization in vivo. To verify how Sal exerts its effects on microglia polarization and neuron protection, we performed the mechanism study in vitro in microglia cell line BV‐2 and neuron cell line PC12. The results showed that Sal prevents apoptosis of PC12 cells in coculture with LPS‐induced M1 BV‐2 microglia, also the inflammatory secretion phenotype of M1 BV‐2 microglia was suppressed by Sal, and further studies demonstrated that autophagic flux regulation through AMPK/mTOR pathway was involved in Sal regulated microglia polarization after SCI. Overall, our study illustrated that Sal could promote spinal cord injury functional recovery in rats, and the mechanism may relate to its microglia polarization modulation through AMPK‐/mTOR‐mediated autophagic flux stimulation.

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“…For instance, Park et al [26] reported that rapamycin protected human neuroblastoma SH-SY5Y cells against fipronil-induced apoptotic cell death. Kanno et al [18] found that rapamycin reduced locomotor impairment and neuronal death after spinal cord injury in mice. This effect of rapamycin was reported to be mediated through activation of autophagy by inhibiting the mammalian target of rapamycin (mTOR) signaling pathways [36].…”

Section: Introductionmentioning

confidence: 99%

Rapamycin protects dopaminergic neurons against rotenone-induced cell death in primary mesencephalic cell culture

Radad

Moldzio²,

Rausch³

2015

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The role of mTOR signaling pathway in spinal cord injury

Cited by 87 publications

References 75 publications

Rapamycin suppresses microglial activation and reduces the development of neuropathic pain after spinal cord injury

Rapamycin suppresses microglial activation and reduces the development of neuropathic pain after spinal cord injury

Salidroside attenuates neuroinflammation and improves functional recovery after spinal cord injury through microglia polarization regulation

Rapamycin protects dopaminergic neurons against rotenone-induced cell death in primary mesencephalic cell culture

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