Loss of Protection by Antiepileptic Drugs in Lipopolysaccharide-primed Pilocarpine-induced Status Epilepticus is Mediated via Inflammatory Signalling

Neuroscience. 2020 Aug 21;442:1-16. doi: 10.1016/j.neuroscience.2020.06.024. Epub 2020 Jun 24.

Abstract

The evidences from various studies show the association of peripheral and neuronal inflammation with complex pathophysiology of status epilepticus (SE). In this view, the present work attempted to develop a model of neuronal inflammation mediated SE by combining both epileptic and inflammatory components of the disease and also to mimic SE co-morbid with systemic inflammation by peripheral administration of the lipopolysaccharide (LPS) 2 h prior to the pilocarpine (PILO) induction in C57BL/6 mice. We evaluated the anti-convulsant and neuroprotective effects of 7-day prophylactic treatment with three conventional anti-epileptic drugs (Sodium valproate, SVP 300 mg/kg p.o.; Carbamazepine CBZ 100 mg/kg p.o.; Levetiracetam; LEV 200 mg/kg p.o.) of widespread clinical use. Morris water maze and Rota rod tests were carried out 24-h post-exposure to evaluate the neurobehavioral co-morbidities associated with neuroinflammation-mediated status epilepticus. Upon priming with LPS, the loss of protection against PILO-induced seizures was observed by SVP and CBZ, however, LEV showed protection by delaying the seizures. Dramatic elevation in the seizure severity and neuronal loss demonstrated the possible pro-convulsant effect of LPS in the PILO model. Also, the decreased cytokine levels by the AEDs showed their association with NF-κB, IL-1β, IL-6, TNF-α and TGF-β pathways in PILO model. The loss of protective activities of SVP and CBZ in LPS+PILO model was due to increased cytokine levels associated with over-activation of neuroinflammatory pathways, however, partial efficacy of LEV is possibly due to association of other neuroinflammatory mechanisms. The current work provides direct evidence of the contribution of increased peripheral and neuronal inflammation in seizures via regulation of inflammatory pathways in the brain.

Keywords: antiepileptic drugs; cognition; cytokine release; inflammation; lipopolysaccharide; pilocarpine-induced status epilepticus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticonvulsants* / pharmacology
  • Anticonvulsants* / therapeutic use
  • Disease Models, Animal
  • Lipopolysaccharides / therapeutic use
  • Lipopolysaccharides / toxicity
  • Mice
  • Mice, Inbred C57BL
  • Pilocarpine / toxicity
  • Status Epilepticus* / chemically induced
  • Status Epilepticus* / drug therapy

Substances

  • Anticonvulsants
  • Lipopolysaccharides
  • Pilocarpine