Human chorionic gonadotropin decreases cerebral cystic encephalomalacia and parvalbumin interneuron degeneration in a pro-inflammatory model of mouse neonatal hypoxia-ischemia

Human chorionic gonadotropin (hCG) is an immunoregulatory and neurotrophic glycoprotein of potential clinical utility in the neonate at risk for cerebral injury. However, hCG has not been demonstrated to affect the pro-degenerative actions of inflammation in neonatal brain injury. Here we utilize a neonatal mouse model of mild hypoxia-ischemia (HI) combined with intraperitoneal administration of lipopolysaccharide (LPS) to evaluate the neuroprotective actions of hCG in the setting of systemic inflammation. Intraperitoneal treatment with hCG significantly decreased tissue loss and cystic degeneration in the hippocampus and cerebral cortex of term-equivalent neonatal mice exposed to LPS and HI. Noting that parvalbumin immunoreactive interneurons have been broadly implicated in neurodevelopmental disorders, hCG significantly improved the injury-mediated reduction of these neurons in the cerebral cortex, striatum and hippocampus. Concomitantly, hCG decreased the amount of Iba1 immunoreactive microglia in most of the injured brain regions. These observations implicate hCG as an agent capable of improving the neurological morbidity associated with peripheral inflammation in the neonate affected by HI. Future preclinical studies should aim at demonstrating added neuroprotective benefit by hCG in the context of therapeutic hypothermia and further exploring the mechanisms responsible for this effect. This research is likely to advance the therapeutic role of gonadotropins as a treatment for neonates with neonatal brain injury.