Premium
Pharmaco‐resistant Neonatal Seizures: Critical Mechanistic Insights from a Chemoconvulsant Model
Author(s) -
Kharod Shivani C.,
Carter Brandon M.,
Kadam Shilpa D.
Publication year - 2018
Publication title -
developmental neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.716
H-Index - 129
eISSN - 1932-846X
pISSN - 1932-8451
DOI - 10.1002/dneu.22634
Subject(s) - status epilepticus , neonatal seizure , phenobarbital , epilepsy , seizure threshold , downregulation and upregulation , encephalopathy , neuroscience , medicine , drug resistant epilepsy , pharmacology , anticonvulsant , anesthesia , biology , biochemistry , gene
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.