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.
Highlights
Recent evidence indicates that collateral circulation is critical for the outcome of ischemic stroke
In cultured vascular endothelial progenitor cells derived from mouse iPSCs, immunocytochemical staining revealed that NBP (10 μM) exposure for 48 hrs significantly increased the expression of newly formed vascular marker PDGFRα [39], while the phosphorylated VEGFR2 (p-VEGFR2) remained the same (Fig. 1A - 1D)
The present investigation demonstrates that NBP treatment after ischemic stroke increases the expression of several regenerative factors and arteriogenesis in ischemic and peri-infarct regions, helping to restore local cerebral blood flow (LCBF) and functional activity in stroke mice
Summary
Recent evidence indicates that collateral circulation is critical for the outcome of ischemic stroke. 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. A clinical study shows that the level of circulating CD34/prominin-1(CD133)/ VEGFR-2-triple positive vascular endothelial progenitor cells are significantly increased in stroke patients receiving NBP treatment compared with controls [18]. These patients have improved NIHSS score on poststroke Day 90. NBP could promote post-stroke arteriogenesis including collateral arteries as a underlying mechanism for its protective and regenerative effects
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