ATP-mediated protein kinase B Akt/mammalian target of rapamycin mTOR/p70 ribosomal S6 protein p70S6 kinase signaling pathway activation promotes improvement of locomotor function after spinal cord injury in rats.

ABSTRACT

The protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/p70 ribosomal S6 protein kinase (p70S6K) signaling pathway, as a central controller of cell growth, proliferation, survival, and differentiation in response to extracellular signals, growth factors, nutrient availability, energy status of the cell, and stress, has recently gained attention in neuroscience. The effects of this signaling pathway on repair of spinal cord injury (SCI), however, have not been well elucidated. ATP is increasingly recognized as an important regulator of signal transduction pathways, and plays important roles in functional recovery after nervous system injury. In the present study, we examined the ATP-induced changes of the Akt/mTOR/p70S6K signaling pathway in injured spinal cord of adult rats and potential therapeutic effects of this pathway on SCI-induced locomotor dysfunction. SCI was produced by extradural weight-drop using modified Allen's stall with damage energy of 50 g-cm force. The rats were divided into four groups SCI plus ATP, SCI plus saline, SCI plus ATP and rapamycin, and sham-operated. Using immunostaining studies, Western blot analyses and real-time qualitative RT-PCR analyses, we demonstrated that the Akt/mTOR/p70S6K signaling pathway is present in the injured spinal cord and the expression of its components at the protein and mRNA levels is significantly elevated by exogenous administration of ATP following SCI. We observed the effectiveness of the activated Akt/mTOR/p70S6K signaling pathway in improving locomotor recovery, significantly increasing the expression of nestin, neuronal nuclei (NeuN), neuron specific enolase (NSE), and neurofilament 200 (NF200), and relatively inhibiting excessive reactive astrogliosis after SCI in a rapamycin-sensitive manner. We concluded that ATP injection produced a significant activation of the Akt/mTOR/p70S6K signaling pathway in the injured spinal cord and that enhancement of rapamycin-sensitive signaling produces beneficial effects on SCI-induced motor function defects and repair potential. We suggest that modulation of this protein kinase signaling pathway activity should be considered as a potential therapeutic strategy for SCI.