Novel Therapies for Neonatal Seizures December 3, 2010

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1 Novel Therapies for Neonatal Seizures December 3, 2010 Kevin Staley Massachusetts General Hospital Harvard Medical School American Epilepsy Society Annual Meeting

2 Disclosure Name of Commercial Interest None Type of Financial Relationship None Volodya Dzhala Joseph Glykys Waldi Swiercz American Epilepsy Society Annual Meeting

3 The concentration of chloride in neurons: A. Is increased by the chloride transporter NKCC1 B. Is decreased by the chloride transporter KCC2 C. Changes the size and direction of current flowing through GABA A ion channels D. Alters the efficacy of anticonvulsants E. All of the above

4 Neonatal seizures: now vs. 50 years ago same treatment: phenobarbital, phenytoin same outcomes 58% eventually responded to R X Seizure frequency Painter, Scher, Stein NEJM 1999

5 Neonatal seizures: now vs. 50 years % Incidence Holden et al Peds 82 (NCPP) All births 25%<2.5kg ago same treatment: phenobarbital, phenytoin same outcomes Brunquell et al J Peds 02 2 All NICU 33% < 2.5kg % Mortality Pisani et al Neurology 07 5 All NICU 50%< 2.5 kg % Cerebral Palsy % Mental Retardation

6 KCC2 and NKCC1 Cl transporters set neuronal Cl i and thus the direction of GABA gated Cl currents GABA is inhibitory GABA is excitatory NKCC1 Pb Na +, K + 2 Cl Mature neurons Developing neurons Modified from Staley Nat Med 9:1110

7 Hypothesis: injuries causing cytoxic edema Trauma Hypoxia Seizures Lead to: Salt (i.e. Cl) accumulation in neurons Reversal of GABA A currents Loss of inhibition Seizures Anticonvulsant failure

8 Measuring neuronal Cl concentration ( Cl i ) using Clomeleon, a genetically expressed dual wavelength sensor of Cl i 1% df YFP ~ 3 mm Cl i = mean of 75 neurons 1. Shallow YFP/CFP ratio vs Cl i 2. YFP is sensitive to ph and oxidation 3. Tissue scattering of yellow light > cyan, so Ratio (Cl i ) changes with tissue path length Background subtraction must be done per frame Kuner et al. Neuron 2000 Gykys et al. Neuron 2009

9 What is the physiogical neuronal Cl and E GABA? P5 whole hippocampus GABA agonist GABA reduces action potentials i.e. it is inhibitory Spike frequency, Hz

10 Post traumatic changes in E GABA Brain slice: worst case shear injury? van den Pol J Neurosci 1996

11 Neuronal Cl i in brain slices is increased near the cut edges P6 acute hippcampal slice Z stack of CA1 neurons in P6 hippocampal slice Cut surface Cl i, mm Cl i, mm

12 Interneurons and pyramidal cells Intact P6 hippocampal prep Neuronal Cl i in non traumatized whole hippocampal preparation

13 Neuronal Cl i near cut edges of brain slices 0 50um um um P6 CA3, acute hippocampal slice P6 CA3, whole hippocampus 0 50um um um

14 Traumatic axotomy: Cl i changes the GABA A response from inhibition to excitation GABA A agonist slice GABA A agonist

15 Slice trauma increases Cl i in mature neurons also Cl i mm

16 Oxygen Glucose Deprivation increases neuronal Cl i Oxygen Glucose Deprivation: Late Cl i in acute slices adult mice Pond et al. J Neurosci M bumetanide OGD in P5 hippocampus: also sustained Cl i

17 Ictal, NKCC1 dependent increase in neuronal Cl i P6, 0 Mg 2+ o Dzhala et al J Neurosci 2010

18 Control Therapeutic implications: Traumatic / hypoxic / ictal Cl i reverses GABA currents, causing Pb to fail P5 whole hippocampus Pb works great after 1 2 seizures Pb fails if R X after many sz Summary: Phenobarbital efficacy, % Dzhala et al P5 J whole Neurosci hippocampal preparation 2010

19 Therapeutic implications: Pb efficacy by blocking Cl i via NKCC1 after traumatic / hypoxic / ictal injury P5 rat Whole hippocampus 0 Mg 2+ o seizures Dzhala et al. Ann Neurol 2008

20 Electroclinical uncoupling of neonatal seizures PB 81% of EEG seizures + EEG 19% of EEG seizures 27% of clinically identified seizures no clinical signs + clinical signs no EEG seizure 73% of clinically identified seizures Murray, Boylan et al. Arch. Dis. Child Mizrahi Neurology 1987

21 Uncoupling of neonatal seizures as a consequence of regional variance in Cl i NKCC1: GABA Excites KCC2: GABA Inhibits Glykys et al. Neuron 2009 G GABA Barbiturates Benzodiazepines

22 Bumetanide trials: Risks of conventional vs bumetanide R X Silver stain, thalamus Ikonomidou et al. Ann NY Acad Sci 993:104 Ge et al. Nature 439: 589, 2006 Wang and Kriegstein J Nsci 2008 Cancedda and Poo J NSci 2008

23 At risk neonates: HI Post hypoxic Cl i Continuous EEG monitoring Uncoupling: can t use clinical observation EEG seizures Post ictal Cl i GABA excitation seizures Phenobarbital 20 mg / kg Study entry: consent, randomization Further EEG seizures Cl i GABA excitation Pb failure Randomize Phenobarbital qs 30 mg / kg Phenobarbital qs 30 mg / kg + Bumetanide mg / kg Bumetanide: NKCC1 Cl i GABA inhibits so Pb works: synergy

24 Collaborators Massachusetts General Hospital Volodymyr Dzhala Joseph Glykys Waldemar Swiercz Kristopher Kahle Kishore Kuchibhotla Brian Bacskai University of Colorado Audrey Brumback (UCSF) Tim Benke Dan Sdrulla (Wash U) Duke / Singapore George Augustine Boston Children s Frances Jensen Janet Soul Delia Talos Vanderbilt Eric Delpire Greg Matthews U Heidelburg Thomas Kuner MIT Guoping Feng

25 The concentration of chloride in neurons: A. Is increased by the chloride transporter NKCC1 B. Is decreased by the chloride transporter KCC2 C. Changes the size and direction of current flowing through GABA A ion channels D. Alters the efficacy of anticonvulsants E. All of the above

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