title: Angiogenesis as a predictive marker of neurological outcome following hypoxia-ischemia.
abstract: Cerebral ischemia induces angiogenesis within and around infarcted tissue. The protection of existing and growth of new blood vessels may contribute to a more favorable outcome. The present study assessed whether angiogenesis can be used as a marker for neurodegeneration/neuroprotection in a model of hypoxia-ischemia (HI). Increased CD31 immunoreactivity 7 days post-HI indicated increased angiogenesis compared to controls (P<0.001). Treatment with the GABA(A) receptor modulator, clomethiazole (CMZ; 414 mg/kg/day), normalized the level of angiogenesis compared to HI + saline (P<0.001). Conversely, the non-selective nitric oxide synthase (NOS) inhibitor, L-NAME (5 mg/kg/day), markedly decreased angiogenesis compared to controls (P<0.001). Circulating plasma levels of IL-1alpha, IL-1beta and GM-CSF were significantly elevated post-HI. CMZ treatment attenuated these increases while also stimulating IL-10 levels. L-NAME treatment did not alter IL-1alpha or IL-1beta levels, but decreased endogenous IL-10 levels and exacerbated the ischemic lesion (P<0.001). CMZ treatment has been shown to increase NOS levels, while L-NAME halted the HI-induced increase in NOS activity (P<0.001). We conclude that angiogenesis can be used as a marker of neurodegeneration/neuroprotection for cerebral HI and is correlated to NOS activity and circulating inflammatory mediators.
authors.affiliation: Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand. andrew.clarkson@stonebow.otago.ac.nz
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Clarkson
authors.forename: Hanzhong
authors.initials: H
authors.lastname: Liu
authors.forename: Fredericke
authors.initials: F
authors.lastname: Schiborra
authors.forename: Odette
authors.initials: O
authors.lastname: Shaw
authors.forename: Ivan A
authors.initials: IA
authors.lastname: Sammut
authors.forename: David M
authors.initials: DM
authors.lastname: Jackson
authors.forename: Ian
authors.initials: I
authors.lastname: Appleton
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000098:blood supply; D002719:Chlormethiazole / Q000008:administration & dosage; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000097:blood; D020925:Hypoxia-Ischemia, Brain / Q000150:complications*; D053583:Interleukin-1beta / Q000097:blood; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009389:Neovascularization, Pathologic / Q000097:blood / Q000209:etiology* / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000008:administration & dosage; D019001:Nitric Oxide Synthase / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism*; D011237:Predictive Value of Tests; D051381:Rats; D017208:Rats, Wistar
chemical_list: D015415:Biomarkers; D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D018696:Neuroprotective Agents; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D002719:Chlormethiazole; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester