Neuroprotective Effects of Raloxifene on Experimental Spinal Cord Injury in Rats

İsmailoğlu, Özgür; Oral, Baha; Tomruk, Önder; Sütçü, Recep; Kara, Yusuf; Demır, Necdet

doi:10.1097/maj.0b013e3182522651

Cited by 15 publications

(8 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several groups reported that TAM treatment 30 minutes or 2 hours after SCI in male rats produced some locomotor recovery during the first two weeks and reduced the amount of TNF, IL-1β or GFAP positive cells (Guptarak et al, 2014; Ismailogh et al, 2010; Tian et al, 2009). Recently, similar results were reported when the SERM Raloxifene was administered to spinal cord injured rats (Ismailoglu et al, 2013). Unexpectedly, in our injury model TAM did not improve locomotor function during the first 2 weeks after SCI but it did so by the third and fourth week.…”

Section: Discussionsupporting

confidence: 79%

Tamoxifen and estradiol improved locomotor function and increased spared tissue in rats after spinal cord injury: Their antioxidant effect and role of estrogen receptor alpha

et al. 2014

View full text Add to dashboard Cite

17β-Estradiol is a multi-active steroid that imparts neuroprotection via diverse mechanisms of action. However, its role as a neuroprotective agent after spinal cord injury (SCI), or the involvement of the estrogen receptor-alpha (ER-α) in locomotor recovery, is still a subject of much debate. In this study, we evaluated the effects of estradiol and of Tamoxifen (an estrogen receptor mixed agonist/antagonist) on locomotor recovery following SCI. To control estradiol cyclical variability, ovariectomized female rats received empty or estradiol filled implants, prior to a moderate contusion to the spinal cord. Estradiol improved locomotor function at 7, 14, 21, and 28 days post injury (DPI), when compared to control groups (measured with the BBB open field test). This effect was ER-α mediated, because functional recovery was blocked with an ER-α antagonist. We also observed that ER-α was up-regulated after SCI. Long-term treatment (28 DPI) with estradiol and Tamoxifen reduced the extent of the lesion cavity, an effect also mediated by ER-α. The antioxidant effects of estradiol were seen acutely at 2 DPI but not at 28 DPI, and this acute effect was not receptor mediated. Rats treated with Tamoxifen recovered some locomotor activity at 21 and 28 DPI, which could be related to the antioxidant protection seen at these time points. These results show that estradiol improves functional outcome, and these protective effects are mediated by the ER-α dependent and independent-mechanisms. Tamoxifen’s effects during late stages of SCI support the use of this drug as a long-term alternative treatment for this condition.

show abstract

Section: Discussionsupporting

confidence: 79%

Tamoxifen and estradiol improved locomotor function and increased spared tissue in rats after spinal cord injury: Their antioxidant effect and role of estrogen receptor alpha

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Previous studies showed that raloxifene and tamoxifen, two known SERMs used in clinics, reduce microglial activation induced by lipopolysaccharide (Suuronen et al, 2005; Tapia-Gonzalez et al, 2008), irradiaton-induced brain injury (Liu et al, 2010), and spinal cord injury (Ismailoğlu et al, 2010, 2013). Although these studies demonstrate a potential effect of SERMs on the inflammation resolution following different brain insults, all of them focused on young subjects.…”

Section: Introductionmentioning

confidence: 99%

Selective estrogen receptor modulators regulate reactive microglia after penetrating brain injury

Barreto

Santos-Galindo

Garcia-Segura

2014

Front. Aging Neurosci.

View full text Add to dashboard Cite

Following brain injury, microglia assume a reactive-like state and secrete pro-inflammatory molecules that can potentiate damage. A therapeutic strategy that may limit microgliosis is of potential interest. In this context, selective estrogen receptor modulators, such as raloxifene and tamoxifen, are known to reduce microglia activation induced by neuroinflammatory stimuli in young animals. In the present study, we have assessed whether raloxifene and tamoxifen are able to affect microglia activation after brain injury in young and aged animals in time points relevant to clinics, which is hours after brain trauma. Volume fraction of MHC-II+ microglia was estimated according to the point-counting method of Weibel within a distance of 350 μm from the lateral border of the wound, and cellular morphology was measured by fractal analysis. Two groups of animals were studied: (1) young rats, ovariectomized at 2 months of age; and (2) aged rats, ovariectomized at 18 months of age. Fifteen days after ovariectomy animals received a stab wound brain injury and the treatment with estrogenic compounds. Our findings indicate that raloxifene and tamoxifen reduced microglia activation in both young and aged animals. Although the volume fraction of reactive microglia was found lower in aged animals, this was accompanied by important changes in cell morphology, where aged microglia assume a bushier and hyperplasic aspect when compared to young microglia. These data suggest that early regulation of microglia activation provides a mechanism by which selective estrogen receptors modulators (SERMs) may exert a neuroprotective effect in the setting of a brain trauma.

show abstract

“…Several studies also examined the effects of estrogen and estrogenic compounds on myelin degradation and degeneration after SCI (Table 6). Estrogen, raloxifene, and tamoxifen were all shown to decrease the effects of SCI on myelin (Afhami et al, 2016; Cheng et al, 2016; Cuzzocrea et al, 2008; Ismailoglu et al, 2010; Ismailoglu et al, 2013; Sribnick et al, 2005; Tian et al, 2009). It was also shown that these positive effects of estrogens were mediated by ERα and β (Cuzzocrea et al, 2008) as well as GPER (Cheng et al, 2016).…”

Section: Resultsmentioning

confidence: 99%

“…With respect to oedema and blood spinal cord barrier (BSCB) after SCI, estrogens showed a beneficial effect (Table 5). Estrogen, raloxifene, and tamoxifen were all shown to decrease odema and reduce the disruption to the BSCB (Ismailoglu et al, 2010;Ismailoglu et al, 2013;Lee et al, 2015;Sribnick et al, 2005;Tian et al, 2009). There was also a critical time window for estrogen neuroprotection against oedema and BSCB disruption.…”

Section: Both Estrogen and Estrogenic Compounds Attenuate The (Histo)...mentioning

confidence: 99%

The neuroprotective effects of estrogen and estrogenic compounds in spinal cord injury

Shvetcov

Ruitenberg

Delerue

et al. 2022

Preprint

View full text Add to dashboard Cite

Spinal cord injury (SCI) occurs when the spinal cord is damaged from either a traumatic event or disease. SCI is characterised by multiple injury phases that affect the transmission of sensory and motor signals and lead to temporary or long-term functional deficits. There are few treatments for SCI. Estrogens and estrogenic compounds, however, may effectively mitigate the effects of SCI and therefore represent viable treatment options. This review systematically examines the pre-clinical literature on estrogen and estrogenic compound neuroprotection after SCI. Several estrogens were examined by the included studies: estrogen, estradiol benzoate, Premarin, isopsoralen, genistein, and selective estrogen receptor modulators. Across these pharmacotherapies, we find significant evidence that estrogens indeed offer protection against myriad pathophysiological effects of SCI and lead to improvements in functional outcomes, including locomotion. A STRING functional network analysis of proteins modulated by estrogen after SCI demonstrated that estrogen simultaneously upregulates known neuroprotective pathways, such as HIF-1, and downregulates pro-inflammatory pathways, including IL-17. These findings highlight the strong therapeutic potential of estrogen and estrogenic compounds after SCI.

show abstract

Neuroprotective Effects of Raloxifene on Experimental Spinal Cord Injury in Rats

Cited by 15 publications

References 21 publications

Tamoxifen and estradiol improved locomotor function and increased spared tissue in rats after spinal cord injury: Their antioxidant effect and role of estrogen receptor alpha

Tamoxifen and estradiol improved locomotor function and increased spared tissue in rats after spinal cord injury: Their antioxidant effect and role of estrogen receptor alpha

Selective estrogen receptor modulators regulate reactive microglia after penetrating brain injury

The neuroprotective effects of estrogen and estrogenic compounds in spinal cord injury

Contact Info

Product

Resources

About