Table 1.
Preclinical treatment trials in rodent models of TBI to observe effects on seizures
| Treatment | Mechanism | Model | Species, strain, age, sex | Effect on spontaneous seizures | Effect on induced seizures | Other effects/comments | Reference |
|---|---|---|---|---|---|---|---|
| Atipamezole (1 mg/kg/i.p. 30min post-TBI followed by 100 μg/kg/hr SC minipump, for 9weeks; or 100 μg/kg/hr SC minipump for 7 days-9 weeks post-TBI) | α2-adrenergic antagonist | LFPI, severe | Rats, Sprague-Dawley, adult, male | No effect | Reduced PTZ seizure susceptibility | (Nissinen et al., 2017) | |
| Ceftriaxone (200 mg/kg/day i.p., 7 days post-TBI) | Increases expression of GLT-1 (glutamate transporter) | LFPI | Rats, Long Evans, Adult, male | Reduces cumulative seizure duration 12 weeks post-TBI | Prevents decrease of GLT-1. Seizures are spike runs > 10sec; behavioral correlate is not clear. | (Goodrich et al., 2013) | |
| Gabapentin (Starting 1 h post-TBI: −100 mg/kg, 3 times per day for 2 days or - 120 mg/kg/day for 13–15 days SC) | Inhibits α2δ subunit of L-type calcium channels; Inhibits thrombospondin-induced excitatory synapses formation | Undercut cortex model | Rats, Sprague-Dawley, 30 days old, male | N/A | Reduces evoked epileptiform discharges in cortical slices 1 day and 14 days post-gabapentin | Reduces, excitatory synapses, and GFAP expression | (Li et al., 2012) |
| Hypothermia | Hypothermia | LFPI, moderate | Rats, Sprague Dawley, Adult, male | N/A | Reduced number of PTZ seizures, 12 weeks post-TBI | Reduced mossy fiber sprouting | (Atkins et al., 2010) |
| Hypothermia (focal cooling by 2 °C for 5.5 weeks, starting 3 days post-TBI) | Focal cooling by 0.5–2 °C | Rostral parasagittal FPI | Rats, Sprague Dawley | Abolished ictal activity up to 10 weeks after cooling. Seizures are runs of spike waves with freezelike arrest. | N/A | (D’Ambrosio et al., 2013) | |
| Ketogenic diet (starting 3 weeks pre-TBI) | Ketosis, anti-inflammatory, multiple effects | LFPI | Rats, Sprague Dawley, 8 weeks, male | N/A | Increased threshold to flurothyl-induced seizures, 3 or 6weeks post-TBI while ketogenic diet is given but not after it is withdrawn. | (Schwartzkroin et al., 2010) | |
| Minozac (5 mg/kg i.p., 3 h and 6 h post-TBI) | Anti-inflammatory | CCI | CD1 mice, Adult, male | N/A | Reduced susceptibility to electroconvulsive shock seizures, 7 days post-TBI | Improved performance in Barnes maze testing (learning, memory) | (Chrzaszcz et al., 2010) |
| Rapamycin (6 mg/kg/day i.p, start 1 h post-TBI, for 4 weeks) | mTOR inhibition | CCI | CD1 mice, 8 weeks old, males | Reduced PTE risk at 4 months post TBI (13% vs 50% in vehicle treated) | N/A | VEEG monitoring for 16 weeks. Seizures show evolution on EEG, and result in arrest, clonus, rearing and/or falling. | (Guo et al., 2013) |
| Rapamycin (3 or 10 mg/kg i.p. starting the day of CCI and given till sacrifice) | mTOR inhibition | CCI | CD1 mice, 6–8 weeks old | No significant reduction in behavioral seizures | N/A | Seizures: behavioral tail stiffness and freezing > 10 sec | (Butler et al., 2015) |
| Rimonabant (SR141716A) (1 or 10 mg/kg i.p., immediately or 20 min after TBI) | CB1 receptor antagonist | LFPI, moderate | Rats, Wistar, 21 −22 days old | N/A | Reduced susceptibility to kainate induced seizures, 6 weeks post-TBI | (Echegoyen et al., 2009) | |
| Sodium selenate (1 mg/kg/day SC, minipumps, after TBI for 12 weeks) | Activates protein phosphatase 2A (PP2A) containing the PR55 regulatory subunit and decreases p-tau | LFPI, severe | Rats, Long Evans, adult, male | Reduced seizure frequency during treatment and 3–4 weeks postwashout | N/A | VEEG monitoring starting at 10 weeks post-TBI; monitoring done at 10–12 weeks (on treatment) and 15–16 weeks post-TBI (washout) | (Liu et al., 2016) |
CCI: controlled cortical impact; EEG: electroencephalography; FPI: fluid percussion injury; LFPI: lateral FPI; mTOR: mechanistic target of rapamycin; PP2A: protein phosphatase 2A; p-tau: hyperphosphorylated tau; PTE: post-traumatic epilepsy; PTZ: pentylenetetrazole; TBI: traumatic brain injury; vEEG: video EEG.