Premarin stimulates estrogen receptor-α to protect against traumatic brain injury in male rats*

Chen, Sheng-Hsien; Chang, Chia‐Yu; Chang, Hsiu-Kang; Chen, Wei‐Chun; Lin, Mao‐Tsun; Wang, Jhi-Joung; Chen, Jeffrey Cheng-Yu; Chang, Feng-Cheng

doi:10.1097/ccm.0b013e3181bc7986

Cited by 28 publications

(18 citation statements)

References 45 publications

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“…25,[44][45][46] In addition, we analyzed protein expression levels of active caspase 3 in the ipsilateral hippocampus and found that the increase in active caspase 3 protein following TBI induction was significantly reduced following G-1 administration, an intriguing finding. The E2 treatment results are in contrast to earlier work that found E2 provided no significant reduction in caspase-3 immunoreactivity in the hippocampal CA3, hilar, and granule cell layers induced by LFP TBI.…”

Section: E2 or G-1 Increases Cell Survival Decreases Neuronal Degenementioning

confidence: 99%

“…Previous research has implicated the involvement of ERa and the PI3K/Akt signaling pathway in mediating protection afforded by E2 administration, but the contribution of GPER following TBI remains uninvestigated. 18,20,44,45,[59][60][61] Little is known of the function of GPER in the brain or how brain trauma may alter this receptor's activity. It has been reported that GPER is expressed in the CNS of both adult male and female rats, and is found throughout the brain, including the hippocampal formation.…”

Section: Potential Mechanisms Of Action Involved In E2-mediated Neuromentioning

confidence: 99%

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17β-Estradiol Confers Protection after Traumatic Brain Injury in the Rat and Involves Activation of G Protein-Coupled Estrogen Receptor 1

Day

Floyd

D'Alessandro

et al. 2013

Journal of Neurotrauma

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Traumatic brain injury (TBI) is a significant public health problem in the United States. Despite preclinical success of various drugs, to date all clinical trials investigating potential therapeutics have failed. Recently, sex steroid hormones have sparked interest as possible neuroprotective agents after traumatic injury. One of these is 17b-estradiol (E2), the most abundant and potent endogenous vertebrate estrogen. The goal of our study was to investigate the acute potential protective effects of E2 or the specific G protein-coupled estrogen receptor 1 (GPER) agonist G-1 when administered in an intravenous bolus dose 1 hour post-injury in the lateral fluid percussion (LFP) rodent model of TBI. The results of this study show that, when assessed at 24 hours post-injury, E2 or G-1 confers protection in adult male rats subjected to LFP brain injury. Specifically, we found that an acute bolus dose of E2 or G-1 administered intravenously 1 hour post-TBI significantly increases neuronal survival in the ipsilateral CA 2/3 region of the hippocampus and decreases neuronal degeneration and apoptotic cell death in both the ipsilateral cortex and CA 2/3 region of the hippocampus. We also report a significant reduction in astrogliosis in the ipsilateral cortex, hilus, and CA 2/3 region of the hippocampus. Finally, these effects were observed to be chiefly dose-dependent for E2, with the 5 mg/kg dose generating a more robust level of protection. Our findings further elucidate estrogenic compounds as a clinically relevant pharmacotherapeutic strategy for treatment of secondary injury following TBI, and intriguingly, reveal a novel potential therapeutic target in GPER.

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Section: E2 or G-1 Increases Cell Survival Decreases Neuronal Degenementioning

confidence: 99%

Section: Potential Mechanisms Of Action Involved In E2-mediated Neuromentioning

confidence: 99%

17β-Estradiol Confers Protection after Traumatic Brain Injury in the Rat and Involves Activation of G Protein-Coupled Estrogen Receptor 1

Day

Floyd

D'Alessandro

et al. 2013

Journal of Neurotrauma

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“…A major disadvantage of this treatment compared to specific single estrogens is the lack of specificity needed to clearly elucidate mechanisms. However, Premarin has been used previously in multiple studies and possesses advantages such as a well-known pharmacological profile [38]. Future studies, driven by this investigation, focused on elucidating the mechanisms of this phenomenon, should indeed make use of a single kind of estrogen.…”

Section: Discussionmentioning

confidence: 99%

Effect of estrogens on blood glutamate levels in relation to neurological outcome after TBI in male rats

et al. 2011

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“…However, it would require more results to approve it. In addition, sex steroid hormones, such as estrogen and testosterone, have been established as endogenous neuroprotective factors in the CNS injury (Chen et al 2009;Pike et al 2009). Meanwhile, Sex steroid hormones neuroprotective effects are mediated by AR/ERa (Elzer et al 2010;Hammond et al 2001;Li et al 2010).…”

Section: Discussionmentioning

confidence: 99%

Upregulation of p21-activated Kinase 6 in rat brain cortex after traumatic brain injury

et al. 2011

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p21-activated Kinase 6 (PAK6) is a serine/threonine kinase belonging to the p21-activated kinase (PAK) family. PAK kinases are well-known regulators of a wide variety of cellular functions, including regulation of cytoskeleton rearrangement, cell survival, apoptosis and the mitogen-activated protein kinase signaling pathway. To elucidate the expressions and possible functions of PAK6 in central nervous system (CNS) lesion and repair, we performed a traumatic brain injury (TBI) model in adult rats. Western blot analysis revealed that PAK6 level significantly increased at day 3 after damage, and then declined during the following days. Besides, double immunofluorescence staining showed PAK6 was primarily expressed in the neurons and a few of glial cells in the normal group. While after injury, the expression of PAK6 was increased significantly in the astrocytes and neurons, and the astrocytes had largely proliferated. We also examined the expression of proliferating cell nuclear antigen (PCNA) whose change was correlated with the expression of PAK6. Importantly, double immunofluorescence staining revealed that cell proliferation evaluated by PCNA appeared in many PAK6-expressing cells at day 3 after injury. In addition, injury-induced expression of PAK6 was co-labeled by active caspase-3 during neuronal apoptosis after injury. Collectively, we hypothesized PAK6 may play important roles in CNS pathophysiology after TBI and further research is needed to have a good understanding of its function and mechanism.

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Premarin stimulates estrogen receptor-α to protect against traumatic brain injury in male rats*

Abstract: Our results indicate that pharmacologic levels of Premarin therapy-induced estradiol protect against cortical and hippocampal programmed cell death after fluid percussion injury through mechanisms stimulating estrogen receptor-alpha in the male rats.

Cited by 28 publications

References 45 publications

17β-Estradiol Confers Protection after Traumatic Brain Injury in the Rat and Involves Activation of G Protein-Coupled Estrogen Receptor 1

17β-Estradiol Confers Protection after Traumatic Brain Injury in the Rat and Involves Activation of G Protein-Coupled Estrogen Receptor 1

Effect of estrogens on blood glutamate levels in relation to neurological outcome after TBI in male rats

Upregulation of p21-activated Kinase 6 in rat brain cortex after traumatic brain injury

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