Authors :
Presenting Author: Mustafa Hameed, MD – Boston Children's Hospital
Benjamin Hui, BS – Neurology – Boston Children's Hospital; Rui Lin, MS – Neurology – Boston Children's Hospital; Sheryl Anne Vermudez, PhD – Neurology – Boston Children's Hospital; Amanda Liebhardt, BS – Neurology – Boston Children's Hospital; Henry Lee, PhD – Neurology – Boston Children's Hospital; Chris Rundfeldt, PhD – Stiftung Tierärztliche Hochschule Hannover; Wolfgang Löscher, PhD, DVM – Pharmacology – University of Veterinary Medicine, Hannover, Germany; Alexander Rotenberg, Md, PhD – Neurology – Boston Children's Hospital
Rationale:
Prevention of epilepsy is a major unmet need in neurology. Approximately 5% of all epilepsy is due to traumatic brain injury (TBI). Following TBI, there is a seizure-free latency of days to months before post-traumatic epilepsy (PTE) develops. While this epileptogenic window offers an opportunity to intervene to prevent or modify epilepsy, no such treatment currently exists. Epilepsy is a complex network phenomenon, and post-traumatic epileptogenesis (PTE
gen) likely involves different pathophysiological processes. Rational combinations of drugs that engage different targets in the epileptogenic network may be a more effective preventive treatment strategy than single drug therapy. Here we test whether a network pharmacology-based approach to target PTE
gen by various mechanisms, including anti-inflammatory, antioxidant, neuroprotective, and neurotransmitter modulating effects, mitigates the extent of injury and markers of epileptic activity on EEG in the rat fluid percussion injury (FPI) PTE model, by co-administering a triple combination (TC) of the FDA-approved drugs atorvastatin (ATV), levetiracetam (LEV), and ceftriaxone (CRO) following severe FPI.
Methods:
P33-36 male Sprague Dawley rats received severe FPI (n = 14) via a 4-mm diameter left parietal craniotomy centered 5-mm posterior to Bregma and 4-mm lateral to the sagittal suture. Starting six hours after injury, rats were subcutaneously administered either TC ATV/LEV/CRO (4.5/90/90 mg/kg/day in 0.3% meglumine) for one week followed by ATV/LEV (4.5/90 mg/kg/day) only from the second through the fourth week after FPI (FPI-TC); or 0.3% meglumine only for four weeks after TBI (FPI-Meg). Eight weeks after FPI, rats were implanted with wireless EEG transmitters, and 48 hours of video-EEG were recorded from each animal 12 weeks after injury. Following EEG acquisition, rats were transcardially perfused with 4% paraformaldehyde and brains were harvested for immunohistochemical staining of cortical parvalbumin-positive interneurons (PVIs).
Results:
Triple combination treatment significantly decreased the incidence of electrographic seizures longer than five seconds, 12 weeks after FPI (FPI-Meg: 43%; FPI-TC: 0%; one-tailed Barnard’s test; p = 0.048). PVI count in the perilesional cortex was also significantly higher in FPI-TC rats compared to FPI-Meg controls 12 weeks after injury (p = 0.003; Mann-Whitney test).
Conclusions:
Reduced seizure incidence and preserved perilesional PVI counts indicate a capacity for ATV/LEV/CRO triple combination treatment to preserve cortical inhibitory tone and interrupt PTE
gen after TBI. These results provide a basis for continued work on developing PTE prevention therapies based on network pharmacology and the repurposing of FDA approved drugs.
Funding:
1R43NS119081-01A1 to PrevEp Inc. and BCH; CR, WL and AR are co-founders and have equity in PrevEp Inc.