Alves-Martinez Pilar, Atienza-Navarro Isabel, Vargas-Soria Maria, Carranza-Naval Maria Jose, Infante-Garcia Carmen, Benavente-Fernandez Isabel, Del Marco Angel, Lubian-Lopez Simon, Garcia-Alloza Monica
Division of Physiology, School of Medicine, Universidad de Cadiz, Cadiz, Spain.
Biomedical Research and Innovation Institute of Cádiz Cadiz (INiBICA) Research Unit, Puerta del Mar University Hospital University of Cadiz, Cadiz, Spain.
Front Cell Dev Biol. 2022 Aug 12;10:908045. doi: 10.3389/fcell.2022.908045. eCollection 2022.
Germinal matrix-intraventricular hemorrhage (GM-IVH) is the most frequent intracranial hemorrhage in the preterm infant (PT). Long-term GM-IVH-associated sequelae include cerebral palsy, sensory and motor impairment, learning disabilities, or neuropsychiatric disorders. The societal and health burden associated with GM-IVH is worsened by the fact that there is no successful treatment to limit or reduce brain damage and neurodevelopment disabilities. Caffeine (Caf) is a methylxanthine that binds to adenosine receptors, regularly used to treat the apnea of prematurity. While previous studies support the beneficial effects at the brain level of Caf in PT, there are no studies that specifically focus on the role of Caf in GM-IVH. Therefore, to further understand the role of Caf in GM-IVH, we have analyzed two doses of Caf (10 and 20 mg/kg) in a murine model of the disease. We have analyzed the short (P14) and long (P70) effects of the treatment on brain atrophy and neuron wellbeing, including density, curvature, and phospho-tau/total tau ratio. We have analyzed proliferation and neurogenesis, as well as microglia and hemorrhage burdens. We have also assessed the long-term effects of Caf treatment at cognitive level. To induce GM-IVH, we have administered intraventricular collagenase to P7 CD1 mice and have analyzed these animals in the short (P14) and long (P70) term. Caf showed a general neuroprotective effect in our model of GM-IVH of the PT. In our study, Caf administration diminishes brain atrophy and ventricle enlargement. Likewise, Caf limits neuronal damage, including neurite curvature and tau phosphorylation. It also contributes to maintaining neurogenesis in the subventricular zone, a neurogenic niche that is severely affected after GM-IVH. Furthermore, Caf ameliorates small vessel bleeding and inflammation in both the cortex and the subventricular zone. Observed mitigation of brain pathological features commonly associated with GM-IVH also results in a significant improvement of learning and memory abilities in the long term. Altogether, our data support the promising effects of Caf to reduce central nervous system complications associated with GM-IVH.
生发基质-脑室内出血（GM-IVH）是早产儿（PT）最常见的颅内出血。GM-IVH相关的长期后遗症包括脑瘫、感觉和运动障碍、学习障碍或神经精神疾病。由于没有成功的治疗方法来限制或减少脑损伤和神经发育障碍，与GM-IVH相关的社会和健康负担更加沉重。咖啡因（Caf）是一种与腺苷受体结合的甲基黄嘌呤，常用于治疗早产儿呼吸暂停。虽然先前的研究支持Caf对PT大脑水平的有益作用，但没有专门关注Caf在GM-IVH中作用的研究。因此，为了进一步了解Caf在GM-IVH中的作用，我们在该疾病的小鼠模型中分析了两种剂量的Caf（10和20mg/kg）。我们分析了治疗对脑萎缩和神经元健康的短期（P14）和长期（P70）影响，包括密度、曲率和磷酸化tau蛋白/总tau蛋白比率。我们分析了增殖和神经发生，以及小胶质细胞和出血负担。我们还评估了Caf治疗在认知水平的长期影响。为了诱导GM-IVH，我们向P7 CD1小鼠脑室内注射胶原酶，并在短期（P14）和长期（P70）对这些动物进行分析。在我们的PT型GM-IVH模型中，Caf显示出普遍的神经保护作用。在我们的研究中，给予Caf可减少脑萎缩和脑室扩大。同样，Caf可限制神经元损伤，包括神经突曲率和tau蛋白磷酸化。它还有助于维持脑室下区的神经发生，脑室下区是一个在GM-IVH后受到严重影响的神经源性微环境。此外，Caf可改善皮质和脑室下区的小血管出血和炎症。观察到的与GM-IVH常见相关脑病理特征的减轻也导致长期学习和记忆能力的显著改善。总之，我们的数据支持Caf在减少与GM-IVH相关的中枢神经系统并发症方面的有前景的作用。
