Endoplasmic reticulum stress (ERS) is known to be an essential target in protecting against ischaemic brain injury. In this study, using a vascular dementia (VaD) animal model induced by bilateral common carotid artery occlusion (BCCAO), we evaluated the effect and mechanism of 17β-oestradiol (E2) against VaD by inhibiting ERS at the early stage (14 d, 21 d, 28 d) and late stage (3 m) after BCCAO in the hippocampal CA1 region of ovariectomized rats. The results showed that the activation of the PERK-eIF2α-ATF4-CHOP axis, a typical ERS pathway, was significantly increased at the early and late stages after BCCAO. JNK (c-Jun N-terminal kinase)-cJun, a pro-death pathway, also displayed the same pattern as the ERS axis. E2 treatment profoundly suppressed the impairments caused by BCCAO. Further mechanistic studies revealed that cerebral blood flow (CBF) was sharply decreased at 14 d and returned to the normal level at 21 d after BCCAO. E2 could not change CBF, while it unexpectedly enhanced the ability to carry oxygen. This is evidenced by the fact that the protein expression of haemoglobin α/β (Hα/β), an oxygen carrier, robustly increased at BCCAO 21 d and 3 m after E2 treatment. The oxygen carrier increased strongly after 21 d and 3 m of BCCAO treated with E2. Moreover, E2 correspondingly enhanced the protein expression of hypoxia-inducible factor 1α (HIF 1α) in both the early and late stage after BCCAO in the hippocampal CA1 region. Finally, E2 administration markedly decreased the activities of caspase-8, caspase-3, and caspase-12 and increased the number of NeuN-positive cells. These findings suggest that E2 serves as a neuroprotectant to alleviate VaD by suppressing ERS injury involving the haemoglobin/HIF 1α signalling pathway.
Keywords: 17β-oestradiol; Chronic cerebral hypoperfusion; Endoplasmic reticulum stress; Haemoglobin; Hypoxia-inducible factor 1α.
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