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. Here, we discuss the progress on animal models of epilepsies 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 pro-inflammatory 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 of these 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.

Cannabidiol reduces seizures and associated behavioral comorbidities in a range of animal seizure and epilepsy models

“…CBD presently demonstrated efficacy in the acute mouse MES, subcutaneous pentylenetetrazol, and 6‐Hz assays at both 32‐ and 44‐mA stimulus intensities. CBD also demonstrated a PI > 1.5 in the 6‐Hz model of pharmacoresistant epilepsy at a 44‐mA stimulus intensity, which substantially differentiates this compound from many other FDA‐approved ASDs, including VPA . The activity of FBM is also preserved in the 44‐mA version of the 6‐Hz assay (Table ); the PI of FBM is also much greater than CBD in this assay (4.6 for FBM vs 1.6 for CBD; Table ).…”

Neuroinflammation in neocortical epilepsy measured by PET imaging of translocator protein

“…5 Evidence from both animal models and human studies sug gests that inflammatory processes play a role in epilepsy. 7 Inflammatory pathways including interleukin-1 receptor/toll-like receptor signaling, cyclooxygenase-2, tumor necrosis factor-α, complement signaling, and chemokines have been implicated. 7 Inflammatory pathways including interleukin-1 receptor/toll-like receptor signaling, cyclooxygenase-2, tumor necrosis factor-α, complement signaling, and chemokines have been implicated.…”

Risk of seizures and status epilepticus in older patients with liver disease

“…Conversely, other literature suggests an increased γ‐aminobutyric acidergic tone in patients with acute and chronic liver failure as a result of increased pregnenolone, and the progesterone metabolites tetrahydroprogesterone (allopregnanolone) and tetrahydrodeoxycorticosterone, which would argue against the hypothesis that liver disease might cause seizures. However, there is also an increase in proinflammatory cytokines in this population, which may lead to increased epileptogenesis . Amidst this uncertainty, our population‐based study suggests that, on the whole, liver disease is not an independent risk factor for seizures.…”

“…However, there is also an increase in proinflammatory cytokines in this population, which may lead to increased epileptogenesis. 19,20 Amidst this uncertainty, our population-based study suggests that, on the whole, liver disease is not an independent risk factor for seizures. The one exception is the association that we found between cirrhosis and status epilepticus.…”