Abstract
Endogenous neural stem/progenitor cells (eNSPCs) proliferate and differentiate into neurons and glial cells after spinal cord injury (SCI). We have previously shown that melatonin (MT) plus exercise (Ex) had a synergistic effect on functional recovery after SCI. Thus, we hypothesized that combined therapy including melatonin and exercise might exert a beneficial effect on eNSPCs after SCI. Melatonin was administered twice a day and exercise was performed on a treadmill for 15 min, six days per week for 3 weeks after SCI. Immunohistochemistry and RT-PCR analysis were used to determine cell population for late response, in conjunction with histological examination and motor function test. There was marked improvement in hindlimb function in SCI+MT+Ex group at day 14 and 21 after injury, as documented by the reduced size of the spinal lesion and a higher density of dendritic spines and axons; such functional improvements were associated with increased numbers of BrdU-positive cells. Furthermore, MAP2 was increased in the injured thoracic segment, while GFAP was increased in the cervical segment, along with elevated numbers of BrdU-positive nestin-expressing eNSPCs in the SCI+MT+Ex group. The dendritic spine density was augmented markedly in SCI+MT and SCI+MT+Ex groups. These results suggest a synergistic effect of SCI+MT+Ex might create a microenvironment to facilitate proliferation of eNSPCs to effectively replace injured cells and to improve regeneration in SCI.
Highlights
The stem cell field may serve as the glue that bonds and focuses many multidisciplinary approaches for spinal cord repair [1]
The body weight of the spinal cord injury (SCI) group increased more than that of the SCI+MT and SCI+MT+Ex groups at day 21 after SCI. These results indicate a synergistic interaction between physical exercise and exogenous melatonin administration, because melatonin treatment combined with exercise significantly improved functional recovery, as compared with SCI
Significantly increased numbers of BrdU/nestin double positive cells were found in the 1 mm rostral perilesion site on longitudinal sections from SCI+MT+Ex group at day 21 after spinal cord injury, indicating a synergistic effect of melatonin and exercise on behavioral recovery associated with a nestin-positive neural stem cell population
Summary
The stem cell field may serve as the glue that bonds and focuses many multidisciplinary approaches for spinal cord repair [1]. Endogenous neural stem/progenitor cells (eNSPCs) are found in the ependymal regions lining the central canal in the spinal cord [2] They are capable of proliferation, migration, and maturation into oligodendrocytes, astrocytes, and neurons [3,4], and play an important role in reorganization after spinal cord injury (SCI) [5]. The SCI+MT+Ex group had significantly reduced iNOS mRNA levels and more motor neurons in the ventral horn, as compared to the Con and SCI+Ex groups, suggesting that a novel therapeutic strategy using melatonin combination with exercise reduced the side effects related to exercise-induced fatigue, impairment, and injury-induced secondary damage [28,30]. This study was undertaken to examine the effect of the SCI+MT+Ex regime on eNSPCs in the adult rat spinal cord after injury, to elucidate whether proliferating eNSPCs are being stimulated, and what cell type is being replaced
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