Dl-3-n-butylphthalide regulates cholinergic dysfunction in chronic cerebral hypoperfusion rats

Abstract

<jats:sec><jats:title>Objectives</jats:title><jats:p> To investigate whether dl-3-n-butylphthalide (NBP) affects cholinergic system function and ameliorates cognitive decline in a rat model of vascular dementia (VaD). </jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p> The VaD rat model was established by bilateral common carotid artery ligation (two-vessel occlusion, 2VO). Rats were divided into five groups: control, sham, 2VO, 2VO+NBP (80 mg/kg; intragastric), and 2VO+donepezil (1 mg/kg; intragastric). Treatments were administered once daily for 2 weeks from day 21 post-surgery. Spatial learning and memory were evaluated by Morris water maze performance. Hippocampal choline acetyltransferase (ChAT), acetylcholinesterase (AChE), vesicular acetylcholine transporter (VAChT), vascular endothelial growth factor (VEGF), and brain-derived neurotrophic factor (BDNF) expressions were detected using immunohistochemistry, immunofluorescence, and real-time polymerase chain reaction methods. </jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p> The daily escape latency was significantly longer in 2VO rats than in the sham or control groups, while the time spent in the target quadrant was significantly shorter. The daily escape latency of the 2VO+NBP group was significantly shorter compared with the 2VO group. Following NBP treatment, ChAT, AChE, VAChT, and BDNF expressions were significantly upregulated in the hippocampus. </jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p> Central cholinergic dysfunction may be involved in VaD pathogenesis. NBP treatment significantly improved spatial learning and memory in VaD rats, and may enhance cholinergic system function via BDNF-mediated neuroprotection. </jats:p></jats:sec>

The Mechanisms of Cucurbitacin E as a Neuroprotective and Memory-Enhancing Agent in a Cerebral Hypoperfusion Rat Model: Attenuation of Oxidative Stress, Inflammation, and Excitotoxicity

“…Acetylcholine plays an important part in regulating biological rhythms (e.g., wakefulness, sleep), stress response, inflammatory response, and vascular tone (Jin et al, 2015). In line with earlier findings (Sun et al, 2020), in this study, CH increased the AChE activity that might adversely affect the acetylcholine levels in the brain. Following the energy depletion and ionic imbalance, accumulation of glutamate in synapse depolarizes the postsynaptic membrane, triggers Ca 2+ influx and nitric oxide release that establishes a vicious cycle of Ca 2+dependent catabolic (proteolytic) mechanisms (Belov Kirdajova et al, 2020).…”

Efficacy and Safety of DL-3-n-Butylphthalide in the Treatment of Poststroke Cognitive Impairment: A Systematic Review and Meta-Analysis

“…DL-3-n-butylphthalide (NBP) is a new drug developed independently in China that acts on multiple pathological links of acute ischemic stroke ( Wang et al, 2018 ). In addition to promoting the recovery of cognitive function after stroke, recent clinical studies have demonstrated that NBP can improve the oxidative stress response of the nervous system ( Lv et al, 2018 ), inhibit neuronal apoptosis and autophagy ( Xu J et al, 2017 ), regulate central cholinergic function ( Zhao et al, 2014 ; Sun et al, 2020 ) and promote neuroplasticity ( Yang et al, 2015 ). A randomized controlled study involving 281 patients with subcortical nondementia VCI also showed that 6 months of NBP treatment effectively improved the cognitive and overall function of patients ( Jia et al, 2016 ).…”

Brain-Derived Neurotrophic Factor Signaling in the Pathophysiology of Alzheimer’s Disease: Beneficial Effects of Flavonoids for Neuroprotection

“…Recently, the effect of dl-3-n-butylphthalide (NBP) on hippocampal expression levels of ChAT, acetylcholinesterase (AChE), vesicular acetylcholine transporter (VAChT), and the BDNF was examined. A rat model of vascular dementia established by bilateral common carotid artery ligation exhibited decreased spatial learning and memory evaluated with a Morris water maze test, although administration of NBP reversed the decreased learning and memory function [ 66 ]. NBP treatment also increased ChAT, AChE, VAChT, and BDNF expressions, suggesting that central cholinergic dysfunction is involved in vascular dementia pathogenesis and NBP is effective to protect the cholinergic system via activating the BDNF signaling [ 66 ].…”

“…A rat model of vascular dementia established by bilateral common carotid artery ligation exhibited decreased spatial learning and memory evaluated with a Morris water maze test, although administration of NBP reversed the decreased learning and memory function [ 66 ]. NBP treatment also increased ChAT, AChE, VAChT, and BDNF expressions, suggesting that central cholinergic dysfunction is involved in vascular dementia pathogenesis and NBP is effective to protect the cholinergic system via activating the BDNF signaling [ 66 ]. Interestingly, the influence of focused ultrasound (FUS)-mediated blood–brain barrier opening in the cholinergic degeneration rat model was reported [ 67 ].…”