Continuous tamoxifen delivery improves locomotor recovery 6 h after spinal cord injury by neuronal and glial mechanisms in male rats

Abstract

No treatment is available for patients with spinal cord injury (SCI). Patients often arrive to the hospital hours after SCI suggesting the need of a therapy that can be used on a clinically relevant window. Previous studies showed that Tamoxifen (TAM) treatment 24h after SCI benefits locomotor recovery in female rats. Tamoxifen exerts beneficial effects in male and female rodents but a gap of knowledge exists on: the therapeutic window of TAM, the spatio-temporal mechanisms activated and if this response is sexually dimorphic. We hypothesized that TAM will favor locomotor recovery when administered up-to 24h after SCI in male Sprague-Dawley rats. Rats received a thoracic (T10) contusion using the MACSIS impactor followed by placebo or TAM (15mg/21days) pellets in a therapeutic window of 0, 6, 12, or 24h. Animals were sacrificed at 2, 7, 14, 28 or 35days post injury (DPI) to study the molecular and cellular changes in the acute and chronic stages. Immediate or delayed therapy (t=6h) improved locomotor function, increased white matter spared tissue, and neuronal survival. TAM reduced reactive gliosis during chronic stages and increased the expression of Olig-2. A significant difference was observed in estrogen receptor alpha between male and female rodents from 2 to 28 DPI suggesting a sexually dimorphic characteristic that could be related to the behavioral differences observed in the therapeutic window of TAM. This study supports the use of TAM in the SCI setting due to its neuroprotective effects but with a significant sexually dimorphic therapeutic window.

Astrocytes Mediate Protective Actions of Estrogenic Compounds after Traumatic Brain Injury

“…In vivo studies have shown that several estrogenic compounds, such as estradiol, phytoestrogens (genistein), some SERMs and tibolone, decrease reactive astrogliosis and glial scar formation after TBI [123, 169-171, 199-201]. After spinal cord injury, tamoxifen has been shown to first increase astrogliosis at day 2 after injury and then gradually decrease astrogliosis [202]. This suggests that tamoxifen may accelerate the process of astrogliosis, increasing reactive astrocytes in the acute injury phase, where astrocytes may release trophic factors to protect neurons, and decrease reactive astrocytes in the chronic injury phase.…”

“…The SERM raloxifene increases neurotransmitter receptor binding in brain regions associated with cognition and memory, and enhances the transcription and protein levels of neurotrophic factors such as tropomyosin receptor kinase A (TrkA), BDNF and ChAT in experimental models of TBI in rats [177]. Another SERM, tamoxifen, has been shown to reduce tissue damage and promote functional recovery after traumatic injury of the spinal cord [202]. The phytoestrogen resveratrol reduced neuronal loss in all ipsi- and contralateral hippocampal regions while improving exploratory activity and memory abilities in albino Wistar rats submitted to TBI [178].…”

Delayed short-term tamoxifen treatment does not promote remyelination or neuron sparing after spinal cord injury

“…Tamoxifen is a known repressor of astrocyte reactivity acutely after SCI [42,43,55]. Here, we labeled for GFAP to determine if tamoxifen delivered after glial scar formation yielded similar results.…”

“…For example, tamoxifen injected intraperitoneally in adult female rats acutely after toxin-induced demyelination in the brain stimulated NG2 + oligodendrocyte progenitor cell differentiation into oligodendrocytes [OLs] and accelerated the rate of remyelination [35]. Furthermore, 21 days of tamoxifen treatment beginning immediately after SCI reduced inflammation, decreased glial reactivity, promoted cell survival, increased white matter sparing, and enhanced functional recovery in rats and cats [38][39][40][41][42][43]. Interestingly, if tamoxifen treatment was delayed until 42 days after SCI, then hindlimb motor recovery was not changed; the impact of delayed tamoxifen treatment on tissue repair was not assessed [43].…”

“…Without tamoxifen, it would be impossible to induce cell-specific GFP expression in controls. In addition, previous studies that propose tamoxifen as a neuroprotective treatment have given tamoxifen within 3 days of disease or trauma [35,[38][39][40][41][42]. It is unknown if delayed tamoxifen treatment yields similar results.…”