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Abstracts

Effects of Potential Anti-epileptogenic Drugs on High Frequency Oscillations in the Fluid Percussion Injury Rat Model of Post-traumatic Epilepsy: An epibios4rx Project 2 Study from the Melbourne Site

Abstract number : 1.037
Submission category : 1. Basic Mechanisms / 1C. Electrophysiology/High frequency oscillations
Year : 2022
Submission ID : 2204890
Source : www.aesnet.org
Presentation date : 12/3/2022 12:00:00 PM
Published date : Nov 22, 2022, 05:26 AM

Authors :
Matthew Hudson, PhD – Central Clinical School, Monash University, Melbourne, VIC, Australia.; Pablo Casillas-Espinosa, MD,PhD – Department of Neuroscience – Central Clinical School, Monash University, Melbourne, VIC, Australia.; Rhys Brady, PhD – Department of Neuroscience – Central Clinical School, Monash University, Melbourne, VIC, Australia.; Idrish Ali, PhD – Department of Neuroscience – Central Clinical School, Monash University, Melbourne, VIC, Australia.; Glenn Yamakawa, PhD – Department of Neuroscience – Central Clinical School, Monash University, Melbourne, VIC, Australia.; Juliana Silva, PhD – Department of Neuroscience – Central Clinical School, Monash University, Melbourne, VIC, Australia.; Emma Braine, MSc – Department of Neuroscience – Central Clinical School, Monash University, Melbourne, VIC, Australia.; Patricia Saletti, PhD – Albert Einstein College of Medicine, Bronx, New York, U.S.A.; Cesar Santana-Gomez, PhD – David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Florencia Chena-Becerra, PhD – Albert Einstein College of Medicine, Bronx, New York, U.S.A.; Richard Staba, PhD – David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Solomon Moshe, M.D. – Albert Einstein College of Medicine, Bronx, New York, U.S.A.; Aristea Galanopoulou, PhD – Albert Einstein College of Medicine, Bronx, New York, U.S.A.; Nigel Jones, PhD – Department of Neuroscience – Central Clinical School, Monash University, Melbourne, VIC, Australia.; Sandy Shultz, PhD – Department of Neuroscience – Central Clinical School, Monash University, Melbourne, VIC, Australia.; Terence O'Brien, MD – Department of Neuroscience – Central Clinical School, Monash University, Melbourne, VIC, Australia.

Rationale: An important hindrance to the identification of effective disease-modifying treatments for post-traumatic epilepsy (PTE) is the absence of any predictive biomarkers which might be indicative of epileptogenesis. Recent evidence in the lateral fluid percussion injury (LFPI) rat model of traumatic brain injury (TBI) have indicated high-frequency oscillations (HFO) may represent a potential early biomarker of epileptogenesis after TBI. The aim of the present study is to assess the effects of potential anti-epileptogenic drugs (levetiracetam, sodium selenate, and Z944) on HFOs in the rat FPI model.

Methods: Male Sprague-Dawley rats (11 weeks old) were used. LFPI rats underwent a left parietal 5mm craniotomy and subjected to ~3.2 atm pressure pulse. Rats were divided into three different treatment groups, LFPI control group (saline 0.9% bolus and infusion, n=41), LFPI treated with levetiracetam (LEV; 200 mg/kg bolus, infusion 200 mg/kg/day, n=15), clinically approved as a ASM therapy after TBI; LFPI treated with sodium selenate (bolus 0.34mg/kg, infusion 1 mg/kg/day, n=15) an anti-tau drug and LFPI treated with Z944, a selective T-type Ca2+ channel blocker (bolus 1.25 mg/kg, infusion 30 mg/day, n=8). Animals received a bolus dose immediately after LFPI. One-hour post-LFPI rats were implanted with osmotic pumps that deliver the different treatments continuously for 7 days, and also underwent EEG surgery to implant epidural and intracerebral electrodes. EEG was then acquired continuously for 14 days. 10 minute clean EEG segments were extracted at days 0, 1,6 and 13 post-LFPI and HFO analysis was performed using RippleLab, separating the events in ripples (80-200Hz) and fast ripples bands (200-500Hz).

Results: HFOs were observed in ~90% of rats, predominately in electrodes around the lesion, and were predominantly in the fast ripple band. ANOVA Post hoc tests revealed that LEV treatment reduced fast ripples (p=0.032), but not ripples (p=0.862). While sodium selenate treatment also reduced fast ripples (p=0.049), the rate of ripples were increased (p=0.036), when compared to vehicle treated controls. In contrast, Z944 treatment had no significant effect on the rate of HFOs.

Conclusions: LEV and sodium selenate both significantly reduced the numbers of fast ripples post-LFPI. Considering previous research has shown HFOs may be predictive of epileptogenesis in the LFPI rats, this effect of levetiracetam and sodium selenate to reduce fast ripples could be a biomarker of potential anti-epileptogenesis post-TBI in this model.

Funding: Funded by NINDS U54 NS100064
Basic Mechanisms