Targeting the mitochondrial permeability transition pore for neuroprotection in a piglet model of neonatal hypoxic‐ischemic encephalopathy. Issue 6 (5th March 2021)

• Record Type: Journal Article
• Authors: Chen, May W.; Santos, Polan; Kulikowicz, Ewa; Koehler, Raymond C.; Lee, Jennifer K.; Martin, Lee J.
• Is Part Of: Journal of neuroscience research. Volume 99:Issue 6(2021)
• Page Start: 1550
• Page End: 1564
• Publication Date: 2021-03-05
• Subjects: ANT -- CypD -- ischemic‐necrosis -- mitochondria -- neonatal brain damage -- neuronal cell death -- neuroprotection -- RRID:AB_478282 -- RRID:AB_2191808 -- RRID:AB_2630358 -- RRID:AB_2756816 -- RRID:AB_10862212 -- RRID:AB_10864110 -- RRID:SCR_002798 -- RRID:SCR_003210 -- VDAC; Neurobiology -- Periodicals; 612
• DOI: 10.1002/jnr.24821
• Languages: English
• ISSNs: 0360-4012

Abstract

Abstract: Neonatal hypoxic‐ischemic encephalopathy (HIE) causes significant morbidity despite treatment with therapeutic hypothermia. Mitochondrial dysfunction may drive the mechanisms underlying neuronal cell death, thereby making mitochondria prime targets for neuroprotection. The mitochondrial permeability transition pore (mPTP) is one such target within mitochondria. In adult animal models, mPTP inhibition is neuroprotective. However, evidence for mPTP inhibition in neonatal models of neurologic disease is less certain. We tested the therapeutic efficacy of the mPTP small molecule inhibitor GNX‐4728 and examined the developmental presence of brain mPTP proteins for drug targeting in a neonatal piglet model of hypoxic‐ischemic brain injury. Male neonatal piglets were randomized to hypoxia‐ischemia (HI) or sham procedure with GNX‐4728 (15 mg/kg, IV) or vehicle (saline/cyclodextrin/DMSO, IV). GNX‐4728 was administered as a single dose within 5 min after resuscitation from bradycardic arrest. Normal, ischemic, and injured neurons were counted in putamen and somatosensory cortex using hematoxylin and eosin staining. In separate neonatal and juvenile pigs, western blots of putamen mitochondrial‐enriched fractions were used to evaluate mitochondrial integrity and the presence of mPTP proteins. We found that a single dose of GNX‐4728 did not protect putamen and cortical neurons from cell death after HI. However, loss of mitochondrial matrix integrity occurred within 6h after HI, and while mPTP components are present in the neonatal brain their levels were significantly different compared to that of a mature juvenile brain. Thus, the neonatal brain mPTP may not be a good target for current neurotherapeutic drugs that are developed based on adult mitochondria. Abstract : GNX‐4728, a mitochondrial permeability transition pore inhibitor, does not protect against hypoxia‐ischemia induced neuronal necrosis in piglet putamen (indicated by bolt strike zone). Acute depletion of mitochondrial SOD2 and developmental differences in mitochondrial proteins, such as CypD, may limit the efficacy of mitochondrial‐targeted drugs for neonatal brain injury.