Pharmaco-resistant Neonatal Seizures: Critical Mechanistic Insights from a Chemoconvulsant Model

Dev Neurobiol. 2018 Nov;78(11):1117-1130. doi: 10.1002/dneu.22634. Epub 2018 Aug 31.

Abstract

Neonatal seizures are harmful to the developing brain and are associated with mortality and long-term neurological comorbidities. Hypoxic-ischemic encephalopathy (HIE) seizures represent a significant proportion of such seizures. Phenobarbital (PB) remains the first line anti-seizure drug (ASD) treatment but fails ~50% of the time. Translational models of neonatal seizures are crucial to investigating mechanisms underlying PB-resistance. A model of PB-resistant ischemic seizures in postnatal day 7 (P7) CD-1 mice reported K-Cl cotransporter 2 (KCC2) degradation that has been shown to be due to activation of the TrkB pathway. We investigated PB-efficacy in a pentylenetetrazole (PTZ) model of neonatal seizures in the same strain and age using identical treatment protocols to gain insights into mechanisms underlying PB-resistance. A single dose of PTZ (80 mg/kg; IP) consistently induced repetitive seizures that did not progress to status epilepticus (SE). PB (25 mg/kg; IP, single dose) significantly suppressed the PTZ-induced seizures. This was associated with significant KCC2 upregulation and stable Na-K-Cl cotransporter 1 (NKCC1) expression at 24h. The TrkB pathway was not activated. PTZ seizure burdens were significantly higher than those reported for ischemic seizures, indicating seizure severity did not dictate the differences in PB-efficacy. Bumetanide (BTN) (0.1-0.2 mg/kg; IP) did not work as an anti-seizure agent, similar to the ischemic model. When investigating mechanisms underlying the emergence of PB-resistance in translational models, the method by which seizures are induced may dictate mechanisms underlying emergence of PB-resistance.

Keywords: KCC2; bumetanide; neonatal seizures; pentylenetetrazole; phenobarbital.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Newborn
  • Anticonvulsants / pharmacology*
  • Brain / drug effects*
  • Brain / metabolism
  • Brain / virology
  • Disease Models, Animal
  • K Cl- Cotransporters
  • Male
  • Mice
  • Phenobarbital / pharmacology*
  • Seizures / virology*
  • Symporters / drug effects*

Substances

  • Anticonvulsants
  • Symporters
  • Phenobarbital