Effect of Methylene Blue and PI3K-Akt Pathway Inhibitors on the Neurovascular System after Chronic Cerebral Hypoperfusio
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Effect of Methylene Blue and PI3K-Akt Pathway Inhibitors on the Neurovascular System after Chronic Cerebral Hypoperfusion in Rats Yunxia Li 1
&
Xin Wang 1 & Meng Liu 1 & Wei Zhang 1 & Renren Li 1 & Zhiyu Nie 1
Received: 19 February 2019 / Accepted: 23 April 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Methylene blue (MB) has a protective effect on cognitive decline caused by chronic hypoperfusion, but the specific mechanism is not clear. This article aims to determine whether MB protects vascular neurons through PI3K/Akt and plays a role in improving cognitive impairment. Molecular biological methods, the hippocampal neuronal density test, the hippocampal vascular network density test, and dynamic enhanced magnetic resonance imaging (MRI) were used to detect the blood–brain barrier permeability and Evans blue leakage rate in the hippocampus. We also observed and evaluated the changes in the above results after administration of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway protein inhibitor LY294002. There were significant differences for cerebral blood flow (CBF) between the chronic cerebral hypoperfusion (CCH) + MB group (100 ml/100 g/min) and the CCH group (60 ml/100 g/min, P < 0.05). After using LY294002, the CBF of the CCH + MB + LY294002 group dropped to 82 ml/100 g/min. The vascular density in the CCH + MB group was 23%, which is significantly higher than that in the CCH group (15.1%) (P < 0.05). The vascular density (17.5%) in the CCH + MB + LY294002 group was significantly higher than that in the CCH group but lower than that in the CCH + MB group. Western blotting results showed that one week after intraperitoneal injection of MB, the expression of t-Akt and p-Akt in the CCH + MB group was increased after CCH, and LY294002 partially blocked this up-regulation effect (CCH + MB + LY294002 group). MB is a potential therapy for the relief of mild cognitive impairment associated with CCH, vascular dementia, and Alzheimer’s disease. Keywords Methylene blue . PI3K-Akt pathway . LY294002 . Chronic cerebral hypoperfusion
Introduction Chronic cerebral hypoperfusion (CCH) leads to vascular dementia (VaD) and Alzheimer’s disease (AD), both featuring cognitive impairment. In the brain, it causes mild long-term spatial memory impairment and significant short-term memory deficits in addition to dysregulated synaptic proteins, selective neurodegeneration, and insulin signaling [Zhao et al. 2014; Auchter et al. 2014). Vascular injuryand cognitive impairment are receiving enhanced attention as potentially modifiable factors for * Yunxia Li [email protected] * Zhiyu Nie [email protected] 1
Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai 200065, People’s Republic of China
dementias in later life. Because an alternative electron carrier enhances brain metabolism, methylene blue (MB) showed neuroprotection and brain injury protection. Chen et al. confirmed that neuroprotective effec
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