title: Pharmacological preconditioning in global cerebral ischemia.
abstract: Single dose 3-nitropropionic acid (3-NPA) 24 hr before global ischemia improves neuronal survival in both, neocortex and hippocampus ('chemical preconditioning'). Neuronal survival after transient global ischemia requires new protein synthesis during recovery, especially of those with anti-apoptotic function. Bcl-2-protein is expressed in neurons that survive cerebral ischemia and may parallel the time course of tolerance after ischemic preconditioning. With this study we examined whether differences in bcl-2-protein expression compared to baseline may be involved in the induction of ischemic tolerance using 3-NPA. Male Wistar rats received either a single intraperitoneal (i.p.) dose of 3-NPA (20 mg/kg), and were observed for 3 (n = 4), 12 (n = 5) or 24 hours (n = 5) or the same amount of vehicle and were observed for 24 h (n = 8, controls). Immunohistochemistry allowed to compare the intensity of bcl-2 immunoreactivity at three subsequent time points in hippocampus, dentate gyrus and parietal neocortex with that of control animals. A single dose of 3-NPA caused a significant increase of bcl-2 protein immunoreactivity in hippocampal neurons, i.e. CA 1 (5 out of 5 animals, p = 0.003), CA 3 (5/5, p = 0.003), CA 4 (4/5, p = 0.025), and neocortex (5/5, p = 0.004), in a time dependent manner over a period of 24 hr after injection. Neuronal bcl-2 protein expression in CA 2 and dentate gyrus remained unchanged. The data suggest a possible role of bcl-2-protein in chemical induction of ischemic tolerance using a single subtoxic dose of 3-NPA. Bcl-2-protein expression may be initiated by increased levels of reactive oxygen species (ROS) after 3-NPA administration, as shown by others. Additional bcl-2 protein may then be available to (1) control postischemic ROS burst, (2) protect the mitochondrial membranes, and (3) inhibit pro-apoptotic mechanisms.
authors.affiliation: Institut of Neurosurgical Pathophysiology, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: A M
authors.initials: AM
authors.lastname: Brambrink
authors.forename: H
authors.initials: H
authors.lastname: Noga
authors.forename: A
authors.initials: A
authors.lastname: Astheimer
authors.forename: A
authors.initials: A
authors.lastname: Heimann
authors.forename: O
authors.initials: O
authors.lastname: Kempski
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D002470:Cell Survival / Q000187:drug effects; D007274:Injections, Intraperitoneal; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009574:Nitro Compounds; D011422:Propionates / Q000008:administration & dosage*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D009574:Nitro Compounds; D011422:Propionates; D019253:Proto-Oncogene Proteins c-bcl-2; C015392:3-nitropropionic acid