Neuroprotective effect of Bax-inhibiting peptide on neonatal brain injury.
OBJECTIVE
Mitochondria play a critical role in mediating cell death in both the adult and immature brain. The cyclophilin D mitochondrial membrane permeability transition pore is critical in adult ischemia, whereas in neonatal hypoxic-ischemic (HI) brain injury, mitochondrial permeabilization appears to be primarily Bax-dependent. The aim of this study was to evaluate the neuroprotective effect of a cell-penetrating Bax-inhibiting peptide (BIP) on neonatal mouse HI brain injury.


METHODS
BIP (5 microL, 5 mg/mL) or a BIP-negative control (5 microL, 5 mg/mL) was injected intracerebroventricularly immediately before HI in postnatal day 9 mice. Mice were euthanized at different time points after HI for evaluation of brain injury, Bax activation, release of proapoptotic proteins, and caspase activation. The trace fear conditioning and cylinder tests were performed for evaluation of the functional recovery after BIP treatment.


RESULTS
At 5 days after HI, there was a 41.2% reduction of brain injury in BIP-treated mice compared with BIP-negative control treated animals. Myelin basic protein and neurofilament quantification revealed that BIP reduced white matter injury. BIP treatment conferred improvement in both sensorimotor and memory functions at 7 weeks after HI. BIP protection was associated with a reduction of Bax activation, mitochondrial permeabilization, and downstream caspase activation.


CONCLUSIONS
Bax inhibition provides neuroprotection and functional improvement in a neonatal mouse model of HI.
Wang
Xiaoyang
X
Department of Physiology, Perinatal Center, Sahlgrenska Academy, University of Gothenburg, Box 432, S-405 30 Gothenburg, Sweden. xiaoyang.wang@fysiologi.gu.se
Han
Wei
W
Du
Xiaonan
X
Zhu
Changlian
C
Carlsson
Ylva
Y
Mallard
Carina
C
Jacotot
Etienne
E
Hagberg
Henrik
H
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D003213:Conditioning, Psychological / Q000187:drug effects; D005260:Female; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D020127:Recovery of Function / Q000187:drug effects*; D018709:Statistics, Nonparametric
C539791:Bax-inhibiting peptide, BIP; D018696:Neuroprotective Agents; D009842:Oligopeptides