Role of JAK-STAT Signalling on Motor Function Recovery after Spinal Cord Injury

Outline

• 1. Introduction
• 2. Jak-Stat Signalling Pathway
• 3. Jak-Stat Pathway Activation in Response to Sci
• 4. Role of Jak-Stat in Axon Regeneration and Collateral Sprouting
• 5. Role of Jak-Stat in Local Neuron Response
• 6. Role of Jak-Stat in Glial Response
• 7. Role of Jak-Stat in the Inflammatory Response
• 8. Conclusion and Clinical Implications
• Acknowledgments

8. Conclusion and clinical implications

Cytokine upregulation and JAK-STAT signalling activation are endogenous mechanism that are activated in response to SCI and can be used to improve motor recovery. Cell type specific and in vitro studies have identified the role of STATs modulation in spinal cord cells. STAT3 has been the most extensively studied STAT transcription factor in SCI, but promising results have been found in other STATs and further studies should continue to determine the roles of STAT1 and STAT5 in SCI. Moreover, further studies with transgenic models should focus in other specific cell responses not studied up to now, like motoneuron and NSPC responses.

Several preclinical studies have shown positive outcomes for motor recovery and tissue sparing in JAK-STAT cytokine treatments (Table 2). Thus, modulation of the JAK-STAT signalling presents an opportunity to modulate neuron and glial response after an SCI in clinical settings. The hematopoietic cytokines have been already used in clinical studies for several pathologies, therefore are advanced in comparison with other JAK-STAT cytokines. Discussion of G-CSF and EPO treatments for SCI can be found in previous chapters [45, 86], while for GM-CSF there is one SCI clinical study finished which consisted in cytokine administration with transplant of bone marrow cells [87]. Although clinical studies have not been assessed for other cytokines in CNS trauma, there are clinical studies involving other pathologies that could be translated to SCI. The anti-inflammatory and neuroprotective mechanism of IL10 could also be assessed with a recombinant human IL10 that has been used for HIV infection and other several pathologies [46]. Emfilermin is a recombinant human LIF that has been tested, although with a lack of effectiveness, in clinical trials for embryo implantation and peripheral neuropathy [88, 89] that could also be used in SCI or other CNS diseases. Finally, tocilizumab, an anti-human IL6R, has shown positive outcomes in clinical studies for rheumatoid arthritis [90] and could be used for anti-inflammatory treatment in the spinal cord acute response.