The selective oestrogen receptor modulator, bazedoxifene, mimics the neuroprotective effect of 17β‐oestradiol in diabetic ischaemic stroke by modulating oestrogen receptor expression and the MAPK/ERK1/2 signalling pathway

Abstract

Because neuroprotection in stroke should be revisited in the era of recanalisation, the present study analysed the potential neuroprotective effect of the selective oestrogen receptor modulator, bazedoxifene acetate (BZA), in an animal model of diabetic ischaemic stroke that mimics thrombectomy combined with adjuvant administration of a putative neuroprotectant. Four weeks after induction of diabetes (40 mg kg -1 streptozotocin, i.p.), male Wistar rats were subjected to transient middle cerebral artery occlusion (intraluminal thread technique, 60 minutes) and assigned to one of three groups treated with either: vehicle, BZA (3 mg kg -1 day -1 , i.p.) or 17β-oestradiol (E 2 ) (100 μg kg -1 day -1 , i.p.). At 24 hours post-ischaemia-reperfusion, brain damage (neurofunctional score, infarct size and apoptosis), expression of oestrogen receptors (ER)α, ERβ and G protein-coupled oestrogen receptor), and activity of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK)1/2 and phosphoinositide 3-kinase/Akt pathways were analysed. At 24 hours after the ischaemic insult, both BZA-and E 2 -treated animals showed lower brain damage in terms of improved neurofunctional condition, decreased infarct size and decreased apoptotic cell death.Ischaemia-reperfusion induced a significant decrease in ERα and ERβ expression without affecting that of G protein-coupled oestrogen receptor, whereas BZA and E 2 reversed such a decrease. The ischaemic insult up-regulated the activity of both the MAPK/ERK1/2 and phosphoinositide 3-kinase/Akt pathways; BZA and E 2 attenuated the increased activity of the ERK1/2 pathway, without affecting that of the Akt pathway. The results of the present study lend further support to the consideration of BZA as an effective and safer alternative overcoming the drawbacks of E 2 with respect to improving diabetic ischaemic stroke outcome after successful reperfusion. K E Y W O R D S 17β-oestradiol, apoptosis, bazedoxifene, diabetes, ischaemic stroke, selective oestrogen receptor modulators How to cite this article: Burguete MC, Jover-Mengual T, López-Morales MA, et al. The selective oestrogen receptor modulator, bazedoxifene, mimics the neuroprotective effect of 17β-oestradiol in diabetic ischaemic stroke by modulating oestrogen receptor expression and the MAPK/ERK1/2 signalling pathway. J Neuroendocrinol. 2019;31:e12751.

The Cerebroprotein Hydrolysate-I Plays a Neuroprotective Effect on Cerebral Ischemic Stroke by Inhibiting MEK/ERK1/2 Signaling Pathway in Rats

“… 4 , 15 Some earlier studies have found that the level of phosphorylated MAPK changes in the brain tissue after stroke, and the phosphorylated MEK activates the downstream kinase ERK1/2, which in turn initiates the downstream pathway to regulate cell growth, differentiation, and other physiological and pathological processes by activating CREB and subsequently modifying BDNF. 12 , 20 , 29 Burguete et al 20 confirmed that ischemia/reperfusion enhanced the activity of the MAPK/ERK1/2 signaling pathway and markedly increased the phosphorylation of ERK1/2. Wang et al 29 and other studies also indicate that the MEK-ERK1/2 pathway could be activated after cerebral ischemia in rats, and by intervening the MEK-ERK1/2 pathway could alleviate the apoptosis and inflammatory reaction of ischemic rats.…”

“…The results of this study showed that pMEK1/2, pERK1/ 2, and pCREB proteins were highly expressed in the ischemic cortex of rats in the model group, which was consistent with previous results. 12,20,29,30 Compared with the sham group, the apoptosis of nerve cells and mNSS increased dramatically, and it prompts that CIRI can activate the MEK-ERK-CREB signaling pathway. After treatment with CH-I, the expression of pMEK1/2, pERK1/2, and pCREB were decreased, and the apoptosis and nerve function injury were alleviated compared with the model group.…”

“…Some evidence has shown that CIRI can activate the MAPK/ERK1/2 signal pathway, and then activate downstream mediators, leading to an inflammatory reaction, apoptosis, and other pathological processes. 20 , 29 MAPK is a group of ubiquitous serine and threonine protein kinases in cells, and its expression level is relatively high in the central nervous system. Rat sarcoma/Rapidly accelerated fibrosarcoma (Ras/Raf)/MEK/ERK is the most classical signaling pathway of MAPK, and under the action of various growth factors and external stimuli, Raf can bind to MEK1/2 and phosphorylate it after Ras activation, which activates MEK1/2 and activated MEK1/2 can transfer phosphoric acid to the threonine and tyrosine residues of downstream kinase ERK1/2 to initiate the downstream ERK1/2 pathway.…”

“… 19 CIRI can activate the MEK/ERK1/2 signaling pathway, which can reduce brain nerve cell death and improve prognosis by inhibiting the MEK/ERK1/2 signaling pathway. 19 , 20 This study sought to investigate whether CH-I could play a neuroprotective effect against CIRI by intervening the MEK/ERK1/2 signaling pathway and downstream CREB pathway.…”

Bazedoxifene, a Selective Estrogen Receptor Modulator, Promotes Functional Recovery in a Spinal Cord Injury Rat Model

“…Furthermore, research has revealed multiple neuroprotective effects of BZA in various central nervous system (CNS) injury models. Specifically, BZA has been shown to reduce ischemic brain damage and apoptosis by modulating the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)1/2 and phosphatidylinositol 3kinase (PI3K)/protein kinase B (AKT) signaling pathways [19,20]. Moreover, BZA has been found to attenuate impaired cognitive function and increased blood-brain barrier (BBB) permeability by modulating inflammation via MAPK pathway suppression in a traumatic brain injury (TBI) model [21].…”