Abstracts

Rationale: Status epilepticus (SE) is a life threatening medical emergency manifested by seizures lasting longer than 5 minutes or multiple ictal events for 30 minutes without return to baseline. Up to 40% of cases are resistant to current antiepileptic drugs, highlighting the need for novel and effective treatments. Modification of cellular metabolism (e.g. ketogenic diet) has been shown to control seizures in a variety of clinical syndromes and animal models. 2-Deoxyglucose (2-DG), a glycolytic inhibitor, has significant antiepileptic effects in multiple in vitro and in vivo seizure models. Fructose-1,6-Bisphosphate (FBP), another glycolytic metabolite, likewise demonstrates anticonvulsant properties and is thought to act by diverting glycolysis towards the pentose phosphate pathway. In vitro studies have shown that FBP blocks Cav channels and stops epileptiform activity. The current study investigated whether acute treatment with 2-DG or FBP could terminate SE in the developing brain. Methods: Sprague Dawley rat pups (P10-19) were implanted with screw electroencephalographic (EEG) electrodes under ketamine (50-80 mg/kg, i.p.) anesthesia. Video-EEG recordings, using a Pinnacle Technology tethered system, started once rats recovered from anesthesia. After 30-min baseline recording, animals received pilocarpine (300 mg/kg, i.p.) to induce SE. 2-DG (500mg/kg, i.p.) or FBP (1g/kg, i.p.) was given 30 minutes after SE onset; rats underwent EEG monitoring for 1 additional hour. For quantitative analysis, the power spectral density (PSD), which represents the frequency and amplitude of the EEG signal, was obtained using the open-source application, Brainstorm. Average PSDs for each condition (baseline; SE; 2-DG or FBP) were compared. Results: All rat pups exhibited typical behavioral (Racine scale: III-V) and electrographic seizures ~15 min after pilocarpine injection. After 2-DG or FBP administration, the behavioral and electrical manifestations of SE gradually attenuated and returned to the baseline state in ~15 min (2-DG, n=8) or ~10 min (FBP, n=6). Only 2 animals (1 from each experimental group) continued to have seizure-like events after 2-DG or FBP. Similar PSD patterns were seen following both 2-DG and FBP treatments. Compared to baseline, the average power during SE was increased across all frequencies, with spikes in the delta (0.5-3 Hz) and theta (4-8 Hz) ranges. Following 2-DG and FBP treatments, the average power spectra returned to baseline. Conclusions: These data show that the glycolysis metabolites, 2-DG and FBP, consistently block pilocarpine-induced SE in neonatal rats, supporting a role for rapid metabolic modulation of neuronal excitability. Both 2-DG and FBP effectively stopped clinical SE and reversed EEG power spectrum abnormalities, suggesting that these agents act quickly to suppress ongoing seizure activity, supporting their potential translational role. The mechanisms by which 2-DG and FBP acutely reduce neuronal excitability require further study. Funding: No funding