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

Abstract

The pregnancy hormone, human chorionic gonadotropin (hCG) is an immunoregulatory and neurotrophic glycoprotein of potential clinical utility in the neonate at risk for cerebral injury. Despite its well-known role in its ability to modulate the innate immune response during pregnancy, hCG has not been demonstrated to affect the pro-degenerative actions of inflammation in neonatal hypoxia-ischemia (HI). Here we utilize a neonatal mouse model of mild HI combined with intraperitoneal administration of lipopolysaccharide (LPS) to evaluate the neuroprotective actions of hCG in the setting of endotoxin-mediated systemic inflammation. Intraperitoneal treatment of hCG shortly prior to LPS injection significantly decreased tissue loss and cystic degeneration in the hippocampal and cerebral cortex in the term-equivalent neonatal mouse exposed to mild HI. Noting that parvalbumin immunoreactive interneurons have been broadly implicated in neurodevelopmental disorders, it is notable that hCG significantly improved the injury-mediated reduction of these neurons in the cerebral cortex, striatum and hippocampus. The above findings were associated with a decrease in the amount of Iba1 immunoreactive microglia in most of these 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. Key pointsO_LIIntraperitoneal administration of human chorionic gonadotropin (hCG) decreases lipopolysaccharide (LPS)-augmented hypoxic-ischemic neurodegeneration in the term-equivalent mouse neonate C_LIO_LIPretreatment with hCG reduces LPS-mediated cystic encephalomalacia of the cerebral cortex and ameliorates hippocampal tissue loss after neonatal hypoxia-ischemia (HI) C_LIO_LIhCG decreases LPS+HI-mediated parvalbumin immunoreactive interneuron loss in the cerebral cortex, hippocampus and dorsal striatum. C_LIO_LIhCG decreases LPS+HI-augmented microglial Iba1 immunoreactivity in the cerebral cortex and hippocampus. C_LI