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

Zhilin Xiong,Yonghui Xiang,Chi Kwan Tsang,Ling Zeng,Zhen Jing,Wenxian Li,Li’An Huang,Lihui Zhu,Changzheng Shi,Yiwen Ruan,Weibiao Lu

doi:10.3389/fnagi.2017.00238

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.

Highlights

Chronic cerebral hypoperfusion (CCH) occurs in the early stages of senile dementia including Alzheimer’s disease (AD), vascular dementia (VaD) and mixed dementia (Pappas et al, 1996; Yoshikawa et al, 2003; Schuff et al, 2009; Zhao and Gong, 2015), which has been considered to play an important role in neurodegeneration in the development of dementia and AD
NBP treatment protects neurons against neuronal degeneration, reduces apoptosis and glial reactivity and cognitive impairment in chronic cerebral hypoperfusion (CCH) caused by Bilateral common carotid artery occlusion (BCCAO)
We found that NBP was able to significantly elevate cerebral blood flow (CBF) level in the cortex, striatum and hippocampus from an early stage (1 week) and returned it to a normal level at 2 weeks following BCCAO

Summary

Introduction

Chronic cerebral hypoperfusion (CCH) occurs in the early stages of senile dementia including Alzheimer’s disease (AD), vascular dementia (VaD) and mixed dementia (Pappas et al, 1996; Yoshikawa et al, 2003; Schuff et al, 2009; Zhao and Gong, 2015), which has been considered to play an important role in neurodegeneration in the development of dementia and AD. The mechanisms underlying dementia caused by CCH involve neuronal loss (Pappas et al, 1996; Bang et al, 2013), white matter lesion (Tomimoto et al, 2003; Chida et al, 2011), glial activation (Simpson et al, 2007), synaptic dysfunction (Simpson et al, 2007), oxidative stress (Ritchie et al, 2004; Kašparová et al, 2005), accumulation of Aβ (Li et al, 2009b; Okamoto et al, 2012) and aggravation of progressive cognitive deficits (de la Torre, 2012; Choi et al, 2015).

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Conclusion