Biomedical Research Foundation, Hospital Clínico San Carlos - IdISSC, Madrid, 28040, Spain.
Vivacell Biotechnology España S.L.U., Córdoba, Spain.
Eur J Pharmacol. 2024 Jun 5;972:176554. doi: 10.1016/j.ejphar.2024.176554. Epub 2024 Apr 4.
Currently there is no effective treatment for neonatal stroke, an acute neurologic syndrome with sequelae, due to focal ischemic, thrombotic, or hemorrhagic event occurring in the perinatal period. VCE-004.8, an aminoquinone exhibiting activity on CB2 and PPARγ receptors, is neuroprotective in adult mice models of acute and chronic brain damaging conditions. We hereby aimed to study VCE-004.8 neuroprotection in a rat model of neonatal stroke.
7-day-old (P7) Wistar rats of both sexes were submitted to Middle Cerebral Artery Occlusion (MCAO), receiving i.p. 30 min after vehicle (MCAO + VEH) or VCE-004.8 5 mg/kg (MCAO + VCE). Non-occluded rats served as controls (SHAM). MCAO consequences were assessed at P14 by MRI, histological (TUNEL staining), biochemical (lactate/n-acetyl aspartate ratio by 1H-NMR spectroscopy) and motor studies (grasp test), and at P37 assessing myelination (MBP signal), hemiparesis and hyperlocomotion. Effects of VCE-004.8 on excitotoxicity (glutamate/n-acetyl aspartate, 1H-NMR), oxidative stress (protein nitrosylation, Oxyblot) and neuroinflammation (Toll-like receptor 4 and TNFa expression, Western blot) were assessed at P14. Therapeutic window was assessed by delaying drug administration for 12 or 18 h.
Post-MCAO administration of VCE-004.8 reduced the volume of infarct and histological and biochemical brain damage, reducing hyperlocomotion, restoring motor performance and preserving myelination, in a manner linked to the modulation of excitotoxicity, oxidative stress and neuroinflammation. VCE-004.8 was still effective being administered 12-18 h post-insult.
These data suggest that this drug could be effective for the treatment of stroke in newborns.
目前，由于围产期发生局灶性缺血、血栓形成或出血事件，新生儿卒中这一急性神经系统综合征仍缺乏有效的治疗方法，且会遗留后遗症。VCE-004.8 是一种氨基喹啉，在成年急性和慢性脑损伤模型中具有 CB2 和 PPARγ 受体活性，具有神经保护作用。本研究旨在探讨 VCE-004.8 对新生大鼠卒中模型的神经保护作用。
7 日龄（P7）Wistar 雌雄大鼠接受大脑中动脉闭塞（MCAO），在给予载体（MCAO+VEH）或 VCE-004.8（5mg/kg）30min 后进行 MCAO。未闭塞的大鼠作为对照（SHAM）。在 P14 时通过 MRI、组织学（TUNEL 染色）、生物化学（1H-NMR 光谱测量乳酸/乙酰天门冬氨酸比）和运动研究（抓握试验）评估 MCAO 后果，并在 P37 时评估髓鞘形成（MBP 信号）、偏瘫和过度活跃。在 P14 时通过 1H-NMR 评估 VCE-004.8 对兴奋性毒性（谷氨酸/乙酰天门冬氨酸）、氧化应激（蛋白硝基化，Oxyblot）和神经炎症（Toll 样受体 4 和 TNFa 表达，Western blot）的影响。通过延迟给药 12 或 18h 评估治疗窗。
MCAO 后给予 VCE-004.8 可减少梗死体积和组织学及生化脑损伤，减少过度活跃，恢复运动功能并保持髓鞘形成，其方式与调节兴奋性毒性、氧化应激和神经炎症有关。VCE-004.8 在损伤后 12-18h 给药仍有效。
这些数据表明，该药物可能对新生儿卒中的治疗有效。
