Abstract
The learning and memory impairment caused by chronic cerebral hypoperfusion (CCH) is permanent and seriously affects the daily life of patients and their families. The compound 3′-daidzein sulfonate sodium (DSS) protects against CCH-mediated memory impairment and hippocampal damage in a rat model. In the present study, we further investigated the underlying mechanisms of this effect in the rat two-vessel occlusion (2VO) and the oxygen and glucose deprivation (OGD) primary hippocampal neuron models. The hippocampal expression of the activity-regulated cytoskeleton associated protein (Arc) following DSS administration was detected in vivo and in vitro and behavioral testing was used to investigate the role of Arc in the DSS-mediated rescue of CCH-induced neurotoxicity. DSS increased hippocampal Arc expression both in vivo and in vitro. Arc overexpression increased and Arc knockdown decreased hippocampal neuronal densities in rat 2VO model, when compared to DSS treatment alone. Arc overexpression decreased and Arc knockdown increased apoptotic hippocampal neurons in rat 2VO and OGD primary hippocampal neuron models, when compared to DSS treatment alone. Arc overexpression enhanced and Arc knockdown inhibited the beneficial effect of DSS on 2VO-induced cognitive impairment. DSS restored the neuronal OGD-mediated phosphorylation decrease in protein kinase alpha (PKA), extracellular signal-regulated protein kinases 1/2 (ERK1/2) and cAMP response element binding protein (CREB), in vitro. PKA and ERK1/2 inhibition blocked the DSS-mediated effects on neuronal apoptosis and OGD-induced Arc downregulation. In conclusion, DSS protects against CCH-mediated cognitive impairment and hippocampal damage via Arc upregulation, which is activated by the PKA/CREB and ERK/CREB signaling pathways. Our study further confirms the potential use of DSS as an effective treatment for CCH-associated diseases.
Highlights
Chronic cerebral hypoperfusion (CCH) can lead to a sustained cerebral blood flow reduction between 25 and 50% for over 6 months
The results indicate that Arc expression was decreased in the 2VO group, when compared to the sham group, while Daidzein sulfonate sodium (DSS) treatment restored Arc downregulation in a dose-dependent manner (Figure 1A)
Western blot analysis of Arc expression revealed a decrease in the oxygen and glucose deprivation (OGD) group, as compared to the cell group, while DSS treatment was able to restore this decrease in Arc expression in a dose-dependent manner (Figure 1B)
Summary
Chronic cerebral hypoperfusion (CCH) can lead to a sustained cerebral blood flow reduction between 25 and 50% for over 6 months. DSS inhibits neuronal apoptosis induced by cerebral ischemiareperfusion (Liu et al, 2017) and DSS treatment provides neuroprotection in a focal cerebral ischemia rat model (Li et al, 2018a) Based on these results we predicted that DSS might play a role in improving impairments of learning and memory caused by CCH. We demonstrated that DSS protects against memory impairment and hippocampal damage caused by permanent carotid artery occlusion in the two-vessel occlusion method (2VO) (Li et al, 2018b) This model is a widely used experimental tool for the investigation of CCH-mediated neuronal damage and cognitive impairment (Ni et al, 1995; Ohta et al, 1997; Farkas et al, 2004). We examine whether DSS regulates neuronal Arc expression through the protein kinase alpha (PKA) or extracellular signalregulated protein kinase (ERK) signaling pathway, as seen in rat pheochromocytoma (PC12) cells (Waltereit et al, 2001; Epstein and Finkbeiner, 2018)
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