Authors :
Presenting Author: Ana Mejia-Bautista, MS – SUNY Downstate Health Sciences University
Hillary Michelson, PhD – Physiology & Pharmacology – SUNY Downstate Health Sciences University; Anika Sanjana, B.S. – Physiology & Pharmacology – SUNY Downstate Health Sciences University; Oluwafunmilayo Famuyiwa, B.S. – Physiology & Pharmacology – SUNY Downstate Health Sciences University; Jeffrey Goodman, PhD – Developmental Biology – The New York State Institute for Basic Research; Douglas Ling, PhD – Physiology & Pharmacology – SUNY Downstate Health Sciences University
Rationale:
After a severe traumatic brain injury (TBI), up to 40% of patients develop posttraumatic epilepsy (PTE). There are currently no clinical treatments available to prevent its development. Our group has shown that in the controlled cortical impact (CCI) model of TBI in rats, there is a progressive increase in evoked and spontaneous epileptiform activity during the first weeks after injury, as measured ex vivo in neocortical slices [Yang et al., 2010]. We found that early intervention with SV2A-ligand anti-seizure medications (ASMs) significantly reduced the development of neocortical epileptiform activity [Yang et al., 2021; Ling et al., 2022]. The goal of this study was to further evaluate the antiepileptogenic efficacy of the SV2A-ligand ASMs using in vivo assessments of seizures. Due to the low incidence of spontaneous seizures in rodent TBI models, we developed an in vivo test for epileptogenesis that uses a low dose of the convulsant agent, 4-aminopyridine (4-AP), to assess seizure susceptibility after injury. With this test, we evaluated the antiepileptogenic efficacy of early, post-injury administration of brivaracetam (BRV), an FDA-approved SV2A-ligand ASM.
Methods:
Sprague-Dawley rats aged P24-35 were subjected to severe CCI injury. Rats were anesthetized with isoflurane and placed in a stereotaxic frame. Following the midline incision, a 6.0 mm craniotomy was made over the right somatosensory cortex and a 5.0 mm impactor was driven to a 2.0 mm depth at 4.0 m/s. A plastic skull cap was secured over the impact site with veterinary adhesive. Separate groups of rats were given a single IP dose of BRV after CCI injury: one group received 21 mg/kg (BRV21) at 0–2 min after injury and the other 100 mg/kg (BRV100) at 30 min after injury. Uninjured controls underwent the same surgical procedure but were not subjected to the CCI injury. Four to eight weeks after injury, animals were challenged with a single, low dose of 4-AP (3.0–3.5 mg/kg, IP) and monitored for 60–70 min for stage 4/5 behavioral seizures [Racine, 1972].
Results:
Compared to uninjured controls (n=26), CCI rats (n=22) showed a two-fold increase in seizure susceptibility (36% vs 73% respectively; p< 0.05). Both groups of BRV-treated CCI rats exhibited significant reductions in seizure susceptibility compared to untreated CCI rats (BRV21, n=10: 30% vs 73%; p< 0.05; BRV100, n=5: 20% vs 73%; p< 0.05), with neither BRV group statistically different from uninjured controls.