■新的中风患者的绝对数量每年都在增加,并且仍然只有少数食品和药物管理局(FDA)批准的治疗方法对患者有效。丹参酮IIA(TanIIA)是缺血性中风的有希望的潜在治疗剂,在临床前啮齿动物研究中已显示出成功,但在人类患者中导致不一致的疗效结果。Tan-IIA的物理性质,包括短半衰期和低溶解度,提示聚(乳酸-共-乙醇酸)(PLGA)纳米颗粒辅助递送可导致改善生物利用度和治疗功效。这项研究的目的是开发负载TanIIA的纳米颗粒(TanIIA-NP),并评估其对猪缺血性中风模型中脑病理变化和随之而来的运动功能缺陷的治疗作用。
■TanIIA-NP处理的神经干细胞在证明抗氧化作用的体外测定中显示SOD活性降低。与仅用载体处理的猪相比,用TanIIA-NP处理的缺血性中风猪显示出减少的半球肿胀(7.85±1.41vs.16.83±0.62%),随之而来的中线偏移(MLS)(1.72±0.07vs.2.91±0.36mm),和缺血性病变体积(9.54±5.06vs.12.01±0.17cm3),与仅用载体处理的猪相比。治疗还导致扩散率降低(-37.30±3.67vs.-46.33±0.73%)和白质完整性(-19.66±5.58vs.-30.11±1.19%)以及缺血性中风后24小时出血减少(0.85±0.15vs2.91±0.84cm3)。此外,TanIIA-NP导致12岁时循环带中性粒细胞百分比降低(7.75±1.93vs.14.00±1.73%)和卒中后24小时(4.25±0.48vs5.75±0.85%)提示炎症反应减轻。此外,时空步态缺陷,包括节奏,周期时间,步进时间,周期的摆动百分比,步幅长度,与对照猪相比,TanIIA-NP治疗的猪中风后相对平均压力变化较轻。
■这一概念验证研究的结果强烈表明,在卒中后急性期施用TanIIA-NP可能通过限制自由基形成来减轻神经损伤,从而在转化猪缺血性卒中模型中导致不太严重的步态缺陷。中风是美国功能性残疾的主要原因之一,步态缺陷是一个主要组成部分,这些有前景的结果表明,TanIIA-NP急性给药可能改善许多未来卒中患者的功能结局和生活质量.
UNASSIGNED: The absolute number of new stroke patients is annually increasing and there still remains only a few Food and Drug Administration (FDA) approved treatments with significant limitations available to patients. Tanshinone IIA (Tan IIA) is a promising potential therapeutic for ischemic stroke that has shown success in pre-clinical rodent studies but lead to inconsistent efficacy results in human patients. The physical properties of Tan-IIA, including short half-life and low solubility, suggests that Poly (lactic-co-glycolic acid) (PLGA) nanoparticle-assisted delivery may lead to improve bioavailability and therapeutic efficacy. The objective of this study was to develop Tan IIA-loaded nanoparticles (Tan IIA-NPs) and to evaluate their therapeutic effects on cerebral pathological changes and consequent motor function deficits in a pig ischemic stroke model.
UNASSIGNED: Tan IIA-NP treated neural stem cells showed a reduction in SOD activity in in vitro assays demonstrating antioxidative effects. Ischemic stroke pigs treated with Tan IIA-NPs showed reduced hemispheric swelling when compared to vehicle only treated pigs (7.85 ± 1.41 vs. 16.83 ± 0.62%), consequent midline shift (MLS) (1.72 ± 0.07 vs. 2.91 ± 0.36 mm), and ischemic lesion volumes (9.54 ± 5.06 vs. 12.01 ± 0.17 cm3) when compared to vehicle-only treated pigs. Treatment also lead to lower reductions in diffusivity (-37.30 ± 3.67 vs. -46.33 ± 0.73%) and white matter integrity (-19.66 ± 5.58 vs. -30.11 ± 1.19%) as well as reduced hemorrhage (0.85 ± 0.15 vs 2.91 ± 0.84 cm3) 24 h post-ischemic stroke. In addition, Tan IIA-NPs led to a reduced percentage of circulating band neutrophils at 12 (7.75 ± 1.93 vs. 14.00 ± 1.73%) and 24 (4.25 ± 0.48 vs 5.75 ± 0.85%) hours post-stroke suggesting a mitigated inflammatory response. Moreover, spatiotemporal gait deficits including cadence, cycle time, step time, swing percent of cycle, stride length, and changes in relative mean pressure were less severe post-stroke in Tan IIA-NP treated pigs relative to control pigs.
UNASSIGNED: The findings of this proof of concept study strongly suggest that administration of Tan IIA-NPs in the acute phase post-stroke mitigates neural injury likely through limiting free radical formation, thus leading to less severe gait deficits in a translational pig ischemic stroke model. With stroke as one of the leading causes of functional disability in the United States, and gait deficits being a major component, these promising results suggest that acute Tan IIA-NP administration may improve functional outcomes and the quality of life of many future stroke patients.