Inhibition of different pathways influencing Na + homeostasis protects organotypic hippocampal slice cultures from hypoxic/hypoglycemic injury

• Published in: Neuropharmacology 2000-09, Vol.39 (10), p.1779-1787
• Main Authors: Breder, Jörg, Sabelhaus, Clemens F, Opitz, Thoralf, Reymann, Klaus G, Schröder, Ulrich H
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Brain Ischemia - physiopathology; Cation channels; Cell Death; Culture Techniques; Dizocilpine Maleate - pharmacology; Electrophysiology; Hippocampus - metabolism; Hippocampus - pathology; Hippocampus - physiopathology; Homeostasis; Hypoglycemia - physiopathology; Hypoxia - physiopathology; Ischemia; Medical sciences; Na +/Ca 2+ exchanger; Neurons - drug effects; Neurons - pathology; Neuropharmacology; Neuroprotection; Neuroprotective agent; Organotypic slice cultures; Pharmacology; Pharmacology. Drug treatments; Quinoxalines - pharmacology; Rats; Rats, Wistar; Receptors, AMPA - antagonists & inhibitors; Receptors, AMPA - physiology; Receptors, Kainic Acid - antagonists & inhibitors; Receptors, Kainic Acid - physiology; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - physiology; Sodium - metabolism; Sodium Channel Blockers; Sodium Channels - physiology; Sodium-Calcium Exchanger - antagonists & inhibitors; Tetrodotoxin - pharmacology; Thiourea - analogs & derivatives; Thiourea - pharmacology
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/S0028-3908(00)00027-7

A prominent feature of cerebral ischemia is the excessive intracellular accumulation of both Na + and Ca 2+, which results in subsequent cell death. A large number of studies have focused on pathways involved in the increase of the intracellular Ca 2+ concentration [Ca 2+] i, whereas the elevation of intracellular Na + has received less attention. In the present study we investigated the effects of inhibitors of different Na + channels and of the Na +/Ca 2+ exchanger, which couples the Na + to the Ca 2+ gradient, on ischemic damage in organotypic hippocampal slice cultures. The synaptically evoked population spike in the CA1 region was taken as a functional measure of neuronal integrity. Neuronal cell death was assessed by propidium iodide staining. The Na + channel blocker tetrodotoxin, and the NMDA receptor blocker MK 801, but not the AMPA/kainate receptor blocker NBQX prevented ischemic cell death. The novel Na +/Ca 2+ exchange inhibitor 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulfonate (KB-R7943), which preferentially acts on the reverse mode of the exchanger, leading to Ca 2+ accumulation, also reduced neuronal damage. At higher concentrations, KB-R7943 also inhibits Ca 2+ extrusion by the forward mode of the exchanger and exaggerates neuronal cell death. Neuroprotection by KB-R7943 may be due to reducing the [Ca 2+] i increase caused by the exchanger.