Visiting Graduate Student University of Virginia School of Medicine Charlottesville, Virginia, United States
Background: Hypoxia-ischemia (HI) is a leading cause of death and neurodevelopmental disability among neonates. The only available intervention, therapeutic hypothermia, has limitations. Recently lactate which is increased in the serum and brain after neonatal HI, was discovered to have a receptor, hydroxycarboxylic acid receptor 1 (HCAR1) and direct signaling effects in the brain. A few studies have found that it may have neuroprotective potential in neonatal HI.
Our prior work revealed that mice lacking HCAR1 experience more frequent and severe seizures following HI injury compared to wildtype mice. Further, we have demonstrated that lactate applied to neonatal hippocampal slices decreases neuronal excitability, a hallmark of acute HI injury and seizures. Additionally, we observe that HCAR1 agonist, 3,5-dihydroxybenzoic acid (DHBA) results in EEG suppression when injected systemically. These findings shed light on HCAR1 as a promising therapeutic target to investigate. Objective: Our goal is to evaluate the neuroprotective effect of HCAR1 activation after neonatal HI by measuring the frequency and severity of acute HI seizures. Design/Methods: HCAR1 knockout (KO) and wildtype (WT) mice will undergo cranial electrode implantation on postnatal day (p)9. On p10, mice will be subjected to HI (unilateral carotid ligation 8% O2 x 60min). Mice will be randomized to receive an intraperitoneal injection of lactate (2g/kg) or saline before ligation and at the start of hypoxia. Seizure burden will be measured using continuous EEG recording throughout prior to, during and post-hypoxia. We expect lactate to decrease the seizure burden in WT, but not KO mice.
For DHBA administration, C57/Bl6 mice will undergo electrode implantation and HI as described above. Mice will receive either intraperitoneal DHBA (3g/kg) or saline injection. Seizure burden will be measured as described above. We expect decreased seizure burden after DHBA injection, but not saline. Data will be collected by February 2024 (10 mice/ea. group, both sexes) and analyzed in March using LabChart and GraphPad software.
