Pharmaco-resistant Neonatal Seizures: Critical Mechanistic Insights from a Chemoconvulsant Model.
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.
Pubmed ID: 30136373 RIS Download
Research resources used in this publication
- Alpha-Tubulin Mouse Monoclonal Antibody (RRID:AB_2637092) (antibody)
- Anti-phospho-TrkB (Tyr816) Antibody (RRID:AB_2721199) (antibody)
- Mouse Anti-TrkB Monoclonal Antibody, Unconjugated, Clone 47 (RRID:AB_397508) (antibody)
- KCC2 Antibody (Phospho-Ser940) (RRID:AB_2721198) (antibody)
- KCC2 Antibody (RRID:AB_2721238) (antibody)
- Rabbit Anti-KCC2 (K+ / Cl- Cotransporter) Polyclonal antibody, Unconjugated (RRID:AB_310611) (antibody)
- Rabbit Anti-Na+-K+-Cl- Cotransporter 1 (NKCC1) Polyclonal antibody, Unconjugated (RRID:AB_91514) (antibody)
- Phospho-PLCgamma1 (Tyr783) Antibody (RRID:AB_330855) (antibody)
- PLCG1 Monoclonal Antibody (2B1) (RRID:AB_2163544) (antibody)
- Anti-phospho-TrkB (Tyr816) Antibody (RRID:AB_2721199) (antibody)
- Alpha-Tubulin Mouse Monoclonal Antibody (RRID:AB_2637092) (antibody)
- Phospho-PLCgamma1 (Tyr783) Antibody (RRID:AB_330855) (antibody)
- Rabbit Anti-KCC2 (K+ / Cl- Cotransporter) Polyclonal antibody, Unconjugated (RRID:AB_310611) (antibody)
- KCC2 Antibody (Phospho-Ser940) (RRID:AB_2721198) (antibody)
- KCC2 Antibody (RRID:AB_2721238) (antibody)
- Mouse Anti-TrkB Monoclonal Antibody, Unconjugated, Clone 47 (RRID:AB_397508) (antibody)
- PLCG1 Monoclonal Antibody (2B1) (RRID:AB_2163544) (antibody)
- Rabbit Anti-Na+-K+-Cl- Cotransporter 1 (NKCC1) Polyclonal antibody, Unconjugated (RRID:AB_91514) (antibody)
Additional research tools detected in this publication
None foundAntibodies used in this publication
- KCC2 Antibody (Phospho-Ser940) (RRID:AB_2721198)
- Rabbit Anti-KCC2 (K+ / Cl- Cotransporter) Polyclonal antibody, Unconjugated (RRID:AB_310611)
- PLCG1 Monoclonal Antibody (2B1) (RRID:AB_2163544)
- Mouse Anti-TrkB Monoclonal Antibody, Unconjugated, Clone 47 (RRID:AB_397508)
- Rabbit Anti-Na+-K+-Cl- Cotransporter 1 (NKCC1) Polyclonal antibody, Unconjugated (RRID:AB_91514)
- Alpha-Tubulin Mouse Monoclonal Antibody (RRID:AB_2637092)
- Anti-phospho-TrkB (Tyr816) Antibody (RRID:AB_2721199)
- Phospho-PLCgamma1 (Tyr783) Antibody (RRID:AB_330855)
- KCC2 Antibody (RRID:AB_2721238)
Associated grants
- Agency: NICHD NIH HHS, United States
Id: R01 HD090884
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This is a list of tools and resources that we have found mentioned in this publication.
KCC2 Antibody (Phospho-Ser940) (antibody)
RRID:AB_2721198
This polyclonal targets KCC2
View all literature mentionsRabbit Anti-KCC2 (K+ / Cl- Cotransporter) Polyclonal antibody, Unconjugated (antibody)
RRID:AB_310611
This polyclonal targets KCC2 (K+ / Cl- Cotransporter)
View all literature mentionsPLCG1 Monoclonal Antibody (2B1) (antibody)
RRID:AB_2163544
This monoclonal targets PLCG1
View all literature mentionsMouse Anti-TrkB Monoclonal Antibody, Unconjugated, Clone 47 (antibody)
RRID:AB_397508
This monoclonal targets TrkB
View all literature mentionsRabbit Anti-Na+-K+-Cl- Cotransporter 1 (NKCC1) Polyclonal antibody, Unconjugated (antibody)
RRID:AB_91514
This polyclonal targets Na+-K+-Cl- Cotransporter 1 (NKCC1)
View all literature mentionsAlpha-Tubulin Mouse Monoclonal Antibody (antibody)
RRID:AB_2637092
This monoclonal targets alpha-Tubulin
View all literature mentionsAnti-phospho-TrkB (Tyr816) Antibody (antibody)
RRID:AB_2721199
This polyclonal targets TrkB
View all literature mentionsPhospho-PLCgamma1 (Tyr783) Antibody (antibody)
RRID:AB_330855
This polyclonal targets Phospho-PLCgamma1 (Tyr783)
View all literature mentionsAlpha-Tubulin Mouse Monoclonal Antibody (antibody)
RRID:AB_2637092
This monoclonal targets alpha-Tubulin
View all literature mentionsAnti-phospho-TrkB (Tyr816) Antibody (antibody)
RRID:AB_2721199
This polyclonal targets TrkB
View all literature mentionsMouse Anti-TrkB Monoclonal Antibody, Unconjugated, Clone 47 (antibody)
RRID:AB_397508
This monoclonal targets TrkB
View all literature mentionsKCC2 Antibody (Phospho-Ser940) (antibody)
RRID:AB_2721198
This polyclonal targets KCC2
View all literature mentionsRabbit Anti-KCC2 (K+ / Cl- Cotransporter) Polyclonal antibody, Unconjugated (antibody)
RRID:AB_310611
This polyclonal targets KCC2 (K+ / Cl- Cotransporter)
View all literature mentionsRabbit Anti-Na+-K+-Cl- Cotransporter 1 (NKCC1) Polyclonal antibody, Unconjugated (antibody)
RRID:AB_91514
This polyclonal targets Na+-K+-Cl- Cotransporter 1 (NKCC1)
View all literature mentionsPhospho-PLCgamma1 (Tyr783) Antibody (antibody)
RRID:AB_330855
This polyclonal targets Phospho-PLCgamma1 (Tyr783)
View all literature mentionsPLCG1 Monoclonal Antibody (2B1) (antibody)
RRID:AB_2163544
This monoclonal targets PLCG1
View all literature mentionsAnti-phospho-TrkB (Tyr816) Antibody (antibody)
RRID:AB_2721199
This polyclonal targets TrkB
View all literature mentionsAlpha-Tubulin Mouse Monoclonal Antibody (antibody)
RRID:AB_2637092
This monoclonal targets alpha-Tubulin
View all literature mentionsPhospho-PLCgamma1 (Tyr783) Antibody (antibody)
RRID:AB_330855
This polyclonal targets Phospho-PLCgamma1 (Tyr783)
View all literature mentionsRabbit Anti-KCC2 (K+ / Cl- Cotransporter) Polyclonal antibody, Unconjugated (antibody)
RRID:AB_310611
This polyclonal targets KCC2 (K+ / Cl- Cotransporter)
View all literature mentionsKCC2 Antibody (Phospho-Ser940) (antibody)
RRID:AB_2721198
This polyclonal targets KCC2
View all literature mentionsMouse Anti-TrkB Monoclonal Antibody, Unconjugated, Clone 47 (antibody)
RRID:AB_397508
This monoclonal targets TrkB
View all literature mentionsPLCG1 Monoclonal Antibody (2B1) (antibody)
RRID:AB_2163544
This monoclonal targets PLCG1
View all literature mentionsRabbit Anti-Na+-K+-Cl- Cotransporter 1 (NKCC1) Polyclonal antibody, Unconjugated (antibody)
RRID:AB_91514
This polyclonal targets Na+-K+-Cl- Cotransporter 1 (NKCC1)
View all literature mentions
