2. Academic Validation
  3. The cell-permeable mitochondrial calcium uniporter inhibitor Ru265 preserves cortical neuron respiration after lethal oxygen glucose deprivation and reduces hypoxic/ischemic brain injury

The cell-permeable mitochondrial calcium uniporter inhibitor Ru265 preserves cortical neuron respiration after lethal oxygen glucose deprivation and reduces hypoxic/ischemic brain injury

  • J Cereb Blood Flow Metab. 2020 Jun;40(6):1172-1181. doi: 10.1177/0271678X20908523.
Robyn J Novorolsky 1 2,  Matthew Nichols 1 2,  Jong S Kim 3 4,  Evgeny V Pavlov 5,  Joshua J Woods 6,  Justin J Wilson 6,  George S Robertson 1 2 7
Affiliations

Affiliations

  • 1 Department of Pharmacology, Faculty of Medicine, Dalhousie University, Life Sciences Research Institute, Halifax, Canada.
  • 2 Brain Repair Centre, Faculty of Medicine, Dalhousie University, Life Sciences Research Institute, Halifax, Canada.
  • 3 Department of Community Health and Epidemiology, Faculty of Medicine, Centre for Clinical Research, Dalhousie University, Halifax, Nova Scotia, Canada.
  • 4 Department of Microbiology, Faculty of Medicine, Centre for Clinical Research, Dalhousie University, Nova Scotia, Canada.
  • 5 Department of Basic Sciences, College of Dentistry, New York University, NY, USA.
  • 6 Department of Chemistry and Chemical Biology, Cornell University, Baker Laboratory, Ithaca, NY, USA.
  • 7 Department of Psychiatry, Faculty of Medicine, Dalhousie University, Life Sciences Research Institute, Halifax, Canada.
PMID: 32126877 DOI: 10.1177/0271678X20908523
Abstract

The mitochondrial calcium (CA2+) uniporter (MCU) mediates high-capacity mitochondrial CA2+ uptake implicated in ischemic/reperfusion cell death. We have recently shown that inducible MCU ablation in Thy1-expressing neurons renders mice resistant to sensorimotor deficits and forebrain neuron loss in a model of hypoxic/ischemic (HI) brain injury. These findings encouraged us to compare the neuroprotective effects of Ru360 and the recently identified cell permeable MCU inhibitor Ru265. Unlike Ru360, Ru265 (2-10 µM) reached intracellular concentrations in cultured cortical neurons that preserved cell viability, blocked the Protease activity of CA2+-dependent calpains and maintained mitochondrial respiration and glycolysis after a lethal period of oxygen-glucose deprivation (OGD). Intraperitoneal (i.p.) injection of adult male C57Bl/6 mice with Ru265 (3 mg/kg) also suppressed HI-induced sensorimotor deficits and brain injury. However, higher doses of Ru265 (10 and 30 mg/kg, i.p.) produced dose-dependent increases in the frequency and duration of seizure-like behaviours. Ru265 is proposed to promote convulsions by reducing CA2+ buffering and energy production in highly energetic interneurons that suppress brain seizure activity. These findings support the therapeutic potential of MCU inhibition in the treatment of ischemic stroke but also indicate that such clinical translation will require Drug Delivery strategies which mitigate the pro-convulsant effects of Ru265.

Keywords

Calcium; cerebral ischemia; mitochondria; motor seizures; neuroprotection.

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