L-3-n-butylphthalide protects against vascular dementiaviaactivation of the Akt kinase pathway**

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Abstract

Research Highlights

(1) 3-N-butylphthalide, a green botanical medicine, is a successfully synthesized and stable chemical drug used for the treatment of ischemic stroke that has independent intellectual property rights in China. Three different stereo-isomers have been identified: l-, dl-, and d-3-n-butylphthalide. The first L-isomer, originally extracted from celery seed, was artificially synthesized from racemic acid, also known as butylphthalide. L-3-n-butylphthalide has been shown to reduce β-amylase-induced neuronal apoptosis and improve cognitive function in Alzheimer's disease animal models.

Research Highlights

(2) As a neuroprotective drug for cerebrovascular disease, 3-n-butylphthalide has been confirmed to protect nerve cells in animal experiments of stroke. Because of the significant effects of l-3-n-butylphthalide in the clinical treatment of acute ischemic stroke, this study also adopted l-3-n-butylphthalide for the treatment of vascular dementia.

Research Highlights

(3) This is the first report that shows pretreatment with l-3-n-butylphthalide can improve cognitive deficits and neuronal loss in the hippocampus of cerebral repetitive ischemia/reperfusion mice.

Research Highlights

(4) L-3-n-butylphthalide may be a potentially beneficial and promising drug for the treatment and prevention of vascular dementia through upregulation of Akt expression in the hippocampus.

As a neuroprotective drug for the treatment of ischemic stroke, 3-n-butylphthalide, a celery seed extract, has been approved by the State Food and Drug Administration of China as a clinical therapeutic drug for ischemic stroke patients. L-3-n-butylphthalide possesses significant efficacy in the treatment of acute ischemic stroke. The activated Akt kinase pathway can prevent the death of nerve cells and exhibit neuroprotective effects in the brain after stroke. This study provides the hypothesis that l-3-n-butylphthalide has a certain therapeutic effect on vascular dementia, and its mechanism depends on the activation of the Akt kinase pathway. A vascular dementia mouse model was established by cerebral repetitive ischemia/reperfusion, and intragastrically administered l-3-n-butylphthalide daily for 28 consecutive days after ischemia/reperfusion, or 7 consecutive days before ischemia/reperfusion. The Morris water maze test showed significant impairment of spatial learning and memory at 4 weeks after operation, but intragastric administration of l-3-n-butylphthalide, especially pretreatment with l-3-n-butylphthalide, significantly reversed these changes. Thionine staining and western blot analylsis showed that preventive and therapeutic application of l-3-n-butylphthalide can reduce loss of pyramidal neurons in the hippocampal CA1 region and alleviate nerve damage in mice with vascular dementia. In addition, phosphorylated Akt expression in hippocampal tissue increased significantly after l-3-n- butylphthalide treatment. Experimental findings demonstrate that l-3-n-butylphthalide has preventive and therapeutic effects on vascular dementia, and its mechanism may be mediated by upregulation of phosphorylated Akt in the hippocampus.

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