A Combination Therapy Promotes Quipazine-induced Weight-supported Stepping in Spinalized Adult Rats

Our original hypothesis was that the combination of cellular transplants of neural and glial restricted precursor cells, 2) passive cycling, and 3) chronic 5-HT2 receptor agonist treatment with quipazine would result in increased locomotor recovery compared to the individual treatment elements alone. We found that the combination therapy promoted weight-supported stepping in the open field and without body weight support or tail stimulation under acute quipazine administration. None of the other treatment groups were capable of supporting their own weight or performing weight-supported steps even when placed on the motorized treadmill. This is the first report of quipazine-induced stepping without the use of a body weight-support system or trainer- provided stimulation. Next we investigated anatomical connections within the lesion of the combination therapy animals and did not find evidence of reconnection of the caudal spinal cord. Examination of the NRP/GRP cell transplants revealed that the combination therapy promoted an increase in AP+ cell survival and caudal migration. The vast majority of the NRP/GRP cell transplants did not differentiate into mature cell types. Within the lumbar spinal cord molecular investigation of neurotrophin factor expression revealed that the combination therapy animals had increased expression of the neurotrophin, BDNF compared to the individual treatment elements and injury alone. This increase in BDNF mRNA expression was found to be increased in the lumbar motoneurons of the combination therapy animals as well suggesting that they may contribute to the increased BDNF mRNA expression observed in the whole lumbar spinal cord. The dendritic arborizations of motoneurons associated with hind limb muscle that resisted atrophy through passive cycling showed preservation of the dendritic branching in the combination therapy animals and those receiving passive cycling only. Furthermore, the mRNA expression of the 5-HT2A and 5-HT 2C receptors of the lumbar motoneurons were also increased in the combination therapy animal compared to injury only, although no differences were observed within the intermediate grey area. Taken together these data suggest that the combination therapy led to an increase in spinal plasticity through stimulation of the lumbar spinal cord that resulted in the production of weight-supported stepping without supraspinal input.