Is Lactate Neuroprotective? Effects of Lactate on Acute Seizure Activity in Neonatal Hypoxic-ischemic Brain Injury
Abstract number :
1.003
Submission category :
1. Basic Mechanisms / 1A. Epileptogenesis of acquired epilepsies
Year :
2022
Submission ID :
2204235
Source :
www.aesnet.org
Presentation date :
12/3/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:24 AM
Authors :
Angelina June, MD – University of Virginia; Weronika Matysik, BS – University of Virginia; Jaideep Kapur, MD, PhD – University of Virginia; Jennifer Burnsed, MD, MSc – University of Virginia
Rationale: Hypoxic-ischemic encephalopathy (HIE) is a serious brain injury that causes significant morbidity and mortality in newborns worldwide and is the most common cause of neonatal seizures. Even with therapeutic hypothermia (TH), the only approved therapy for HIE, a high percentage of infants who survive HIE have persistent neurodevelopmental deficits, including epilepsy and cerebral palsy. Lactate is a known byproduct and clinical biomarker of anaerobic glycolysis that is elevated in neonates with HIE. However, little is known about the effects of lactate as a signaling molecule in HIE. Emerging research suggests that lactate may have a key neuroprotective role in neonatal HIE through interactions with the lactate receptor HCAR1 (hydroxycarboxylic acid receptor). Recent animal studies have shown that elevated lactate above physiologic levels decreases neuronal excitability, thus inhibiting seizure activity. The lactate receptor HCAR1 may be vital to this effect as it has been previously shown to modulate neuronal firing rates. Lactate and HCAR1 may therefore be promising novel therapeutic targets for neonatal HIE. This project aims to identify if lactate receptor HCAR1 is neuroprotective against acute seizure activity caused by neonatal hypoxic-ischemic (HI) brain injury. We hypothesize that knockout (KO) neonatal mice without the lactate receptor HCAR1 will exhibit more severe acute seizure activity in the setting of HI brain injury.
Methods: Wild-type (WT) and HCAR1 KO neonatal mice were stereotactically implanted with electroencephalography (EEG) headsets on post-natal day 9 (p9). On post-natal day 10 (p10), the mice were connected to a video EEG rig and exposed to hypoxia-ischemia using a modified Rice-Vannucci model. Video EEG recordings were obtained at baseline, during recovery from unilateral carotid ligation, 8% hypoxia (60 minutes), and post-hypoxia for a total duration of 3 hours.
Results: Video EEGs were then analyzed for electrographic seizure activity including seizure number and duration in the WT (n = 6) and HCAR1 KO (n = 7) mice. The median number of seizures in the WT and HCAR1 KO group were 7 and 11, respectively. The average time of individual seizures in the WT and HCAR1 KO group were 34 and 62 seconds, respectively (p = 0.004).
Conclusions: In a neonatal mouse model of HIE, HCAR1 KO mice have significantly longer acute seizure activity compared to WT mice. The effects of signaling pathways associated with the lactate receptor HCAR1 may be neuroprotective in neonatal HIE. Future directions include quantifying seizure burden, power spectral analysis of background activity, and histological analysis of brain injury.
Funding: None
Basic Mechanisms