The Complex effects of Anti-Epileptic Drugs and Neonatal Seizures

In my invited commentary in Epilepsia we discuss the original research by Kaila, Löscher and colleagues (Johne et al. 2021) that illustrates the effects and lack of effects of Anti-Epileptic Drugs (AEDs) on asphyxia-induced neonatal seizures, and we suggest a possible scenario explaining why this happens. 

Using a new neonatal asphyxia model, the authors report different effects of Phenobarbital (PHB), Midazolam (MDZ) and the NKCC1 specific antagonist Bumetanide (BUM). We argue that this is due in part to the complex mechanisms that underlie the actions of GABA, and especially during development when it switches from depolarizing to hyperpolarizing actions, changes intracellular chloride concentration ([Cl]i) levels, and the type of seizures. Indeed, the efficacy -and heterogeneity of effects- of AEDs depends on the timing of administration, as well as the frequency and chronicity of recurrent seizures, the latter of which leads to augmented neuronal [Cl]i levels and a shift in GABA polarity.

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References :

  • Ben-Ari Y, Delpire E. Phenobarbital, midazolam, bumetanide, and neonatal seizures: The devil is in the details. Epilepsia. 2021, 
  • Johne M, Römermann K, Hampel P, Gailus B, Theilmann W, Ala-Kurikka T, et al. Phenobarbital and midazolam suppress neonatal seizures in a noninvasive rat model of birth asphyxia, whereas bumetanide is ineffective. Epilepsia. 2020; 

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