Postinjury estrogen treatment of chronic spinal cord injury improves locomotor function in rats

Abstract

Spinal cord injury (SCI) causes loss of neurological function and, depending on serverity, may cause paralysis. The only recommended pharmacotherapy for the treatment of SCI is high-dose methylprednisolone and its use is controversial. We have previously shown that estrogen treatment attenuated cell death, axonal and myelin damage, calpain and caspase activities, and inflammation in acute SCI. The aim of this study was to examine whether post-treatment of SCI with estrogen would improve locomotor function by protecting cells and axons and reducing inflammation during chronic phase following injury. Moderately severe injury (40 g.cm force) was induced in male Sprague-Dawley rats following laminectomy at T10. Three groups of animals were used: sham (laminectomy only), vehicle (dimethyl sulfoxide or DMSO) treated injury group, and estrogen treated injury group. Animals were treated with 4 mg/kg estrogen at 15 min and 24 h post-injury followed by 2 mg/kg estrogen daily for the next 5 days. Following treatment, animals were sacrificed at the end of 6 weeks following injury, and 1-cm segments of spinal cord (lesion, rostral to lesion, and caudal to lesion) were removed for biochemical analyses. Estrogen treatment reduced COX-2 activity, blocked NF-κB translocation, prevented glial reactivity, attenuated neuron death, inhibited activation and activity of calpain and caspase-3, decreased axonal damage, reduced myelin loss in the lesion and penumbra, and improved locomotor function when compared with vehicle treated animals. These findings suggest that estrogen may be useful as a promising therapeutic agent for prevention of damage and improvement of locomotor function in chronic SCI.

Estrogens and atherosclerosis: insights from animal models and cell systems

“…For instance, E 2 treatment blocked NF-kB translocation and prevented glial reactivity in rats undergoing chronic spinal cord injury (Sribnick et al 2010). Similarly, both E 2 and synthetic ER agonists normalized NF-kB activation and pro-inflammatory cytokine production as well as reduced TLR4 expression in Kupfer cells following trauma-hemorrhage in rats and mice, and these effects were shown to be specifically mediated by ERa (Hsieh et al 2007, Suzuki et al 2007.…”

Detection of novel mutations and review of published data suggests that hereditary spastic paraplegia caused by spastin (SPAST) mutations is found more often in males

“…A difference in the expression of the wild type allele could be relevant, but there is no data on expression levels in males and females. There are several lines of evidence to suggest that oestrogens may be neuroprotective [25]; with specific relevance to spastin-related HSP, a spinal cord disease possibly caused by disrupted neuronal transport [5,6], oestrogens are helpful in rat spinal cord injury [26], and may augment retrograde motor neuronal transport [27]. We therefore speculate that the explanation for males with SPAST mutations appearing more likely to be penetrant may be relative protection conferred to the spinal cord by oestrogens in women.…”

Novel Neuroinflammatory Targets in the Chronically Injured Spinal Cord

“…1). NFκB has been shown to be activated after SCI as early as 30 minutes after injury [65], and its activation is an important step in the development of inflammation after SCI [66].…”