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

Abstract

Spinal cord injury (SCI) is a condition with no available cure. The initial physical impact triggers a cascade of molecular and cellular events that generate a nonpermissive environment for cell survival and axonal regeneration. Spinal cord injured patients often arrive at the clinic hours after the initial insult. This indicates the need to study and develop treatments with a long therapeutic window of action and multiactive properties, which target the complex set of events that arise after the initial trauma. We provide evidence that tamoxifen (TAM), a drug approved by the Food and Drug Administration, exerts neuroprotective effects in an animal model when applied up-to 24 h after SCI. We hypothesized that continuous TAM administration will improve functional locomotor recovery by favoring myelin preservation and reducing secondary damage after SCI. Adult female Sprague-Dawley rats (*230 g) received a moderate contusion to the thoracic (T9-T10) spinal cord, using the MASCIS impactor device. To determine the therapeutic window available for TAM treatment, rats were implanted with TAM pellets (15 mg) immediately or 24 h after SCI. Locomotor function (Basso, Beattie, Bresnahan open field test, grid walk, and beam crossing tests) was assessed weekly for 35 days post-injury. TAMtreated rats showed significant functional locomotor recovery and improved fine movements when treated immediately or 24 h after SCI. Further, TAM increased white matter preservation and reduced secondary damage caused by astrogliosis, axonal degeneration, and cell death after trauma. These results provide evidence for TAM as a potential therapeutic agent to treat SCI up to 24 h after the trauma.

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

“…Although tamoxifen transiently increased lethargy, control and tamoxifen mice scored similarly on the BMS scale and had a similar number of foot falls on the automated horizontal ladder. These results contradict other CNS trauma studies that show tamoxifen improves anatomical and motor recovery in female and male SCI rodents [39][40][41]55], but this is likely attributed to differences in the timing of dosing. Previous studies began tamoxifen treatment within 24 hours of injury, then gave low doses of tamoxifen chronically via intraperitoneal injection [39,41] or intrathecal infusion [40,55].…”

“…This is opposite of previous reports that suggest tamoxifen is neuroprotective and increases neuron survival [39,41,42,55]. Tamoxifen is known to be toxic to humans and rodents at high doses [72][73][74]; therefore, it is possible that giving tamoxifen at 300 mg/kg, compared to 1 mg/kg [39,55], was toxic and induced neuronal cell death. However, when examining neurons at specific differences rostral and caudal to the lesion epicenter, tamoxifen did not change neuron density.…”

“…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.…”

“…Immediately after injury the spinal cord undergoes massive cellular and molecular changes, including increased cell death [64,65], infiltration of inflammation cells in the lesion [2][3][4][5][6], axon degeneration [7][8][9][10], and OL and myelin loss [13-16, 66, 67]. Studies that report a neuroprotective effect of tamoxifen have given it during this acute phase, capitalizing on tamoxifen's ability to reduce inflammation, decrease glial reactivity, and promote cell survival [39][40][41][42]55]. Here, we gave tamoxifen 19-22dpi, which is after the glial scar has formed and most white matter, glial, and neuron loss has stabilized [66][67][68][69][70].…”

BDNF Overexpression Exhibited Bilateral Effect on Neural Behavior in SCT Mice Associated with AKT Signal Pathway

“…The most serious result of SCI is caused by secondary injury, resulted in a mass of cell death [27][28][29][30]. After SCT, NeuN expression was significantly down-regulated and NeuN has been used as a marker of neuron to indicate that neuronal death emerged in SCT.…”