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Pharmaco-resistant Neonatal Seizures: Critical Mechanistic Insights from a Chemoconvulsant Model
Shivani C Kharod1, Brandon M Carter1, Shilpa D Kadam1,2
1Neuroscience Laboratory, Hugo Moser Research Institute at Kennedy Krieger, Baltimore, Maryland, 21205.
Insights
Phenobarbital (PB) effectively treats pentylenetetrazole (PTZ)-induced neonatal seizures by upregulating KCC2. However, seizure induction methods significantly influence PB efficacy and resistance mechanisms in translational models.
Area of Science:
- Neuroscience
- Developmental Neuroscience
- Pharmacology
Background:
- Neonatal seizures, particularly those from hypoxic-ischemic encephalopathy (HIE), pose risks for mortality and long-term neurological issues.
- Phenobarbital (PB) is the primary treatment for neonatal seizures but has a failure rate of approximately 50%.
- Understanding PB resistance mechanisms is vital, necessitating reliable translational models.
Purpose of the Study:
- To investigate the efficacy of phenobarbital (PB) in a pentylenetetrazole (PTZ)-induced neonatal seizure model.
- To explore the underlying mechanisms of PB resistance in this model, comparing it to an ischemic seizure model.
- To determine if seizure severity influences PB efficacy.
Main Methods:
- Utilized a pentylenetetrazole (PTZ) model in postnatal day 7 (P7) CD-1 mice to induce neonatal seizures.
- Administered a single dose of PB (25 mg/kg) to assess its anti-seizure effects.
- Analyzed K-Cl cotransporter 2 (KCC2) and Na-K-Cl cotransporter 1 (NKCC1) expression, and TrkB pathway activation.
- Compared seizure burden and PB efficacy with previously reported data from an ischemic seizure model.
Main Results:
- PB significantly suppressed PTZ-induced seizures.
- This suppression was linked to KCC2 upregulation and stable NKCC1 expression, without TrkB pathway activation.
- PTZ seizure burdens were higher than in the ischemic model, suggesting seizure severity does not solely determine PB resistance.
- Bumetanide (BTN) showed no anti-seizure effect, mirroring findings in the ischemic model.
Conclusions:
- The method of seizure induction critically impacts the mechanisms underlying phenobarbital (PB) resistance in neonatal seizure models.
- The pentylenetetrazole (PTZ) model demonstrates PB efficacy with KCC2 upregulation, contrasting with PB resistance observed in ischemic models.
- Investigating seizure mechanisms requires careful consideration of the specific model used to induce seizures.
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.
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