Abstract
Hippocampal neuron death is a key factor in vascular dementia (VD) induced by chronic cerebral hypoperfusion (CCH). Dl-3-n-butylphthalide (NBP) is a multiple-effects drug. Therefore, the potential molecular mechanisms underlying CCH and its feasible treatment should be investigated. This study had two main purposes: first, to identify a potential biomarker in a rat model of CCH induced VD using antibody microarrays; and second, to explore the neuroprotective role of NBP at targeting the potential biomarker. Glial cell line-derived neurotrophic factor (GDNF)/GDNF family receptor alpha-1 (GFRα1)/receptor tyrosine kinase (Ret) signaling is altered in the hippocampus of CCH rats; however, NBP treatment improved cognitive function, protected against hippocampal neuron apoptosis via regulation of GDNF/GFRα1/Ret, and activated the phosphorylation AKT (p-AKT) and ERK1/2 (p-ERK1/2) signaling. We also found that 1 h oxygen-glucose deprivation (OGD) followed by 48 h reperfusion (R) in cultured hippocampal neurons led to downregulation of GDNF/GFRα1/Ret. NBP upregulated the signaling and increased neuronal survival. Ret inhibitor (NVP-AST487) inhibits Ret and downstream effectors, including p-AKT and p-ERK1/2. Additionally, both GDNF and GFRα1 expression are markedly inhibited in hippocampal neurons by coincubation with NVP-AST487, particularly under conditions of OGD/R. GDNF/GFRα1/Ret signaling and neuronal viability can be maintained by NBP, which activates p-AKT and p-ERK1/2, increases expression of Bcl-2, and decreases expression of Bax and cleaved caspase-3. The current study showed that GDNF/GFRα1/Ret signaling plays an essential role in the CCH induced VD. NBP was protective against hippocampal neuron apoptosis, and this was associated with regulation of GDNF/GFRα1/Ret and AKT/ERK1/2 signaling pathways, thus reducing cognitive impairment.
Highlights
Vascular dementia is widely recognized as the second most common type of dementia
The cortex in the chronic cerebral hypoperfusion (CCH)-treated (BCCAO 8w) rats had lower cerebral blood flow (CBF) at 8th week after bilateral common carotid artery occlusion (BCCAO), while the cortex in NBP-treated rats showed recovery of CBF [Left cortex: CBF decreased to 70.18% ± 15.25 in the CCH-treated group, compared to preBCCAO (P < 0.01); CBF was increased to 96.49% ± 10.67 in the NBP-treated group compared BCCAO 8w (P < 0.01)
Right cortex: CBF decreased to 67.48% ± 19.19 in the CCH-treated compared with pre-BCCAO (P < 0.01); CBF was increased to 90.69 ± 11.64% in the NBP-treated group compared to BCCAO 8w (P < 0.05)] (Figure 1D)
Summary
Vascular dementia is widely recognized as the second most common type of dementia. VD is primarily related to diverse cerebrovascular diseases, such as CCH (Du et al, 2017; Duncombe et al, 2017; Yin et al, 2018). CCH is induced by chronic, moderate and persistent deficit of CBF, increasing evidence from laboratorial and clinical researches has indicated CCH is a robustly common factor in pathogenesis of cerebrovascular diseases and neurodegenerative disorders, results in the development and progression of cognitive impairment, such as VD (Du et al, 2017). The vascular hypothesis suggests that moderate and persistent cerebral hypoperfusion leads to vasculotoxic and neurotoxic effects due to diminished CBF and prolonged hypoxia, which promotes neurodegeneration and cognitive impairment (Raz et al, 2016). There is uncertainty regarding the exact time of clinical occurrence in hypoperfusion, the irreversibility of neuron damage after reperfusion; understanding the molecular mechanisms underlying hippocampal neuron death in CCH would be more invaluable for the development of new therapeutic approaches to alleviate vascular cognitive impairment
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