Abstract
In research on various central nervous system injuries, bazedoxifene acetate (BZA) has shown two main effects: neuroprotection by suppressing the inflammatory response and remyelination by enhancing oligodendrocyte precursor cell differentiation and oligodendrocyte proliferation. We examined the effects of BZA in a rat spinal cord injury (SCI) model. Anti-inflammatory and anti-apoptotic effects were investigated in RAW 264.7 cells, and blood-spinal cord barrier (BSCB) permeability and angiogenesis were evaluated in a human brain endothelial cell line (hCMEC/D3). In vivo experiments were carried out on female Sprague Dawley rats subjected to moderate static compression SCI. The rats were intraperitoneally injected with either vehicle or BZA (1mg/kg pre-SCI and 3 mg/kg for 7 days post-SCI) daily. BZA decreased the lipopolysaccharide-induced production of proinflammatory cytokines and nitric oxide in RAW 264.7 cells and preserved BSCB disruption in hCMEC/D3 cells. In the rats, BZA reduced caspase-3 activity at 1 day post-injury (dpi) and suppressed phosphorylation of MAPK (p38 and ERK) at dpi 2, hence reducing the expression of IL-6, a proinflammatory cytokine. BZA also led to remyelination at dpi 20. BZA contributed to improvements in locomotor recovery after compressive SCI. This evidence suggests that BZA may have therapeutic potential to promote neuroprotection, remyelination, and functional outcomes following SCI.
Highlights
Spinal cord injury (SCI) is a life-shattering condition that leads to severe and permanent neurological deficits
We revealed the therapeutic potential of bazedoxifene acetate (BZA) by investigating its impact on inflammation, angiogenesis, apoptosis, remyelination, and locomotor outcomes in vitro and in a rat model of SCI
To determine non-cytotoxic working concentrations of BZA, cell viability was measured by CCK-8 assay in PC12 cells
Summary
Spinal cord injury (SCI) is a life-shattering condition that leads to severe and permanent neurological deficits. It is well established that SCI follows a biphasic time course; the initial mechanical injury is caused by impact accompanied by persistent compression of the spinal cord, while the secondary phase is characterized by destructive and self-propagating biochemical changes in neuronal and glial cells that lead to increased dysfunction and cell death [6]. Progressive demyelination leaves axons vulnerable to degeneration, which could diminish the functionality of spared circuits and limit functional improvements [13]. Remyelination appears to be a plausible strategy to protect spared axons from secondary damage and promote functional recovery [7]
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