Subacute AMD3100 Treatment Is Not Efficient in Neonatal Hypoxic-Ischemic Rats

• Published in: Stroke (1970) 2022-02, Vol.53 (2), p.586-594
• Main Authors: Spiess, Daiane Aparecida, Campos, Raquel Maria Pereira, Conde, Luciana, Didwischus, Nadine, Boltze, Johannes, Mendez-Otero, Rosalia, Pimentel-Coelho, Pedro Moreno
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Atrophy; Benzylamines - administration & dosage; Benzylamines - therapeutic use; Brain - pathology; Cognitive Dysfunction - psychology; Cyclams - administration & dosage; Cyclams - therapeutic use; Endpoint Determination; Female; Hypoxia-Ischemia, Brain - drug therapy; Male; Maze Learning; Pregnancy; Psychomotor Performance - drug effects; Rats; Rats, Wistar; Receptors, CXCR4 - antagonists & inhibitors; Sex Characteristics; Treatment Failure
• ISSN: 0039-2499; 1524-4628
• DOI: 10.1161/STROKEAHA.120.033768

Despite the advances in treating neonatal hypoxic-ischemic encephalopathy (HIE) with induced hypothermia, the rates of severe disability are still high among survivors. Preclinical studies have indicated that cell therapies with hematopoietic stem/progenitor cells could improve neurological outcomes in HIE. In this study, we investigated whether the administration of AMD3100, a CXCR4 antagonist that mobilizes hematopoietic stem/progenitor cells into the circulation, has therapeutic effects in HIE. P10 Wistar rats of both sexes were subjected to right common carotid artery occlusion or sham procedure, and then were exposed to hypoxia for 120 minutes. Two subcutaneous injections of AMD3100 or vehicle were given on the third and fourth day after HIE. We first assessed the interindividual variability in brain atrophy after experimental HIE and vehicle treatment in a small cohort of rats. Based on this exploratory analysis, we designed and conducted an experiment to test the efficacy of AMD3100. Brain atrophy on day 21 after HIE was defined as the primary end point. Secondary efficacy end points were cognitive (T-water maze) and motor function (rotarod) on days 17 and 18 after HIE, respectively. AMD3100 did not decrease the brain atrophy in animals of either sex. Cognitive impairments were not observed in the T-water maze, but male hypoxic-ischemic animals exhibited motor coordination deficits on the rotarod, which were not improved by AMD3100. A separate analysis combining data from animals of both sexes also revealed no evidence of the effectiveness of AMD3100 treatment. These results indicate that the subacute treatment with AMD3100 does not improve structural and functional outcomes in a rat HIE model.