Experimental spinal cord injuries : a histopathological, neurological, and pharmacological study in the rat
Sammanfattning: Photochemically-induced ischemic lesions and compression-induced traumatic injuries in the mid-thoracic spinal cord were studied in female rats. The histopathological development of the injuries was found to be similar to that described in other experimental spinal cord injury models and in human post-mortem material. Edema, evidenced with albumin immunoreactivity, increased during the first 24 hours and decreased 72 hours post-lesion. During the first week post-lesion the tissue within the lesion disintegrated and degenerated and axonal retraction bulbs were found adjacent to the lesion. At 3 weeks post-injury gliosis was observed around the lesion, as evidenced by increased immunoreactivity against glial fibrillary acidic protein. The gliosis became more pronounced at 6 weeks post-ischemia at which time geminocytes were also found in the viable tissue surrounding the lesion. The functional capacity following spinal cord injury was tested in rats with photochemically-induced ischemic lesions. A test protocol, the Motor Performance Score (MPS), was developed for fast, easy, and reliable evaluation of motor function in spinal cord injured rats. The MPS was shown to correlate well with morphological descriptors of lesion size in both ischemic and compressive injuries. Regrowing axons were found within the lesion cavity from two weeks post-lesion. To evaluate the amount of regeneration a novel stereological tool utilizing isotropic virtual planes was adapted to estimate neurofilament-immunoreactive fibers within a CNS lesion. Using this tool spontaneous regeneration of axons of central origin could be demonstrated after spinal cord lesions in the rat. The axonal sprouting and/or elongation was extensive between 1 and 5 weeks post-ischemia. Part of this regeneration was abortive but a large number of axons was present even at 15 weeks after the lesion. The axonal nature of the neurofilament-positive fibers was verified in ultra-structural studies and Schwann cells and oligodendrocytes were found adjacent to the axons. Both the selective non-competitive N-methyl-D-aspartate (NMDA) antagonist MK-801 and the non-NMDA antagonist NBQX was found to improve motor function in rats with ischemic lesions. Moreover, for the first time NBQX was demonstrated to protect spinal cord tissue from secondary degeneration to the same degree as MK-801, reducing the lesion volume by 50%. To investigate the protective effect of a clinically used drug, rats with ischemic or traumatic spinal cord injuries were treated with the non competitive NMDA antagonist, memantine. No protective effect was found at doses that have been reported to be protective in cerebral ischemia models. Due to hazardous side effects, higher doses could not be used in our model. The affinity of memantine was shown to be significantly lower for NMDA receptors in the rat spinal cord than for those in the brain. The affinity of memantine to human spinal NMDA receptors was found to be even lower which disqualifies this drug for clinical use in spinal cord injury treatment.
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