The role of the PI3K/Akt/mTOR pathway in glial scar formation following spinal cord injury.

Several studies suggest that glial scars pose as physical and chemical barriers that limit neurite regeneration after spinal cord injury (SCI). Evidences suggest that the activation of the PI3K/Akt/mTOR signaling pathway is involved in glial scar formation. Therefore, inhibition of the PI3K/Akt/mTOR pathway may beneficially attenuate glial scar formation after SCI. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) negatively regulates the PI3K/Akt/mTOR pathway. Therefore, we hypothesized that the overexpression of PTEN in the spinal cord will have beneficial effects after SCI. In the present study, we intrathecally injected a recombinant adenovirus carrying the pten gene (Ad-PTEN) to cause overexpression of PTEN in rats with contusion injured spinal cords. The results suggest overexpression of PTEN in spinal cord attenuated glial scar formation and led to improved locomotor function after SCI. Overexpression of PTEN following SCI attenuated gliosis, affected chondroitin sulfate proteoglycan expression, and improved axon regeneration into the lesion site. Furthermore, we suggest that the activation of the PI3K/Akt/mTOR pathway in astrocytes at 3 days after SCI may be involved in glial scar formation. Because delayed treatment with Ad-PTEN enhanced motor function recovery more significantly than immediate treatment with Ad-PTEN after SCI, the results suggest that the best strategy to attenuate glial scar formation could be to introduce 3 days after SCI. This study's findings thus have positive implications for patients who are unable to receive immediate medical attention after SCI.

Chen CH ，Sung CS ，Huang SY ，Feng CW ，Hung HC ，Yang SN ，Chen NF ，Tai MH ，Wen ZH ，Chen WF ... -  《-》

MiR-17 targets PTEN and facilitates glial scar formation after spinal cord injuries via the PI3K/Akt/mTOR pathway.

We attempted to discover the regulatory role of miR-17 and PTEN in glial scar formation accompanied with spinal cord injuries. We established a spinal cord injury (SCI) model in mice which were transfected with different groups of adenoviruses: miR-17 mimics, miR-17 inhibitors and PTEN cDNAs. The improvement of hind limb functions was assessed using the 21-point Basso-Beattie-Bresnahan (BBB) locomotion scale. Immunohistochemistry was used to detect the expression levels of glial fibrillary acidic protein (GFAP), Vimentin and neurofilaments. The expression of miR-17 was quantified using Real time-PCR (RT-PCR). Western blot was conducted to detect the expressions of PTEN, PI3K, Akt, mTOR and S6. Finally, dual luciferase reporter gene assay was conducted to confirm the target relationship between miR-17 and PTEN. The model group exhibited significantly increased expression levels of GFAP, Vimentin, miR-17, PTEN, PI3K, Akt and mTOR. The above trend was enhanced by the transfection of miR-17 mimics (P<0.05). By contrast, the transfection of miR-17 inhibitors significantly down-regulated the expression of GFAP, Vimentin, PTEN, PI3K, Akt, mTOR and p-S6 whereas the expression of GFAP, Vimentin, PI3K, Akt, mTOR and p-S6 in the cells transfected with PTEN cDNAs significantly decreased (P<0.05). Also, the transfection of miR-17 inhibitors and PTEN cDNAs alleviated the astrogliosis in SCI lesions, contributed to the regeneration of nerve filament and improved the functional recovery of the hind limb of mice. Finally, the targeting relationship between miR-17 and PTEN was verified by the dual luciferase reporter gene assay. MiR-17 is able to target PTEN and stimulate the PI3K/Akt/mTOR pathway. The formation of glial scar resulted from spinal cord injuries can be reduced either by inhibiting miR-17 or by overexpressing PTEN.

Luan Y ，Chen M ，Zhou L 《-》

Effects of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor on glial scar formation after spinal cord injury in rats.

Chung J ，Kim MH ，Yoon YJ ，Kim KH ，Park SR ，Choi BH ... -  《-》

Spinal cord regeneration.

Young W 《-》

MicroRNA-494 improves functional recovery and inhibits apoptosis by modulating PTEN/AKT/mTOR pathway in rats after spinal cord injury.

Multiple cellular, molecular, and biochemical changes contribute to the etiology and treatment outcome of contusion spinal cord injury (SCI). MicroRNAs (miRNAs) aberrant expression have been found after SCI in recent studies. However, little is known about the functional significance of the unique role of miRNAs in SCI. Here, we established a rat SCI model and performed the miRNA microarray to analyze miRNAs expression at different times post-SCI. Microarray data revealed that 14 miRNAs were upregulated and 46 miRNAs were downregulated by 2 times compared with sham rat spinal cords, and miR-494 was one of the miRNAs being most significantly downregulated. Subsequently, we investigated miR-494 function and found that upregulation of miR-494 by agomir-494 improves functional recovery, reduces lesion size and inhibits apoptotic cell in rats following SCI. Moreover, our data showed that miR-494 suppresses phosphatase and tensin homolog (PTEN), a negative regulator of AKT/mTOR pathway, through directly targeting its 3'-UTR in BV-2 cells. Most importantly, we demonstrated that overexpression of miR-494 activates AKT/mTOR signaling pathway via inhibiting PTEN expression in rat SCI model. These findings suggested that miR-494 harbored the protective effect after SCI by modulating PTEN/AKT/mTOR pathway in rats and it is a potential candidate for SCI therapeutics.

Zhu H ，Xie R ，Liu X ，Shou J ，Gu W ，Gu S ，Che X ... -  《-》