DL-3-n-butylphthalide Increases Collateriogenesis and Functional Recovery after Focal Ischemic Stroke in Mice

Abstract

Recent evidence indicates that collateral circulation is critical for the outcome of ischemic stroke. DL-3-n-butylphthalide (NBP), a synthesized compound based on an extract from seeds of celery Apium graveolens Linn , has been used as a therapeutic drug, showing multiple neuroprotective and regenerative activities. A potential effect of NBP on collateral arterial regulation is unknown. We examined the effects of NBP on arteriogenesis of collateral arteries in vitro and a mouse ischemic stroke model. In cultures of mouse iPS cell-derived vascular progenitors, NBP (10 μM) significantly increased α-smooth muscle actin (αSMA)/CD-31 co-labeled cells and the expression of newly formed vasculature marker PDGFRα. A sensorimotor cortex ischemia was induced in transgenic mice expressing αSMA-GFP that allowed direct observation of arterial vasculatures in brain regions. NBP (80 mg/kg) was intranasally delivered 1 hr after stroke and once daily for 14 days. To label proliferating cells, 5-Bromo-2’-deoxyuridine (BrdU, 50 mg/kg, i.p.) was administrated every day from 3 days after stroke. Western blotting of peri-infarct tissue detected increased expressions of VEGF, Ang-1 and reduced nNOS level in NBP-treated mice. The NBP treatment significantly increased αSMA/BrdU co-labeled cells, the diameter of ipsilateral collaterals, and arterial area in ischemic and peri-infarct regions examined 14 days after stroke. Examined 3 days after stroke, NBP prevented functional deficits in the cylinder test and corner test. The NBP treatment of 14 days improved the local cerebral blood flow (LCBF) and functional performance in multiple tests. Thus, NBP promotes collateriogenesis, short and long-term structural and functional improvements after ischemic stroke.

Neuroprotective effect of Dl-3-n-butylphthalide against ischemia–reperfusion injury is mediated by ferroptosis regulation via the SLC7A11/GSH/GPX4 pathway and the attenuation of blood–brain barrier disruption

“…The results showed that the medium-dose DL-NBP alleviated MCAO-induced neurologic deficits, brain water content, and infarction area and improved nerve function and ischemic brain injury compared to the MCAO group. Previous research not only reached the same conclusion Wei et al, 2021) but also proved that BBB destruction could increase tissue swelling and lead to brain damage (Song et al, 2022). These three studies confirm the successful establishment of a model of hypoxic-ischemic brain injury but also serve as a reminder of the damage to the BBB in this injury, which has also been mentioned in other articles (Zhu et al, 2021).…”

“…The primary clinical treatment for ischemic stroke involves thrombolytic drugs, antiplatelet aggregation drugs, and anticoagulants. However, thrombolytic therapy must be carried out within a limited treatment window, dramatically limiting its clinical application (Derek Barthels, 2020;Wei et al, 2021).…”

Dl-3-n-Butylphthalide Rescues Dopaminergic Neurons in Parkinson’s Disease Models by Inhibiting the NLRP3 Inflammasome and Ameliorating Mitochondrial Impairment

“…Drug concentrations were chosen based on previous reports. Some previous studies give us a clue on employing the experimental concentration of NBP ( 43 , 47 ). Combined with our pilot study, 50 mg/kg (low) and 100 mg/kg (high), the two comprehensive considerations were applied in the present study.…”

DL-3-n-butylphthalide for acute ischemic stroke: An updated systematic review and meta-analysis of randomized controlled trials

“…NBP downregulates AQP4 and matrix metalloprotease-9 (Mamtilahun et al, 2021), which may help explain how it protects the blood-brain barrier in the acute phase of ischemic stroke (Hu et al, 2014;Feng et al, 2018;Li et al, 2019b). NBP can promote collateriogenesis, neurogenesis, and angiogenesis; increase axonal growth; and strengthen white matter integrity (Yang et al, 2015;Sun et al, 2017;Zhou et al, 2019;Wang et al, 2020c;Liu et al, 2021b;Qu et al, 2021;Wei et al, 2021). NBP can accelerate the recovery of cerebral blood flow and reduce cognitive impairment (Xiong et al, 2017;Li et al, 2019c).…”