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.

dl‐3‐n‐butylphthalide preserves white matter integrity and alleviates cognitive impairment in mice with chronic cerebral hypoperfusion

“…Production of pro‐inflammatory cytokines like TNFα and IL‐6 was also decreased in LPS‐treated astrocytes in vitro by NBP. Consistent with our results, NBP has been demonstrated to inhibit neuroinflammation in several neurological diseases, including ischemic stroke, multiple sclerosis, AD, and vascular dementia . NBP administration inhibited reactive astrogliosis and ameliorated cognitive deficits in rats with VCI due to chronic cerebral hypoperfusion induced by bilateral common carotid artery occlusion .…”

“…Studies have demonstrated that NBP exerts multi‐target protective effects against ischemic stroke, including reducing oxidative stress, inhibiting inflammatory responses, alleviating neuronal apoptosis, ameliorating BBB damage, and increasing regional blood flow . Moreover, emerging evidence indicates that NBP also have beneficial effects on cognitive function of Alzheimer's Disease (AD) and vascular dementia, through regulating endoplasmic stress, reducing neuronal apoptosis, and glial reactivity …”

Effects of dl‐3‐n‐butylphthalide on serum lipoprotein‐associated phospholipase A2 and hypersensitive C‐reactive protein levels in acute cerebral infarction

“…Dl‐3‐n‐butylphthalide is a drug developed independently for the treatment of ischemic stroke in China, which is an effective component obtained from celery seeds (Tian, Wang, Wang, Zhang, & Zhou, ; Xiong et al, ), and it can be artificially synthesized. Some Chinese scholars (Wang, Ma, et al, ) have summarized the research progress of NBP in the treatment of ischemic stroke in the past 20 years, and it was considered as a promising drug for ischemic stroke.…”

“…Dl-3-n-butylphthalide is a drug developed independently for the treatment of ischemic stroke in China, which is an effective component obtained from celery seeds (Tian, Wang, Wang, Zhang, & Zhou, 2017;Xiong et al, 2017), and it can be artificially synthesized.…”

Dl‐3n‐butylphthalide improves traumatic brain injury recovery via inhibiting autophagy‐induced blood‐brain barrier disruption and cell apoptosis

“…Beclin1 plays an important role in this network interaction. 41 Our previous studies have reported that rats treated with Dl-NBP improved locomotor recovery after SCI by inhibiting ER stress-induced apoptosis, which lasts 28 days. 40 Traumatic brain injury causes activation of mitochondrial apoptosis.…”