Minozac Treatment Prevents Increased Seizure Susceptibility in a Mouse “Two-Hit” Model of Closed Skull Traumatic Brain Injury and Electroconvulsive Shock-Induced Seizures

Abstract

The mechanisms linking traumatic brain injury (TBI) to post-traumatic epilepsy (PTE) are not known and no therapy for prevention of PTE is available. We used a mouse closed-skull midline impact model to test the hypotheses that TBI increases susceptibility to seizures in a ''two-hit'' injury model, and that suppression of cytokine upregulation after the first hit will attenuate the increased susceptibility to the second neurological insult. Adult male CD-1 mice underwent midline closed skull pneumatic impact. At 3 and 6 h after impact or sham procedure, the mice were injected IP with either Minozac (Mzc), a suppressor of proinflammatory cytokine upregulation, or vehicle (saline). On day 7 after sham operation or TBI, seizures were induced using electroconvulsive shock (ECS), and susceptibility to seizures was measured by the current required for seizure induction. Activation of glia, neuronal injury, and metallothionein-immunoreactive cells were quantified in the hippocampus by immunohistochemical methods. Neurobehavioral function over 14-day recovery was quantified using the Barnes maze. Following TBI there was a significant increase in susceptibility to seizures induced by ECS, and this susceptibility was prevented by suppression of cytokine upregulation with Mzc. Astrocyte activation, metallothionein expression, and neurobehavioral impairment were also increased in the two-hit group subjected to combined TBI and ECS. These enhanced responses in the two-hit group were also prevented by suppression of proinflammatory cytokine upregulation with Mzc. These data implicate glial activation in the mechanisms of epileptogenesis after TBI, and identify a potential therapeutic approach to attenuate the delayed neurological sequelae of TBI.

Electroconvulsive shock attenuated microgliosis and astrogliosis in the hippocampus and ameliorated schizophrenia-like behavior of Gunn rat

“…Indeed, the majority of ECS studies on normal animals has shown that ECS has no effect on the activation/proliferation of microglia and astrocytes [34, 35] or even increases the glial activation/proliferation [38, 39]. Only one study has reported that ECS reduces the density of microglial process in the murine hippocampus [37] and one other has shown that ECS inhibits GFAP expression in the rat hippocampus [33].…”

Development of Post-Traumatic Epilepsy after Controlled Cortical Impact and Lateral Fluid-Percussion-Induced Brain Injury in the Mouse

“…The remaining challenge is to determine the magnitude of the seizure susceptibility increase that would unequivocally pinpoint individual animals that will develop epilepsy within a given period of time. Chrzaszcz et al (2010) Only the data collected at least 1 week post-injury are included. CCI, controlled cortical impact; ECS, electroconvulsive shock; FPI, fluid-percussion injury; n.d., no data; P, postnatal day; PTZ, pentylenetetrazol; TBI, traumatic brain injury; ED, epileptiform discharge; EEG, electroencephalogram; GABA, c-aminobutyric acid.…”

Concussive Injury before or after Controlled Cortical Impact Exacerbates Histopathology and Functional Outcome in a Mixed Traumatic Brain Injury Model in Mice

“…1,22 Inasmuch as sequential injury produced additive effects on histopathological and functional outcome, our study is in principle similar to other injury models in which TBI was combined with controlled secondary insults to mimic the clinical scenarios of superimposed hypoxemia, 23,24 systemic hemorrhage, 25 polytrauma, 26 and seizures. 27 Others have also reported TBI consisting of simultaneous linear and angular head acceleration. 28,19 In the model by Marmarou and colleagues, 29 combined impact and linear acceleration produces robust diffuse axonal injury but not contusion.…”