Acute seizure activity in neonatal inflammation-sensitized hypoxia-ischemia in mice.

OBJECTIVE: To examine acute seizure activity and neuronal damage in a neonatal mouse model of inflammation-sensitized hypoxic-ischemic (IS-HI) brain injury utilizing continuous electroencephalography (cEEG) and neurohistology. METHODS: Neonatal mice were exposed to either IS-HI with Escherichia coli lipopolysaccharide (LPS) or HI alone on postnatal (p) day 10 using unilateral carotid artery ligation followed by global hypoxia (n = 10 [5 female, 5 male] for IS-HI, n = 12 [5 female, 7 male] for HI alone). Video cEEG was recorded for the duration of the experiment and analyzed for acute seizure activity and behavior. Brain tissue was stained and scored based on the degree of neuronal injury in the hippocampus, cortex, and thalamus. RESULTS: There was no significant difference in acute seizure activity among mice exposed to IS-HI compared to HI with regards to seizure duration (mean = 63 ± 6 seconds for HI vs mean 62 ± 5 seconds for IS-HI, p = 0.57) nor EEG background activity. Mice exposed to IS-HI had significantly more severe neural tissue damage at p30 as measured by neuropathologic scores (mean = 8 ± 1 vs 23 ± 3, p < 0.0001). INTERPRETATION: In a neonatal mouse model of IS-HI, there was no significant difference in acute seizure activity among mice exposed to IS-HI compared to HI. Mice exposed to IS-HI did show more severe neuropathologic damage at a later age, which may indicate the presence of chronic inflammatory mechanisms of brain injury distinct from acute seizure activity.

P2X7 receptor as a potential therapeutic target for perinatal brain injury associated with preterm birth.

Inflammation-induced preterm birth is the leading cause of perinatal mortality and long-term sequelae in surviving children. IL-1ß is a major contributor to inflammation-induced preterm labor and its sequelae. It has recently been demonstrated that the cytokine storm and its progression depend on IL-1ß release into circulation and that the P2X7 receptor (P2X7R) is the key player of the ATP-driven NLRP3/caspase-1 activation, necessary for the cleavage of pro-IL-1ß to its mature form as well as its subsequent secretion. Being a key component to the inflammatory cascade, P2X7R illuminates a new therapeutic avenue to halt progression of inflammation prior to perinatal brain injury. In this review, we summarize the basic role of the P2X7 receptor in the inflammatory signaling cascade and the possibility of it being used as a therapeutic target in perinatal brain injury. We discuss the antagonists and agonists of the receptor as well as its role in other inflammatory diseases, showing the importance of discovering the functions of the receptor.