Cortical spreading depression activates trophic factor expression in neurons and astrocytes and protects against subsequent focal brain ischemia.
We recently reported that cortical spreading depression (CSD), used to precondition rat brain, reduced cortical infarction volume resulting from focal cerebral ischemia by middle cerebral artery occlusion (MCAO) 3 days later. The mechanisms underlying this protective effect by CSD remains to be explored. In this study, we confirm that CSD is neuroprotective when KCl is applied epidurally rather than intracortically. Neocortical infarct volume was 101.3+/-48.5 mm3 and 45.3+/-44.1 mm3 in the sham and CSD group, respectively (p<0.05). Using image analysis, we identified the cortical region spared from infarction by the prior CSD. We then determined the distribution of brain-derived neurotrophic factor (BDNF) and basic fibroblast growth factor (bFGF) mRNA and the time course of their expression in groups of animals treated with CSD and their controls. We also examined the response of astrocytes to CSD using glial fibrillary acidic protein (GFAP) as a marker. In situ hybridization (done at 0, 3, 12, 24, 72 or 168 h after CSD) showed significant elevation of BDNF mRNA in the cortex immediately after CSD in a distribution surrounding the spared cortex, while bFGF mRNA rose 12 h after CSD and appeared more within the core of the ischemic region. Immunohistochemistry (done at 1, 3 or 7 days after CSD) demonstrated GFAP in the neocortex, with a peak at 3 days after CSD. Heat shock protein 72 (HSP72) expression was not affected by CSD. We concluded that upregulation of trophic factors and activation of glial cells may contribute to the neuroprotection induced by CSD.
Matsushima
K
K
Neuroscience Research Institute, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada.
Schmidt-Kastner
R
R
Hogan
M J
MJ
Hakim
A M
AM
D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D015415:Biomarkers / Q000737:chemistry; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis; D002560:Cerebrovascular Circulation / Q000502:physiology; D013181:Cortical Spreading Depression / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D017403:In Situ Hybridization; D002546:Ischemic Attack, Transient / Q000503:physiopathology / Q000517:prevention & control*; D019194:Ischemic Preconditioning; D008297:Male; D009414:Nerve Growth Factors / Q000096:biosynthesis*; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
D015415:Biomarkers; D019208:Brain-Derived Neurotrophic Factor; D005904:Glial Fibrillary Acidic Protein; D009414:Nerve Growth Factors; D016222:Fibroblast Growth Factor 2