An Inhibitor of the Mitochondrial Permeability Transition Pore Lacks Therapeutic Efficacy Following Neonatal Hypoxia Ischemia in Mice

Research output: Contribution to journalArticle

Abstract

Neonatal hypoxic ischemic (HI) brain injury causes lifelong neurologic disability. Therapeutic hypothermia (TH) is the only approved therapy that partially mitigates mortality and morbidity. Therapies specifically targeting HI-induced brain cell death are currently lacking. Intracellular calcium dysregulation, oxidative stress, and mitochondrial dysfunction through the formation of the mitochondrial permeability transition pore (mPTP) are drivers of HI cellular injury. GNX-4728, a small molecule direct inhibitor of the mPTP that increases mitochondrial calcium retention capacity, is highly effective in adult neurodegenerative disease models and could have potential as a therapy in neonatal HI. A dose of GNX-4728, equivalent to that used in animal models, 300 mg/kg, IP was highly toxic in p10 mice. We then tested the hypothesis that acute administration of 30 mg/kg, IP of GNX-4728 immediately after HI in a neonatal mouse model would provide neuroprotection. This non-lethal lower dose of GNX-4728 (30 mg/kg, IP) improved the respiratory control ratio of neonatal female HI brain tissue but not in males. Brain injury, assessed histologically with a novel metric approach at 1 and 30 days after HI, was not mitigated by GNX-4728. Our work demonstrates that a small molecule inhibitor of the mPTP has i) an age related toxicity, ii) a sex-related brain mitoprotective profile after HI but iii) this is not sufficient to attenuate forebrain HI neuropathology.

Original languageEnglish (US)
Pages (from-to)202-211
Number of pages10
JournalNeuroscience
Volume406
DOIs
StatePublished - May 15 2019

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Ischemia
Brain Injuries
Calcium
Induced Hypothermia
Brain Death
Poisons
Brain
Prosencephalon
Neurodegenerative Diseases
Nervous System
Oxidative Stress
Cell Death
Therapeutics
Animal Models
Morbidity
Mortality
Wounds and Injuries
Hypoxia
mitochondrial permeability transition pore
Neuropathology

Keywords

  • mitochondrial respiratory control ratio
  • neonatal hypoxia ischemia
  • neuronal cell death
  • neuroprotection
  • therapeutics

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

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title = "An Inhibitor of the Mitochondrial Permeability Transition Pore Lacks Therapeutic Efficacy Following Neonatal Hypoxia Ischemia in Mice",
abstract = "Neonatal hypoxic ischemic (HI) brain injury causes lifelong neurologic disability. Therapeutic hypothermia (TH) is the only approved therapy that partially mitigates mortality and morbidity. Therapies specifically targeting HI-induced brain cell death are currently lacking. Intracellular calcium dysregulation, oxidative stress, and mitochondrial dysfunction through the formation of the mitochondrial permeability transition pore (mPTP) are drivers of HI cellular injury. GNX-4728, a small molecule direct inhibitor of the mPTP that increases mitochondrial calcium retention capacity, is highly effective in adult neurodegenerative disease models and could have potential as a therapy in neonatal HI. A dose of GNX-4728, equivalent to that used in animal models, 300 mg/kg, IP was highly toxic in p10 mice. We then tested the hypothesis that acute administration of 30 mg/kg, IP of GNX-4728 immediately after HI in a neonatal mouse model would provide neuroprotection. This non-lethal lower dose of GNX-4728 (30 mg/kg, IP) improved the respiratory control ratio of neonatal female HI brain tissue but not in males. Brain injury, assessed histologically with a novel metric approach at 1 and 30 days after HI, was not mitigated by GNX-4728. Our work demonstrates that a small molecule inhibitor of the mPTP has i) an age related toxicity, ii) a sex-related brain mitoprotective profile after HI but iii) this is not sufficient to attenuate forebrain HI neuropathology.",
keywords = "mitochondrial respiratory control ratio, neonatal hypoxia ischemia, neuronal cell death, neuroprotection, therapeutics",
author = "Jing Fang and Raul Chavez-Valdez and Flock, {Debbie L.} and Oliver Avaritt and Manda Saraswati and Courtney Robertson and Martin, {Lee J} and Frances Northington",
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AU - Fang, Jing

AU - Chavez-Valdez, Raul

AU - Flock, Debbie L.

AU - Avaritt, Oliver

AU - Saraswati, Manda

AU - Robertson, Courtney

AU - Martin, Lee J

AU - Northington, Frances

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