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Study of the Functions and Activities of Neuronal K-Cl Co-Transporter KCC2 Using Western Blotting
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Study of the Functions and Activities of Neuronal K-Cl Co-Transporter KCC2 Using Western Blotting

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Dose-dependent reversal of KCC2 hypofunction and phenobarbital-resistant neonatal seizures by ANA12

B M Carter1, B J Sullivan1, J R Landers1

  • 1Neuroscience Laboratory, Hugo Moser Research Institute at Kennedy Krieger, Baltimore, MD, USA.

Scientific Reports
|August 12, 2018
PubMed

Insights

ANA12, a TrkB antagonist, effectively treated phenobarbital-resistant neonatal seizures in mice by restoring KCC2 function. This offers a promising therapeutic strategy for refractory seizures in newborns.

Area of Science:

  • Neuroscience
  • Neonatal Neurology
  • Pharmacology

Background:

  • Neonatal seizures affect 3.5 per 1000 newborns, with hypoxic-ischemic encephalopathy (HIE) being a major cause.
  • Half of HIE cases are resistant to first-line anti-seizure drugs like phenobarbital (PB).
  • Tyrosine receptor kinase B (TrkB) activation post-ischemia increases neuronal excitability by downregulating K-Cl co-transporter 2 (KCC2).

Purpose of the Study:

  • To evaluate the anti-seizure efficacy of ANA12, a selective TrkB antagonist, in neonatal ischemia models.
  • To investigate ANA12's effects on KCC2 function and TrkB pathway activation following ischemia.
  • To determine if ANA12 can rescue phenobarbital-resistant neonatal seizures.

Main Methods:

  • Three doses of ANA12 were administered to CD1 mice at postnatal days 7 and 10 after inducing neonatal ischemia.
  • Phenobarbital (PB) loading dose was kept constant across all groups.
  • Efficacy was assessed via electroencephalography (EEG) seizure burden, KCC2/pKCC2-S940 levels, and TrkB pathway activation.

Main Results:

  • ANA12 dose-dependently rescued PB-resistant seizures at P7 and improved PB efficacy at P10.
  • ANA12 reversed post-ischemic KCC2 downregulation and TrkB pathway activation at P7, where PB was ineffective alone.
  • Female pups showed a better response to lower ANA12 doses compared to males.

Conclusions:

  • ANA12 demonstrates significant anti-seizure efficacy in neonatal ischemia, particularly for PB-resistant cases.
  • Restoring KCC2 hypofunction via TrkB antagonism is a critical mechanism for preventing refractory neonatal seizures.
  • ANA12 presents a potential therapeutic avenue for managing challenging neonatal seizure conditions.

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