A Review of Recent Advances in Neuroprotective Potential of 3-N-Butylphthalide and Its Derivatives

Abstract

The research of alternative treatment for ischemic stroke and degenerative diseases has always been a priority in neurology. 3-N-Butylphthalide (NBP), a family of compounds initially isolated from the seeds of Apium graveolens Linn., has shown significant neuroprotective effects. Previous extensive studies have demonstrated that NBP promotes a better poststroke outcome and exerts a multitargeted action on several mechanisms, from oxidative stress to mitochondrial dysfunction to apoptosis to inflammation. Additionally, recent findings on several neurological disorders have shown that NBP's beneficial effects extend beyond the management of stroke. However, despite the increasing number of studies toward a better understanding and the rapid advances made in therapeutic options, to date, dl-3-N-butylphthalide, a synthetic variation of l-3-N-butylphthalide, remains the only clinically approved anti-ischemic agent in China, stressing the difficulties for a viable and effective transition from experimental to clinical practice. Events indicate that NBP, due to its multitargeted effect and the adaptability of its basic structure, can be an important game changer and a precursor to a whole new therapeutic approach to several neurological conditions. The present review discusses recent advances pertaining to the neuroprotective mechanisms of NBP-derived compounds and the possibility of their clinical implementation in the management of various neurological conditions.

Dl‐3‐N‐butylphthalide promotes angiogenesis and upregulates sonic hedgehog expression after cerebral ischemia in rats

“…A strength of NBP in the promotion of angiogenesis appears to be targeting multiple elements, which is better than other treatments. 13 Our results supported the notion that NBP promoted angiogenesis after ischemic stroke be- angiogenesis. 51 In addition, Shh promotes the neovascularization of ischemic tissues by promoting angiogenesis when administered either as a recombinant protein or via gene therapy.…”

“…The beneficial effect of NBP is attributed to its anti-inflammatory, anti-apoptotic, antioxidant, pro-mitochondrial function, and pro-neurogenesis properties, etc. 9,[11][12][13] Previous studies found that NBP could protect the brain microvascular endothelial cells against oxygen-glucose deprivation (OGD) through increasing HIF-1α and Bcl-2 expression. NBP could also promote angiogenesis through the increased expression of angiogenic growth factors.…”

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

“…dl ‐3‐n‐butylphthalide (Figure ) is derived from l ‐3‐n‐butylphthalide which is initially extracted from seeds of Chinese celery, Aplumgraveolens . dl ‐3‐n‐butylphthalide was approved by the State Food and Drug Administration of China for treatment for patients with acute ischemic stroke in 2002 . 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 .…”

The novel targets of DL-3-n-butylphthalide predicted by similarity ensemble approach in combination with molecular docking study

“…Since it was approved in 2002, NBP has only been used for treating acute ischemic stroke. Recently, studies also show that NBP has a therapeutic effect on various neurodegenerative diseases, especially vascular dementia and vascular cognitive impairment without dementia (1). In animal experiments, including our own investigations, NBP may reduce cerebral edema, decrease cerebral infarct volume, improve cerebral microcirculation, protect vascular endothelial cells, scavenge free radicals, protect mitochondria, reduce inflammation, inhibit neuronal apoptosis, counteract platelet aggregation, inhibit thrombosis and decrease the expression of β-amyloid protein and tau protein in the brain (1)(2)(3).…”