神经保护五肽 CN-105 改善脑出血转化模型的预后。
Neuroprotective Pentapeptide, CN-105, Improves Outcomes in Translational Models of Intracerebral Hemorrhage.
机构信息
Department of Neurology, Duke University, Durham, NC, USA.
Department of Orthopaedic Surgery, Duke University, Durham, NC, USA.
出版信息
Neurocrit Care. 2021 Oct;35(2):441-450. doi: 10.1007/s12028-020-01184-y. Epub 2021 Jan 21.
BACKGROUND
Intracerebral hemorrhage (ICH) is a devastating form of cerebrovascular disease for which there are no approved pharmacological interventions that improve outcomes. Apolipoprotein E (apoE) has emerged as a promising therapeutic target given its isoform-specific neuroprotective properties and ability to modify neuroinflammatory responses. We developed a 5-amino acid peptide, CN-105, that mimics the polar face of the apoE helical domain involved in receptor interactions, readily crosses the blood-brain barrier, and improves outcomes in well-established preclinical ICH models. In the current study, we investigated the therapeutic potential of CN-105 in translational ICH models that account for hypertensive comorbidity, sex, species, and age.
METHODS
In three separate experiments, we delivered three intravenous doses of CN-105 (up to 0.20 mg/kg) or vehicle to hypertensive male BPH/2 J mice, spontaneously hypertensive female rats, or 11-month-old male mice within 24-h of ICH. Neuropathological and neurobehavioral outcomes were determined over 3, 7, and 9 days, respectively.
RESULTS
In spontaneously hypertensive male mice, there was a significant dose-dependent effect of CN-105 on vestibulomotor function at 0.05 and 0.20 mg/kg doses (p < 0.05; 95% CI: 0.91-153.70 and p < 0.001; 95% CI: 49.54-205.62), while 0.20 mg/kg also improved neuroseverity scores (p < 0.05; 95% CI: 0.27-11.00) and reduced ipsilateral brain edema (p < 0.05; 95% CI: - 0.037 to - 0.001). In spontaneously hypertensive female rats, CN-105 (0.05 mg/kg) had a significant effect on vestibulomotor function (p < 0.01; η = 0.093) and neuroseverity scores (p < 0.05; η = 0.083), and reduced contralateral edema expansion (p < 0.01; 95% CI: - 1.41 to - 0.39). In 11-month-old male mice, CN-105 had a significant effect on vestibulomotor function (p < 0.001; η = 0.111) but not neuroseverity scores (p > 0.05; η = 0.034).
CONCLUSIONS
Acute treatment with CN-105 improves outcomes in translational ICH models independent of sex, species, age, or hypertensive comorbidity.
背景
脑出血（ICH）是一种破坏性的脑血管疾病，目前尚无批准的药物干预措施可以改善其预后。载脂蛋白 E（apoE）因其异构体特异性的神经保护特性和调节神经炎症反应的能力，已成为一个很有前途的治疗靶点。我们开发了一种 5 个氨基酸的肽 CN-105，它模拟了 apoE 螺旋结构域中与受体相互作用的极性表面，能够轻易穿透血脑屏障，并改善既定的脑出血动物模型中的预后。在本研究中，我们研究了 CN-105 在考虑高血压合并症、性别、物种和年龄的转化性脑出血模型中的治疗潜力。
方法
在三个独立的实验中，我们在脑出血后 24 小时内，对高血压雄性 BPH/2J 小鼠、自发性高血压雌性大鼠或 11 月龄雄性小鼠，分别给予三种不同剂量的 CN-105（最高 0.20mg/kg）或载体。分别在 3、7 和 9 天检测神经病理学和神经行为学的结果。
结果
在自发性高血压雄性小鼠中，CN-105 在 0.05 和 0.20mg/kg 剂量下对前庭运动功能有显著的剂量依赖性影响（p<0.05；95%CI：0.91-153.70 和 p<0.001；95%CI：49.54-205.62），而 0.20mg/kg 剂量还能改善神经严重程度评分（p<0.05；95%CI：0.27-11.00）和减少同侧脑水肿（p<0.05；95%CI：-0.037 至-0.001）。在自发性高血压雌性大鼠中，CN-105（0.05mg/kg）对前庭运动功能（p<0.01；η=0.093）和神经严重程度评分（p<0.05；η=0.083）有显著影响，并减少了对侧脑水肿的扩张（p<0.01；95%CI：-1.41 至-0.39）。在 11 月龄雄性小鼠中，CN-105 对前庭运动功能有显著影响（p<0.001；η=0.111），但对神经严重程度评分没有影响（p>0.05；η=0.034）。
结论
急性给予 CN-105 治疗可改善转化性脑出血模型的预后，与性别、物种、年龄或高血压合并症无关。
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