부산대학교 도서관

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 [micro]M) significantly increased [alpha]-smooth muscle actin ([alpha]SMA)/CD-31 co-labeled cells and the expression of newly formed vasculature marker PDGFR[alpha]. A sensorimotor cortex ischemia was induced in transgenic mice expressing [alpha]SMA-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 [alpha]SMA/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. Key words: ischemic stroke, DL-3-n-butylphthalide, arteriogenesis, collateral artery, regeneration, functional recovery
Stroke is a leading cause of human death and disability including long-term functional deficits [1]. Clinical treatments to promote cell survival for ischemic stroke have been limited to thrombolytic therapy [...]