Activation of Akt/mTOR/p70S6K signaling pathway limits excessive astrocytic responses after spinal cord injury in rats

Hu Ling-yun; Zhang Jian-ying; Lin Hong; Gou Lin; Lin Tao; Li Wei; Liu Kang; Sun Zhen-gang

doi:10.3969/j.issn.2095-4344.2015.05.008

Abstract：BACKGROUND:Most investigations have focused on nerve regeneration after spinal cord injury, but for how to inhibit excessive proliferation response of astrocytes after spinal cord injury and improve nerve regenerative environment is rarely reported. <br> OBJECTIVE:To examine the effects of the protein kinase B/mammalian target of rapamycin/p70 ribosomal S6 protein kinase (Akt/mTOR/p70S6K) signal transduction pathway on excessive astrocytic responses after spinal cord injury in adult rats, and to provide the molecular mechanism evidence for improving nerve regenerative environment fol owing spinal cord injury and repairing spinal cord injury. <br> METHODS:The minimal spinal cord injury model was produced in Spraque-Dawley rats. The rat models were divided into four groups:experiment group (receiving 7-day ATP treatment after modeling), control group (receiving 7-day saline treatment after modeling), interference group (receiving 7-day ATP and rapamycin treatment after modeling), and <br> sham-operated group (receiving 7-day saline treatment after laminectomy). Using immunohistochemical staining and western blot analyses, we detected the changes of Akt, p-Akt, mTOR, p-mTOR, p70S6K, p-p70S6K, and glial fibril ary acidic protein expressions in spinal cord tissues after surgery. BBB locomotor rating scale was applied to evaluate the animal’s locomotor performance after different treatments were administered fol owing spinal cord injury. <br> RESULTS AND CONCLUSION:The sham-operated group animals exhibited a low expression of the Akt/mTOR/p70S6K signaling pathway at the protein level, and the expressions increased fol owing spinal cord injury. Prominently elevated levels of its components were observed in the ATP-treated group, whereas rapamycin suppressed the upregulations of the Akt/mTOR/p70S6K signaling molecules induced by ATP. Activated Akt/mTOR/p70S6K signaling pathway significantly attenuated expressions of glial fibril ary acidic protein in the injured spinal cord, limited excessive astrocytic responses, and elevated the BBB scores after spinal cord injury. Rapamycin inhibited the above effects induced by ATP. These findings suggest that ATP-mediated Akt/mTOR/p70S6K signaling pathway activation can inhibit excessive glial scar formation after spinal cord injury, and have the potential of improving the regenerative environment, motor function and promoting repair potential for spinal cord injury, so this signaling pathway should be considered as a potential therapeutic strategy for spinal cord injury.