17<i>β</i>-Estradiol Is Protective in Spinal Cord Injury in Post- and Pre-Menopausal Rats

Chaovipoch, Pimonporn; Jelks, Karen A.; Gerhold, Lynnette M.; West, Eric J.; Chongthammakun, Sukumal; Floyd, Candace L.

doi:10.1089/neu.2006.23.830

Cited by 71 publications

(67 citation statements)

References 126 publications

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“…The findings do not exclude additional effects of estrogens or related steroids that might be mediated by ERβ, or nonclassical effects, on astrocytes or other CNS cell types, including neurons (8,20,21). Sexual dimorphism is increasingly recognized in CNS molecular mechanisms (23), and circulating levels of endogenous or administered estrogens influence disease severity in a wide variety of CNS disorders, including autoimmune inflammation (4), traumatic injury (24,25), stroke (3), and neurodegenerative disease (1,3,26), all of which have postulated inflammatory involvement. Our findings show that astrocytes are the principal cells required for mediating the neuroprotective effects of ERα signaling in an autoimmune CNS inflammatory condition.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotection mediated through estrogen receptor-α in astrocytes

Spence¹,

Hamby

Umeda³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

204

151

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Estrogen has well-documented neuroprotective effects in a variety of clinical and experimental disorders of the CNS, including autoimmune inflammation, traumatic injury, stroke, and neurodegenerative diseases. The beneficial effects of estrogens in CNS disorders include mitigation of clinical symptoms, as well as attenuation of histopathological signs of neurodegeneration and inflammation. The cellular mechanisms that underlie these CNS effects of estrogens are uncertain, because a number of different cell types express estrogen receptors in the peripheral immune system and the CNS. Here, we investigated the potential roles of two endogenous CNS cell types in estrogen-mediated neuroprotection. We selectively deleted estrogen receptor-α (ERα) from either neurons or astrocytes using well-characterized Cre-loxP systems for conditional gene knockout in mice, and studied the effects of these conditional gene deletions on ERα ligand-mediated neuroprotective effects in a wellcharacterized model of adoptive experimental autoimmune encephalomyelitis (EAE). We found that the pronounced and significant neuroprotective effects of systemic treatment with ERα ligand on clinical function, CNS inflammation, and axonal loss during EAE were completely prevented by conditional deletion of ERα from astrocytes, whereas conditional deletion of ERα from neurons had no significant effect. These findings show that signaling through ERα in astrocytes, but not through ERα in neurons, is essential for the beneficial effects of ERα ligand in EAE. Our findings reveal a unique cellular mechanism for estrogen-mediated CNS neuroprotective effects by signaling through astrocytes, and have implications for understanding the pathophysiology of sex hormone effects in diverse CNS disorders.multiple sclerosis | astrogliosis | conditional knockout T he female sex hormone, estrogen, is neuroprotective in many clinical and experimental CNS disorders, including autoimmune conditions such as multiple sclerosis (MS), neurodegenerative conditions such as Alzheimer's and Parkinson diseases, and traumatic injury and stroke (1-4). Estrogen treatment has been shown to ameliorate clinical disease and decrease neuropathology in these disease models (1-4). Pharmacological studies have suggested roles for different estrogen receptors, but the cell types that mediate neuroprotective effects of estrogen are not known for any experimental or clinical condition. Identifying cells that bear specific estrogen receptor subtypes and are essential for specific estrogen-mediated effects is fundamental to elucidating and therapeutically exploiting the mechanisms that underlie estrogen-mediated neuroprotection. Toward this end, we used a genetic loss-of-function strategy. We selectively deleted estrogen receptor-α (ERα) from two different CNS cell types, neurons and astrocytes, and then determined the effects of these conditional gene deletions on the ability of ERα-ligand treatment to ameliorate disease severity of experimental autoimmune encephalomyelitis (EAE) in mice.EAE i...

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Section: Discussionmentioning

confidence: 99%

Neuroprotection mediated through estrogen receptor-α in astrocytes

Spence¹,

Hamby

Umeda³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

204

151

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“…Several studies have reported that 17b-estradiol administration reduces secondary injury and promotes functional recovery after SCI, but the dosing and administration timing vary substantially between studies. For example, we have previously shown that pretreatment with a sustained physiological dose of 17b-estradiol to adult or aged female rats decreased apoptosis in the gray matter, increased white-matter sparing, and increased recovery of hindlimb locomotion (Chaovipoch et al, 2006). Similarly, Webb and colleagues (2006) found that pre-injury administration with a sustained physiological dose of 17b-estradiol reduced the severity of autonomic dysreflexia following SCI in male mice.…”

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confidence: 87%

“…Crush injury to the mid-thoracic spinal cord was performed, with slight modification, as previously described (Chaovipoch et al, 2006). Briefly, rats were anesthetized by an intraperitoneal (i.p.)…”

Section: Surgical Proceduresmentioning

confidence: 99%

“…The BBB open-field locomotor scale was used to evaluate hindlimb locomotor performance following experimental SCI as previously described (Basso et al, 1995;Chaovipoch et al, 2006). In rats that received a gonadectomy prior to injury, post-SCI administration of either the 0.5-or 5.0-mg pellet of E2 significantly improved the BBB open-field scores on days 14, 21, and 28 compared to the group receiving the placebo (0.0 mg) pellet (Fig.…”

Section: Post Spinal Cord Injury Estrogen Administration Increased Fumentioning

confidence: 99%

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Effect of Endogenous Androgens on 17β-Estradiol-Mediated Protection after Spinal Cord Injury in Male Rats

Kachadroka

Hall

Niedzielko

et al. 2010

Journal of Neurotrauma

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Several groups have recently shown that 17b-estradiol is protective in spinal cord injury (SCI). Testosterone can be aromatized to 17b-estradiol and may increase estrogen-mediated protection. Alternatively, testosterone has been shown to increase excitotoxicity in models of central nervous system (CNS) injury. These experiments test the hypothesis that endogenous testosterone in male rats alters 17b-estradiol-mediated protection by evaluating a delayed administration over a clinically relevant dose range and manipulating testicular-derived testosterone. Adult male Sprague Dawley rats were either gonadectomized or left gonad-intact prior to SCI. SCI was produced by a midthoracic crush injury. At 30 min post SCI, animals received a subcutaneous pellet of 0.0, 0.05, 0.5, or 5.0 mg of 17b-estradiol, released over 21 days. Hindlimb locomotion was analyzed weekly in the open field. Spinal cords were collected and analyzed for cell death, expression of Bcl-family proteins, and white-matter sparing. Post-SCI administration of the 0.5-or 5.0-mg pellet improved hindlimb locomotion, reduced urinary bladder size, increased neuronal survival, reduced apoptosis, improved the Bax=Bcl-xL protein ratio, and increased white-matter sparing. In the absence of endogenous testicular-derived androgens, SCI induced greater apoptosis, yet 17b-estradiol administration reduced apoptosis to the same extent in gonadectomized and gonadintact male rats. These data suggest that delayed post-SCI administration of a clinically relevant dose of 17b-estradiol is protective in male rats, and endogenous androgens do not alter estrogen-mediated protection. These data suggest that 17b-estradiol is an effective therapeutic intervention for reducing secondary damage after SCI in males, which could be readily translated to clinical trials.

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“…Following spinal hemisection, Gwak et al (2004) reported that 12-month old rats demonstrated greater locomotor deficits (BBB, paw withdrawal latency) than 40 and 60-day old rats. Chaovipoch et al (2006) inferred a protracted time course of cell death following complete crush atT8-9 in 12-month compared to 2-month old rats, based on the number of TUNEL positive (apoptotic) cells in the gray matter. Finally, Siegenthaler et al (2008a;2008b) reported that following thoracic spinal cord contusion injuries, 12 (aged) and 30-month old (geriatric) rats showed less spontaneous recovery of walking, slower bladder function recovery, greater demyelination and less remyelination than 3-month old rats.…”

Section: Introductionmentioning

confidence: 99%

Effects of Advanced Age on the Morphometry and Degenerative State of the Cervical Spine in a Rat Model

Laing

Cox

Tetzlaff

et al. 2011

The Anatomical Record

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Aging causes changes in the geometry of the human cervical spine that may influence the tissue response to applied loads. Rat models are often used to study spinal cord injuries (SCI) and have the potential to enhance our understanding of the effect of age on SCI. The goal of this study was to characterize the morphometry and degenerative state of the cervical spine in Fisher 344 rats, and to determine the influence of age on these variables. Fifteen rats were split into three age groups: young adult (3 months of age), aged (12-18 months) and geriatric (30 months). Following tissue harvest we used a lCT scanner to image the cervical and upper thoracic spine from each specimen. Analysis software was used to measure variables including canal pinch diameter (the most rostral point on the dorsal aspect of a vertebral body to the most caudal aspect of the lamina on the immediately rostral vertebra), vertebral canal depth, width, and area, vertebral body height, depth, width, and area, and intervertebral disc thickness. Orthopaedic surgeons used midsagittal images to rate the degenerative state of the intervertebral discs. For all measures except disc thickness there was a significant increase (mean (SD) ¼ 15.0 (9.7)%) for the aged compared to young specimens (P < 0.05). There were significant differences between the aged and geriatric specimens for only vertebral body depth (P ¼ 0.016) and area (P ¼ 0.020). Intervertebral disc degeneration was significantly greater on the ventral aspect of the spinal column (P < 0.001), with a trend toward increased degeneration in the geriatric specimens (P ¼ 0.069). The results suggest that agerelated morphometric differences may need to be accounted for in experimental aging models of SCI in rats. Anat Rec, 294:1326Rec, 294: -1336Rec, 294: , 2011. V V C 2011 Wiley-Liss, Inc.

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17β-Estradiol Is Protective in Spinal Cord Injury in Post- and Pre-Menopausal Rats

Cited by 71 publications

References 126 publications

Neuroprotection mediated through estrogen receptor-α in astrocytes

Neuroprotection mediated through estrogen receptor-α in astrocytes

Effect of Endogenous Androgens on 17β-Estradiol-Mediated Protection after Spinal Cord Injury in Male Rats

Effects of Advanced Age on the Morphometry and Degenerative State of the Cervical Spine in a Rat Model

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