Acute and long-term NCX activation reduces brain injury and restores behavioral functions in mice subjected to neonatal brain ischemia. (June 2018)

• Record Type: Journal Article
• Authors: Cerullo, Pierpaolo; Brancaccio, Paola; Anzilotti, Serenella; Vinciguerra, Antonio; Cuomo, Ornella; Fiorino, Ferdinando; Severino, Beatrice; Di Vaio, Paola; Di Renzo, Gianfranco; Annunziato, Lucio; Pignataro, Giuseppe
• Is Part Of: Neuropharmacology. Volume 135(2018)
• Page Start: 180
• Page End: 191
• Publication Date: 2018-06
• Subjects: Na+/Ca2+ exchanger -- Neonatal hypoxia -- Learning and memory -- Motor behaviour; Adenosin-triphosphat (ATP) -- 7-nitro-5-phenyl-1-(pyrrolidin-1-ylmethyl)-1Hbenzo[e][1, 4]diazepin-2(3H)-one (neurounina) -- Cornu Ammonis (CA) -- Glial Fibrillary Acidic protein (GFAP) -- Hypoxic-ischemic encephalopathy (HI) -- Neuron-specific nuclear protein (NeuN) -- Postnatal day 7 (P7) -- Propidium Iodide (PI) -- Right Common Carotid Artery (CCA) -- Sodium/Calcium Exchanger (NCX) -- Transient Middle Cerebral Artery Occlusion (tMCAO) -- Triphenyl-tetrazolium-chloride (TTC); Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2018.03.017
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Hypoxic-ischemic encephalopathy (HI) accounts for the majority of developmental, motor and cognitive deficits in children, leading to life-long neurological impairments. Since the plasmamembrane sodium/calcium exchanger (NCX) plays a fundamental role in maintaining ionic homeostasis during adult brain ischemia, in the present work we aimed to demonstrate (1)the involvement of NCX in the pathophysiology of neonatal HI and (2)a possible NCX-based pharmacological intervention. HI was induced in neonatal mice at postnatal day 7(P7) by unilateral cut of the right common carotid artery, followed by 60 min exposure to 8%O2 . Expression profiles of NCX isoforms from embryos stage to adulthood was evaluated in the hippocampus of hypoxic-ischemic and control mice. To assess the effect of NCX pharmacological stimulation, brain infarct volume was evaluated in brain sections, obtained at several time intervals after systemic administration of the newly synthesized NCX activator neurounina. Moreover, the long term effect of NCX activation was evaluated in adult mice (P60) subjected to neonatal HI and daily treated with neurounina for three weeks. Hypoxic-ischemic insult induced a reduction of NCX1 and NCX3 expression starting from day 7 until day 60. Notably, 8 weeks after HI induction in P7 mice, NCX pharmacological stimulation not only reduced infarct volume but improved also motor behaviour, spatial and visual memory. The present study highlights the significant role of NCX in the evolution of neonatal brain injury and in the learning and memory processes that are impaired in mice injured in the neonatal period. Graphical abstract: Highlights: Hypoxic-ischemic insult induced a reduction of NCX1 and NCX3. 8 weeks after HI induction in P7 mice, NCX pharmacological stimulation reduced infarct volume. Neurounina chronically administered is effective in reducing brain damage with a 7 h time window. The NCX activator neurounina induces an increased expression of NCX3.