Confidence in a theory increases when it is confirmed by relevant data. Alongside some consistent findings, the data in the prevailing thesis largely detail a lack of confirmation of the... Show moreConfidence in a theory increases when it is confirmed by relevant data. Alongside some consistent findings, the data in the prevailing thesis largely detail a lack of confirmation of the neurotrophin hypothesis. And where expected associations were established (e.g., abnormally low serum BDNF concentrations in the depressed state), the meaning often was not that clear (e.g., reverse causation). I therefore conclude, whilst taking limitations into account and acknowledging that the results are contingent upon imperfect and peripheral measurement, that the most reliable evidence in humans does not corroborate the neurotrophin hypothesis. So, given the data, the final words of this thesis are that solid work over novelty shows that the neurotrophin hypothesis should no longer be credited in its original form. All that glitters is not gold - back to the drawing table Show less
Currently, there is no treatment available that restores anatomy and function after spinal cord injury. This thesis explores transplantation of bone marrow-derived mesenchymal stem cells (bone... Show moreCurrently, there is no treatment available that restores anatomy and function after spinal cord injury. This thesis explores transplantation of bone marrow-derived mesenchymal stem cells (bone marrow stromal cells; BMSCs) as a therapeutic approach for spinal cord repair. BMSCs secrete neurotrophic factors, enabling neuroprotection/tissue sparing in a rat model of spinal cord injury. In this model system, bone marrow stromal cell-mediated tissue sparing leads to motor and sensory function improvements. Moreover, we show that BMSCs__ neuroprotective ability can be enhanced by genetically modifying the cells to overexpress brain-derived neurotrophic factor. However, survival of BMSCs in the injured spinal cord is poor and limits their repair capacity. We investigated the effect of three immunosuppressig agents, Minocycline, Methylprednisolone and Cyclosporine, on macrophage suppression and BMSC survival. All three d rugs effectively reduced the macrophage response, without improving transplanted BMSC survival. Transplanting the cells within the reverse thermal gel ESHU, did significantly improve BMSC survival which was associated with increased tissue sparing and improved functional recovery. These effects are likely due to ESHU__s anti-oxidative properties. Future research will need to focus on combinations of neuroprotective BMSC transplants with axonal regenerating promoting therapies to further optimize BMSC-based therapy for spinal cord injury. Show less
