title: Erythropoietin attenuates loss of potassium chloride co-transporters following prenatal brain injury.
abstract: Therapeutic agents that restore the inhibitory actions of γ-amino butyric acid (GABA) by modulating intracellular chloride concentrations will provide novel avenues to treat stroke, chronic pain, epilepsy, autism, and neurodegenerative and cognitive disorders. During development, upregulation of the potassium-chloride co-transporter KCC2, and the resultant switch from excitatory to inhibitory responses to GABA guide the formation of essential inhibitory circuits. Importantly, maturation of inhibitory mechanisms is also central to the development of excitatory circuits and proper balance between excitatory and inhibitory networks in the developing brain. Loss of KCC2 expression occurs in postmortem samples from human preterm infant brains with white matter lesions. Here we show that late gestation brain injury in a rat model of extreme prematurity impairs the developmental upregulation of potassium chloride co-transporters during a critical postnatal period of circuit maturation in CA3 hippocampus by inducing a sustained loss of oligomeric KCC2 via a calpain-dependent mechanism. Further, administration of erythropoietin (EPO) in a clinically relevant postnatal dosing regimen following the prenatal injury protects the developing brain by reducing calpain activity, restoring oligomeric KCC2 expression and attenuating KCC2 fragmentation, thus providing the first report of a safe therapy to address deficits in KCC2 expression. Together, these data indicate it is possible to reverse abnormalities in KCC2 expression during the postnatal period, and potentially reverse deficits in inhibitory circuit formation central to cognitive impairment and epileptogenesis.
authors.affiliation: Department of Neurology, Boston Children's Hospital & Harvard Medical School, 300 Longwood Avenue, Boston MA 02115, USA; Department of Neurosurgery, Boston Children's Hospital & Harvard Medical School, 300 Longwood Avenue, Boston MA 02115, USA.
authors.forename: L L
authors.initials: LL
authors.lastname: Jantzie
authors.affiliation: Department of Pediatrics, Case Western Reserve University School of Medicine, 10900 Euclid Ave., Cleveland, OH 44106, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Getsy
authors.affiliation: Department of Neurology, Boston Children's Hospital & Harvard Medical School, 300 Longwood Avenue, Boston MA 02115, USA; Department of Neurosurgery, Boston Children's Hospital & Harvard Medical School, 300 Longwood Avenue, Boston MA 02115, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Firl
authors.affiliation: Department of Pediatrics, Case Western Reserve University School of Medicine, 10900 Euclid Ave., Cleveland, OH 44106, USA.
authors.forename: C G
authors.initials: CG
authors.lastname: Wilson
authors.affiliation: Department of Neurosciences, Case Western Reserve University School of Medicine, 10900 Euclid Ave., Cleveland, OH 44106, USA.
authors.forename: R H
authors.initials: RH
authors.lastname: Miller
authors.affiliation: Department of Neurology, Boston Children's Hospital & Harvard Medical School, 300 Longwood Avenue, Boston MA 02115, USA; Department of Neurosurgery, Boston Children's Hospital & Harvard Medical School, 300 Longwood Avenue, Boston MA 02115, USA. Electronic address: Shenandoah.Robinson@childrens.harvard.edu.
authors.forename: S
authors.initials: S
authors.lastname: Robinson
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004921:Erythropoietin / Q000276:immunology / Q000627:therapeutic use*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D026121:Indole Alkaloids / Q000494:pharmacology; D002546:Ischemic Attack, Transient / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D027981:Symporters / Q000378:metabolism*; D000096922:K Cl- Cotransporters
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D004791:Enzyme Inhibitors; D004921:Erythropoietin; D018690:Excitatory Amino Acid Agonists; D026121:Indole Alkaloids; D016202:N-Methylaspartate; D018696:Neuroprotective Agents; D027981:Symporters; D000096922:K Cl- Cotransporters; C049985:staurosporine aglycone
keywords: Calpain; Erythropoietin; Hypoxia–ischemia; KCC2; Perinatal brain injury