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. Author manuscript; available in PMC: 2015 Jan 12.
Published in final edited form as: Austin J Cerebrovasc Dis Stroke. 2014 Oct 9;1(6):1026.

Table 1.

Pre-clinical models of electrographic neonatal seizures.

Injury type Model Reference Cl− co-transporter
expression modulation on
day of insult		 Bumetanide
delivery paradigm		 Bumetanide
anti-seizure efficacy
at 0.1 – 0.2 mg/kg** 		Bumetanide with PB
anti-seizure efficacy
Chemo-
convulsant 		Kainic acid in P9 -12 rat Dzhala et al., 20051 N/A 15 min
post-kainic acid		 Anti-seizure + N/A
Kainic acid P5 -7 rat
hippocampus		 Khirug et al., 20102 KCC2 ↑NKCC1 N/A
1 h post-seizure		 N/A N/A N/A
Low Mg2+ in P4 - 6 rat Dzhala et al., 20083 N/A Post- 6 recurrent
seizures induced by
low Mg2+ 		Anti-seizure + Anti-seizure +
PTZ in P7, 12, 18 rat Mares., 20094 N/A Pre-treatment
20 min prior to PTZ		 No effect N/A
Hypoxia 15 min global hypoxia
in P10 rat		 Cleary et al., 20135 KCC2 no change NKCC1 ↑
1 h post-hypoxia		 Pre-treatment
15 min prior to
hypoxia onset		 No effect Anti-seizure +
Ischemia Permanent unilateral
carotid ligation
in P7 and P10 mouse		 Kadam et al., 20116 KCC2 ↓ NKCC1 ↑
4–24h post-ischemia (Fig. 1)		 2 h
post-ischemia onset		 No effect No effect
Kindling Rapid kindling for
80mins
in P11, 14, 21 rat		 Mazarati et al., 20097 N/A Pre-treatment
20 min prior to
kindling		 No effect N/A
*

Flurothyl model in P5-9 rat has reported no anti-seizure effect of higher dose bumetanide (1.8mg/kg) by itself: no Cl− co-transporter expression modulation known (Minlebaev and Khazipov, 20118).

**

The range of bumetanide doses and effects tabulated here are for 0.1–0.2mg/kg based on the dosage proposed in clinical trials (NCT01434225; NCT00380531).

Note: (1) Dzhala VI, Talos DM, Sdrulla DA et al. NKCC1 transporter facilitates seizures in the developing brain. Nat Med 2005;11(11):1205–1213. (2) Khirug S, Ahmad F, Puskarjov M, Afzalov R, Kaila K, Blaesse P. A single seizure episode leads to rapid functional activation of KCC2 in the neonatal rat hippocampus. J Neurosci 2010;30(36):12028–12035. (3) Dzhala VI, Brumback AC, Staley KJ. Bumetanide enhances phenobarbital efficacy in a neonatal seizure model. Ann Neurol 2008;63(2):222–235. (4) Mares P. Age- and dose-specific anticonvulsant action of bumetanide in immature rats. Physiol Res 2009;58(6):927–930. (5) Cleary RT, Sun H, Huynh T et al. Bumetanide enhances phenobarbital efficacy in a rat model of hypoxic neonatal seizures. PLoS One 2013;8(3):e57148. (6) Kadam SD, Markowitz GJ, Kang SK, Kim ST, Johnston MV. Age and gender dependent severity of ischemic neonatal seizures: response to phenobarbital + bumetanide combination therapy in a mouse model. AES annual meeting #3.035 . 2011. (7) Mazarati A, Shin D, Sankar R. Bumetanide inhibits rapid kindling in neonatal rats. Epilepsia 2009;50(9):2117–2122. (8) Minlebaev M, Khazipov R. Antiepileptic effects of endogenous beta-hydroxybutyrate in suckling infant rats. Epilepsy Res 2011;95(1–2):100–109.