Germinal matrix-intraventricular hemorrhage in the preterm newborntherapeutic considerations

Resumen

There are more than 15 million premature births worldwide every year, and preterm birth is the leading cause of death in children. In recent years survival rates of preterm newborns (PT) have increased due to advances in neonatal intensive care and perinatal medicine. Nevertheless, the preterm population is at high risk of suffering severe complications. Also, increased survival rates have resulted in a raise of these compilations, including germinal matrix-intraventricular hemorrhage (GM-IVH). This is the most frequent intracranial hemorrhage associated with prematurity, affecting up to 20%-30% of all PT. Long-term GM-IVH-associated sequelae include cerebral palsy, sensory and motor impairment, learning disabilities or neuropsychiatric disorders. Currently, GM-IVH has no successful treatment and these patients have a tremendous need of new therapeutic approaches that may reduce or reverse brain complications and behavioral problems. In this sense, caffeine (Caf) and tideglusib (Tid) are two drugs that might provide a relevant venue for patients with GM-IVH. Caf, regularly used to treat the apnea of prematurity, is a methylxanthine that binds to adenosine. Caf also has anti-inflammatory and neuroprotective properties. Tid is a glycogen synthase kinase 3-ß inhibitor with neuroprotective effects. However, to our knowledge the effects of these treatments have not been assessed as therapeutic options to reduce brain damage in GM-IVH. Therefore we have administered both compounds to a murine model of GM-IVH of the PT, induced by intraventricular administration of collagenase (Col) to 7 day-old (P7) CD1 mice. We have treated our mice with two doses of Caf (10 and 20 mg/Kg) and we have evaluated the effects of Caf treatment in the short (P14) and long (P70) term. We have analyzed brain atrophy and neuron wellbeing, including neuron density, axonal curvature ratio, and phospho-tau/total tau ratio. We have also analyzed proliferation and neurogenesis, as well as the microglia burden and hemorrhages. Besides, we have assessed the long-term effects of Caf treatment in learning and memory. Caf showed a general neuroprotective effect in our model of GM-IVH of the PT. In our study, Caf diminishes brain atrophy and ventricle enlargement. Likewise, Caf limits neuronal damage, improving neurite curvature and tau phosphorylation. It also contributes to maintaining neurogenesis in the subventricular zone (SVZ), a neurogenic niche that is severely affected after GM-IVH. Furthermore, Caf ameliorates small vessel bleeding and inflammation in both the cortex and the SVZ. 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. In parallel we have also assessed the neuroprotective effects of Tid (5 mg/Kg) in the same animal model, by analyzing brain atrophy, neuronal density, tau phosphorylation and neurofilament light chain (NfL) as well as the presence of microglia in the short term (P14). We have also assessed the effects in proliferation and neurogenesis. Tid treatment reduces brain atrophy and neuronal compromise in the cortex. Furthermore, tau protein hyperphosphorylation and NfL levels are restored in the cortex after Tid treatment, suggesting an improvement in neuronal wellbeing. Similarly, Tid improves neurogenesis in the SVZ after the lesions. Tid also reduces microglia burden in the cortex and the SVZ, suggesting that Tid may also have anti-inflammatory properties. Collectively, our outcomes show that Tid has a positive impact on GM-IVH.