Abstract
The tamoxifen-dependent Cre/lox system in transgenic mice has become an important research tool across all scientific disciplines for manipulating gene expression in specific cell types. In these mouse models, Cre-recombination is not induced until tamoxifen is administered, which allows researchers to have temporal control of genetic modifications. Interestingly, tamoxifen has been identified as a potential therapy for spinal cord injury (SCI) and traumatic brain injury patients due to its neuroprotective properties. It is also reparative in that it stimulates oligodendrocyte differentiation and remyelination after toxin-induced demyelination. However, it is unknown whether tamoxifen is neuroprotective and neuroreparative when administration is delayed after SCI. To properly interpret data from transgenic mice in which tamoxifen treatment is delayed after SCI, it is necessary to identify the effects of tamoxifen alone on anatomical and functional recovery. In this study, female and male mice received a moderate mid-thoracic spinal cord contusion. Mice were then gavaged with corn oil or a high dose of tamoxifen from 19-22 days post-injury, and sacrificed 42 days post-injury. All mice underwent behavioral testing for the duration of the study, which revealed that tamoxifen treatment did not impact hindlimb motor recovery. Similarly, histological analyses revealed that tamoxifen had no effect on white matter sparing, total axon number, axon sprouting, glial reactivity, cell proliferation, oligodendrocyte number, or myelination, but tamoxifen did decrease the number of neurons in the dorsal and ventral horn. Semi-thin sections confirmed that axon demyelination and remyelination were unaffected by tamoxifen. Sex-specific responses to tamoxifen were also assessed, and there were no significant differences between female and male mice. These data suggest that delayed tamoxifen administration after SCI does not change functional recovery or improve tissue sparing in female or male mice.
Highlights
Spinal cord injury (SCI) is a traumatic life-changing event that currently affects ~300,000 people in the United States [1]
In the case of SCI, these sophisticated mouse models are used to study the mechanisms that contribute to widespread tissue damage and to identify new therapeutic targets
The Cre/lox system is based on Cre recombinase, a P1 bacteriophage that cuts out DNA sequences between loxP sites in any cell with active Cre [18]
Summary
Spinal cord injury (SCI) is a traumatic life-changing event that currently affects ~300,000 people in the United States [1]. The clinical signs associated with SCI depend on the level and severity of injury, but often include partial or complete loss of sensory, motor, and autonomic control below the level of injury These deficits result from tissue damage incurred by the initial impact of injury, and are exacerbated by secondary pathophysiological mechanisms. Among these are inflammation [2,3,4,5,6], axon degeneration [7,8,9,10], glial reactivity [11, 12], and demyelination [13,14,15,16], which spread above and below the injury site and can persist for months post-injury [for review see [17]. By combining tamoxifen-dependent Cre recombinase activity with tissue-specific expression of CreERT2, gene expression can be controlled temporally and spatially
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