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Dl-3-n-Butylphthalide Treatment Enhances Hemodynamics and Ameliorates Memory Deficits in Rats with Chronic Cerebral Hypoperfusion.

ABSTRACT: Our previous study has revealed that chronic cerebral hypoperfusion (CCH) activates a compensatory vascular mechanism attempting to maintain an optimal cerebral blood flow (CBF). However, this compensation fails to prevent neuronal death and cognitive impairment because neurons die prior to the restoration of normal CBF. Therefore, pharmacological invention may be critical to enhance the CBF for reducing neurodegeneration and memory deficit. Dl-3-n-butylphthalide (NBP) is a compound isolated from the seeds of Chinese celery and has been proven to be able to prevent neuronal loss, reduce inflammation and ameliorate memory deficits in acute ischemic animal models and stroke patients. In the present study, we used magnetic resonance imaging (MRI) techniques, immunohistochemistry and Morris water maze (MWM) to investigate whether NBP can accelerate CBF recovery, reduce neuronal death and improve cognitive deficits in CCH rats after permanent bilateral common carotid artery occlusion (BCCAO). Rats were intravenously injected with NBP (5 mg/kg) daily for 14 days beginning the first day after BCCAO. The results showed that NBP shortened recovery time of CBF to pre-occlusion levels at 2 weeks following BCCAO, compared to 4 weeks in the vehicle group, and enhanced hemodynamic compensation through dilation of the vertebral arteries (VAs) and increase in angiogenesis. NBP treatment also markedly reduced reactive astrogliosis and cell apoptosis and protected hippocampal neurons against ischemic injury. The escape latency of CCH rats in the MWM was also reduced in response to NBP treatment. These findings demonstrate that NBP can accelerate the recovery of CBF and improve cognitive function in a rat model of CCH, suggesting that NBP is a promising therapy for CCH patients or vascular dementia.

SUBMITTER: Xiong Z

PROVIDER: S-EPMC5526838 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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Project description:BackgroundThis study sought to explore the mechanism underlying the therapeutic effects of electroacupuncture (EA) on spatial memory deficits caused by surgery.MethodsHepatic apex resection was performed under propofol-based total intravenous anesthesia. Male Sprague-Dawley rats were subjected to EA treatment or EA + mitochondrial division inhibitor-1 (mdivi-1) treatment once a day for three consecutive days after surgery. The Morris water maze test was used to evaluate the spatial memory of the rats after surgery. Tissue from the hippocampus of each rat was frozen and used for transcriptomic and proteomic analyses to identify potential targets for EA treatment. Western blotting was used to confirm the protein expression levels. The levels of reactive oxygen species (ROS) and adenosine triphosphate (ATP) were detected using commercial kits. The rat mitochondria were then isolated, and the activity of mitochondrial complex V was assessed.ResultsEA attenuated surgery-induced spatial memory deficits on postoperative day 3, while these effects were reversed by treatment with the mdivi-1 (P<0.05). Ribonucleic acid (RNA)-sequencing revealed that EA upregulated multiple metabolic pathways and the phosphatidylinositol 3‑kinas/protein kinase B signaling pathway. The proteomic and western blotting results suggested that the EA treatment substantially downregulated coiled-coil-helix-coiled-coil-helix domain containing 3 (ChChd3) expression in the hippocampus. The EA treatment significantly increased the autophagy-related protein levels, including phosphatase and tensin homolog-induced kinase 1, Parkin, MAP1LC3 (LC3), and Beclin1, and inhibited the production of ROS and inflammatory cytokine interleukin-1β in the hippocampus (P<0.05).ConclusionsThese results suggest that EA ameliorates postoperative spatial memory deficits and protects hippocampus from oxidative stress and inflammation through enhanced autophagy in an animal model of perioperative neurocognitive disorders (PNDs).

Dataset Information

Dl-3-n-Butylphthalide Treatment Enhances Hemodynamics and Ameliorates Memory Deficits in Rats with Chronic Cerebral Hypoperfusion.

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