Abstract
Spinal cord injury (SCI) causes significant mortality and morbidity. Currently, no FDA-approved pharmacotherapy is available for treating SCI. Previously, low doses of estrogen (17β-estradiol, E2) were shown to improve the post-injury outcome in a rat SCI model. However, the range of associated side effects makes advocating its therapeutic use difficult. Therefore, this study aimed at investigating the therapeutic efficacy of Premarin (PRM) in SCI. PRM is an FDA-approved E2 (10%) formulation, which is used for hormone replacement therapy with minimal risk of serious side effects. The effects of PRM on SCI were examined by magnetic resonance imaging, immunofluorescent staining, and western blot analysis in a rat model. SCI animals treated with vehicle alone, PRM, E2 receptor antagonist (ICI), or PRM + ICI were graded in a blinded way for locomotor function by using the Basso–Beattie–Bresnahan (BBB) locomotor scale. PRM treatment for 7 days decreased post-SCI lesion volume and attenuated neuronal cell death, inflammation, and axonal damage. PRM also altered the balance of pro- and anti-apoptotic proteins in favor of cell survival and improved angiogenesis and microvascular growth. Increased expression of estrogen receptors (ERs) ERα and ERβ following PRM treatment and their inhibition by ER inhibitor indicated that the neuroprotection associated with PRM treatment might be E2-receptor mediated. The attenuation of glial activation with decreased inflammation and cell death, and increased angiogenesis by PRM led to improved functional outcome as determined by the BBB locomotor scale. These results suggest that PRM treatment has significant therapeutic implications for the improvement of post-SCI outcome.
Highlights
PRM treatment significantly reduced the lesion volume at 7 days following Spinal cord injury (SCI) (Figure 2), which indicates a role for PRM in reducing edema in the injured spinal cord and preserving tissue integrity following SCI
Immunostaining of SCI samples showed an increase in the number of NFP and MBP stained cells in injured rats following treatment with PRM (Figure 3)
Tissue damage in SCI is multi-factorial and requires a therapeutic approach that can attenuate a majority of the destructive pathways and promote recovery of motor function
Summary
Spinal cord injury (SCI) is a devastating problem affecting injured individuals and leading to disability. Depending on the extent and severity of injury, SCI can lead to varying degrees of paralysis. No Federal Drug Administration (FDA) approved pharmacotherapies are available to cure and/or improve motor function following injury. While methylprednisolone is a widely used drug for SCI treatment, its use is controversial and has many unwanted side effects as well as weak efficacy [1,2,3,4,5]. The multi-factorial destructive process in SCI makes developing pharmacologic agent(s) that can ameliorate the many destructive pathways involved in spinal cord degeneration difficult
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