Spreading depression induces long-lasting brain protection against infarcted lesion development via BDNF gene-dependent mechanism.
Preconditioning the rat brain with spreading depression for 48 h induces potent ischemic tolerance (infarct tolerance) after an interval of 12-15 days, consequently reducing the infarcted lesion size in the acute phase following focal cerebral ischemia. However, persistence of the morphological and functional neuroprotection has not yet been proven. We tested whether tolerance-derived neuroprotection against focal cerebral ischemia persists or merely delays the progress of cerebral infarction. Prolonged spreading depression was induced in mice by placing a depolarized focus with intracerebral microinfusion of KCl for 24 h; after intervals of 3, 6, 9 or 12 days, temporary focal ischemia was imposed. In the analysis of the infarcted lesion volume 24 h after ischemia, groups with 6 or 9 day interval demonstrated significantly smaller lesion volume compared to time-matched vehicle control group (P=0.002). Significant reduction in cerebral infarction was also observed at the chronic phase, namely 14 days after ischemia (33% reduction) (P=0.021) accompanied with less severe neurological deficits (38% reduction) (P=0.020). Using this technique, we also investigated if the mice with targeted disruption of a single BDNF allele (heterozygous BDNF-deficient mice) can gain the same potency of tolerance as the wild mice. In the result on infarcted lesion volumes following temporary focal ischemia, potent tolerance developed in the wild type (35% reduction) (P=0.007) but not in the heterozygous BDNF-deficient mice (<19% reduction) (P=0.155), indicating that BDNF expression level following spreading depression is contributing to infarct tolerance development.
Laboratory for Cerebrovascular Disorders, Research Institute of the National Cardio-Vascular Center, 5-7-1 Fujishirodai, Suita 565-8565, Japan. hyanamot@res.ncvc.go.jp
Hiroji
H
Yanamoto
Jing-Hui
JH
Xue
Susumu
S
Miyamoto
Izumi
I
Nagata
Yoshikazu
Y
Nakano
Kenichi
K
Murao
Haruhiko
H
Kikuchi
D000818:Animals; D020520:Brain Infarction / Q000235:genetics* / Q000473:pathology* / Q000517:prevention & control; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D013181:Cortical Spreading Depression / Q000235:genetics*; D005260:Female; D002546:Ischemic Attack, Transient / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013997:Time Factors
D019208:Brain-Derived Neurotrophic Factor