Neuroinflammation in epileptogenesis: Insights and translational perspectives from new models of epilepsy

Abstract

Animal models have provided a wealth of information on mechanisms of epileptogenesis and comorbidogenesis, and have significantly advanced our ability to investigate the potential of new therapies. Processes implicating brain inflammation have been increasingly observed in epilepsy research. Herein we discuss the progress on animal models of epilepsy and comorbidities that inform us on the potential role of inflammation in epileptogenesis and comorbidity pathogenesis in rodent models of West syndrome and the Theiler's murine encephalomyelitis virus (TMEV) mouse model of viral encephalitis-induced epilepsy. Rat models of infantile spasms were generated in rat pups after right intracerebral injections of proinflammatory compounds (lipopolysaccharides with or without doxorubicin, or cytokines) and were longitudinally monitored for epileptic spasms and neurodevelopmental and cognitive deficits. Anti-inflammatory treatments were tested after the onset of spasms. The TMEV mouse model was induced with intracerebral administration of TMEV and prospective monitoring for handling-induced seizures or seizure susceptibility, as well as long-term evaluations of behavioral comorbidities of epilepsy. Inflammatory processes are evident in both models and are implicated in the pathogenesis of the observed seizures and comorbidities. A common feature of these models, based on the data so far available, is their pharmacoresistant profile. The presented data support the role of inflammatory pathways in epileptogenesis and comorbidities in two distinct epilepsy models. Pharmacoresistance is a common feature of both inflammation-based models. Utilization of these models may facilitate the identification of age-specific, syndrome- or etiology-specific therapies for the epilepsies and attendant comorbidities, including the drug-resistant forms.

Keywords: Comorbidities; Cytokines; Encephalitis; Epilepsy; Infantile spasms; Infection; Therapies; Viral infection.

Figure 1

Once-daily oral administration of the anticonvulsant, levetiracetam (LEV; 50 mg/kg, p.o.) during days 3–7 post-infection with Theiler’s murine encephalomyelitis virus (TMEV) does not significantly improve seizure burden during the acute symptomatic seizure period. This study was conducted in 4–5 week old male C57Bl/6J mice (Jackson Labs, Bar Harbor, ME) according to our previously published protocols for acute drug evaluation studies in the TMEV model of infection induced seizures, with a viral titer of 2.5 x 105 PFU,^, and a slight modification to include a clinically-relevant dosing paradigm of ASD treatment after the viral infection has occurred (e.g. days 3–7 post-infection). A) The average (Avg) seizure burden of mice with seizures observed during the total 5-day observation period (days 3–7 post-infection) for mice treated with LEV was not significantly different from mice treated with vehicle (VEH; 0.5% methylcellulose (MC); t=0.219, p>0.8). B) However, the cumulative seizure burden of mice treated with LEV was significantly worsened relative to VEH-treated mice (main effect of treatment, F_(1,11)=8.84, p=0.021). C) Finally, the sum seizure burden for each observation session was also significantly worsened in mice treated with once-daily LEV (main effect of treatment, F_(1,11)=12.78, p=0.004). These data, together with our previously published work with anticonvulsant doses of the prototype ASDs VPA and CBZ, illustrate that the TMEV model is a suitable platform for acute evaluations of anticonvulsant efficacy of investigational drugs. Moreover, this model exhibits seizures that are resistant to prototypical ASDs, thereby making it a valid model of pharmacoresistant seizures.