Department of Neurology, Duke University, Durham, NC, USA.
Department of Orthopaedic Surgery, Duke University, Durham, NC, USA.
Neurocrit Care. 2021 Oct;35(2):441-450. doi: 10.1007/s12028-020-01184-y. Epub 2021 Jan 21.
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.
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.
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).
Acute treatment with CN-105 improves outcomes in translational ICH models independent of sex, species, age, or hypertensive comorbidity.
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。
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。
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）。
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。
