bn-80933 and Brain-Ischemia

Glutamate excitotoxicity, oxidative stress, and mitochondrial dysfunctions are common features leading to neuronal death in cerebral ischemia, traumatic brain injury, Parkinson's disease, Huntington's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Nitric oxide (NO) alone or in cooperation with superoxide anion and peroxynitrite is emerging as a predominant effector of neurodegeneration The use of NO synthase (NOS) inhibitors and mutant mice lacking each NOS isoform have provided evidence for the injurious effects of NO derived from neuronal or inducible isoforms. New neuroprotective strategies have been proposed with selective NOS inhibitors for the neuronal (ARL17477) or the inducible (1400 W) isoforms or with compounds combining in one molecule selective nNOS inhibition and antioxidant properties (BN 80933), in experimental ischemia-induced acute neuronal damage. The efficacy of these new strategies is well established in acute neuronal injury but remains to be determined in more chronic neurological diseases.

Topics: Alzheimer Disease; Amidines; Amyotrophic Lateral Sclerosis; Animals; Benzylamines; Brain Injuries; Brain Ischemia; Enzyme Induction; Humans; Huntington Disease; Mice; Mice, Neurologic Mutants; Mice, Transgenic; Nerve Degeneration; Nerve Tissue Proteins; Nervous System Diseases; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Organ Specificity; Polymethacrylic Acids; Pyrazines; Thiophenes

Topics: Animals; Brain; Brain Ischemia; Enzyme Inhibitors; Free Radical Scavengers; Mice; Models, Biological; Neuroprotective Agents; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Pyrazines; Rats; Thiophenes

Formation of the lipid peroxidation product 8-epi-prostaglandin2alpha (8-epi-PGF2alpha) a bioactive marker of oxidative stress, was quantified in in vitro and in vivo models of neuronal death. In culture media of primary rat cortical neurones exposed to hypoxia followed by reoxygenation, a 3.7-fold increase of 8-epi-PGF2alpha concentration was observed in comparison to control cells. In rats submitted to 2h middle cerebral artery occlusion followed by a 22h reperfusion period, a 27-fold increase of 8-epi-PGF2alpha was observed in the ischaemic hemisphere compared with the corresponding hemisphere of sham-operated rats. Treatment with the neuroprotective agent BN 80933 significantly reduced both 8-epi-PGF2alpha elevations in vitro and in vivo. These data suggest that 8-epi-PGF2alpha elevations might reflect the damaging free radical overproduction and subsequent lipid peroxidation during neuronal injury induced by hypoxia and ischaemia. Inhibition of 8-epi-PGF2alpha elevations participates to the neuroprotective effects of BN 80933.

Topics: Animals; Brain Ischemia; Cells, Cultured; Cerebral Cortex; Culture Media, Conditioned; Dinoprost; Enzyme Inhibitors; F2-Isoprostanes; Hypoxia, Brain; Infarction, Middle Cerebral Artery; L-Lactate Dehydrogenase; Neuroprotective Agents; Pyrazines; Rats; Rats, Wistar; Reperfusion Injury; Thiophenes