1. ¹Institute of Neuroscience and Physiology, Göteborg University, Göteborg, Sweden
2. ²Department of Pediatrics, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
3. ³Centre National de la Recherche Scientifique, FRE 2939, Institut Gustave Roussy, Villejuif, France
4. ⁴Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Göteborg, Sweden
5. ⁵Department of Pharmacy, Pharmaceutical Biology and Biotechnology, University of Munich, Munich, Germany
6. ⁶Laboratory of Experimental Neurosurgery, Department of Neurosurgery and Institute for Surgical Research, University of Munich Medical Center – Grosshadern, Munich, Germany
7. ⁷Department of Pediatric Oncology, The Queen Silvia Children's Hospital, Göteborg University, Göteborg, Sweden

Correspondence: C Zhu, Institute of Neuroscience and Physiology, Göteborg University, Box 432, SE 405 30 Göteborg, Sweden. Tel: +46 31 773 3339; Fax: +46 31 773 3401; E-mail: changlian.zhu@neuro.gu.se

Received 11 July 2006; Revised 4 September 2006; Accepted 13 September 2006; Published online 13 October 2006.

Abstract

Nine-day-old harlequin (Hq) mice carrying the hypomorphic apoptosis-inducing factor (AIF)^Hq mutation expressed 60% less AIF, 18% less respiratory chain complex I and 30% less catalase than their wild-type (Wt) littermates. Compared with Wt, the infarct volume after hypoxia-ischemia (HI) was reduced by 53 and 43% in male (YX^Hq) and female (X^HqX^Hq) mice, respectively (P<0.001). The Hq mutation did not inhibit HI-induced mitochondrial release of cytochrome c or activation of calpain and caspase-3. The broad-spectrum caspase inhibitor quinoline-Val-Asp(OMe)-CH₂-PH (Q-VD-OPh) decreased the activation of all detectable caspases after HI, both in Wt and Hq mice. Q-VD-OPh reduced the infarct volume equally in Hq and in Wt mice, and the combination of Hq mutation and Q-VD-OPh treatment showed an additive neuroprotective effect. Oxidative stress leading to nitrosylation and lipid peroxidation was more pronounced in ischemic brain areas from Hq than Wt mice. The antioxidant edaravone decreased oxidative stress in damaged brains, more pronounced in the Hq mice, and further reduced brain injury in Hq but not in Wt mice. Thus, two distinct strategies can enhance the neuroprotection conferred by the Hq mutation, antioxidants, presumably compensating for a defect in AIF-dependent redox detoxification, and caspase inhibitors, presumably interrupting a parallel pathway leading to cellular demise.