The Cancer Drug Tamoxifen: A Potential Therapeutic Treatment for Spinal Cord Injury

Abstract

Tamoxifen (TMX) is a selective estrogen receptor modulator that can mimic the neuroprotective effects of estrogen but lacks its systemic adverse effects. We found that TMX (1 mg/day) significantly improved the motor recovery of partially paralyzed hind limbs of male adult rats with thoracic spinal cord injury (SCI), thus indicating a translational potential for this cancer medication given its clinical safety and applicability and the lack of currently available treatments for SCI. To shed light on the mechanisms underlying the beneficial effects of TMX for SCI, we used proteomic analyses, Western blots and histological assays, which showed that TMX treatment spared mature oligodendrocytes/increased myelin levels and altered reactive astrocytes, including the upregulation of the water channels aquaporin 4 (AQP4), a novel finding. AQP4 increases in TMX-treated SCI rats were associated with smaller fluid-filled cavities with borders consisting of densely packed AQP4-expressing astrocytes that closely resemble the organization of normal glia limitans externa (in contrast to large cavities in control SCI rats that lacked glia limitans-like borders and contained reactive glial cells). Based on our findings, we propose that TMX is a promising candidate for the therapeutic treatment of SCI and a possible intervention for other neuropathological conditions associated with demyelination and AQP4 dysfunction.

Tamoxifen Administration Immediately or 24 Hours after Spinal Cord Injury Improves Locomotor Recovery and Reduces Secondary Damage in Female Rats

“…14 The acute behavioral locomotor recovery (7 DPI) observed in our studies is different from that obtained by Guptarak and colleagues, 14 which observed a recovery at 14 DPI up to the end time point of 35 DPI. The discrepancy may be related to the sex of the animals used in each study and the lesion produced by the impactors used in each research project (NYU/MASCIS versus Infinite Horizon impactor).…”

“…One-way analysis of variance Tukey's multiple comparison test (**p < 0.01), data are mean -SEM, sham (PLB+TAM) n = 9, SCI PLB (rats from t = 0 h + 24 h) n = 4, SCI TAM 0 h n = 3, SCI TAM 24 h n = 3. recovery in the chronic phase of the injury (between 14 and 35 DPI) in male rats. 14 Our results confirmed the behavioral observations obtained by these two groups, but expanded the information to the inclusion of female animals in our studies and extended the therapeutic window up to 24 h versus the previously reported up to 2 h after SCI.…”

“…12 In addition, this multiactive drug also decreased the level of reactive gliosis generated after SCI or brain trauma. 13,14,47,48 In this study, we demonstrated that the levels of GFAP immunoreactive cells decreased significantly when TAM was administered immediately or 24 h after SCI. This result was confirmed by Western blot studies that demonstrated the effect of TAM to reduce the level of GFAP protein in regions rostral, caudal, and at the lesion epicenter.…”

“…Among the expected effects of TAM are reduction of inflammatory cytokines, microglial activation, and reduction in astrogliosis, as has been shown by others in models of SCI 12,14,17,18 and brain ischemia or trauma. 8,13,16,[44][45][46][47][48] Administration of TAM, 30 min after spinal cord contusion, attenuates neuronal apoptosis within the first few days, 12 possibly through the inactivation of caspase-3.…”

“…Analyses performed in male rats demonstrated that TAM administration 2 h after SCI spares oligodendrocytes at the 10th thoracic segment (visualized by counting CC-1 labeled oligodendrocytes) and reduces the cavity size. 14 Another possibility is that TAM may induce differentiation of progenitor cells into oligodendrocytes in the spinal cord, which may initiate a chronic remyelination process contributing to an increase in white matter after SCI. 16,42,43 Both mechanisms were observed by Franco-Rodriguez and colleagues 16 in brain injury, suggesting a similar mechanism may be activated by TAM after SCI.…”