Apoptosis and Delayed Neuronal Damage after Carbon Monoxide Poisoning in the Rat

• Published in: Experimental neurology 1997-09, Vol.147 (1), p.103-114
• Main Authors: Piantadosi, Claude A., Zhang, Jing, Levin, Edward D., Folz, Rodney J., Schmechel, Donald E.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Behavior, Animal - drug effects; Biological and medical sciences; Brain - metabolism; Brain - pathology; Carbon Monoxide Poisoning - genetics; Carbon Monoxide Poisoning - pathology; Carbon Monoxide Poisoning - psychology; Chemical and industrial products toxicology. Toxic occupational diseases; DNA Fragmentation; Gas, fumes; Glutamic Acid - metabolism; Hydroxyl Radical - metabolism; Hydroxylation; Male; Medical sciences; Microdialysis; Microscopy, Electron; Neurons - drug effects; Neurons - physiology; Neurons - ultrastructure; Rats; Rats, Sprague-Dawley; Time Factors; Toxicology
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1006/exnr.1997.6584

Delayed neurological damage after CO hypoxia was studied in rats to determine whether programmed cell death (PCD), in addition to necrosis, is involved in neuronal death. In rats exposed to either air or CO (2500 ppm), microdialysis in brain cortex and hippocampus was performed to determine the extent of glutamate release and hydroxyl radical generation during the exposures. Groups of control and CO-exposed rats also were tested in a radial maze to assess the effects of the CO exposure on learning and memory. At 3, 7, and 21 days after CO exposure brains were perfusion-fixed and hematoxylin–eosin (H&E) was used to assess injury and to select regions for further examination. DNA fragmentation was sought by examining cryosections with the terminal deoxynucleotidyl transferase-mediated dUTP–biotin nick-end labeling (TUNEL) reaction. We found significant increases in glutamate release and ·OH generation during and immediately after CO hypoxia. CO-exposed rats showed learning and memory deficits after exposure associated with heterogeneous cell loss in cortex, globus pallidus, and cerebellum. The frontal cortex was affected most seriously; the damage was slight at Day 3, increased at Day 7, and persistent at Day 21 after CO exposure. TUNEL staining was positive at all three time points, and TUNEL-labeled cells were distributed similarly to eosinophilic cells. The number of cells stained by TUNEL was less than by H&E and amounted to 2 to 5% of all cell nuclei in regions of injury. Ultrastructural features of both neuronal necrosis and apoptosis also were observed readily by electron microscopy. These findings indicate that both necrosis and apoptosis (PCD) contribute to CO poisoning-induced brain cell death.