Combined effects of mechanical and ischemic injury to cortical cells: secondary ischemia increases damage and decreases effects of neuroprotective agents.
Traumatic brain injury (TBI) involves direct mechanical damage, which may be aggravated by secondary insults such as ischemia. We utilized an in vitro model of stretch-induced injury to investigate the effects of mechanical and combined mechanical/ischemic insults to cultured mouse cortical cells. Stretch injury alone caused significant neuronal loss and increased uptake of the dye, propidium iodide, suggesting cellular membrane damage to both glia and neurons. Exposure of cultures to ischemic conditions for 24h, or a combination of stretch and 24h of ischemia, caused greater neuronal loss compared to stretch injury alone. Next, we tested the neuroprotective effects of superoxide dismutase (SOD), and the nitric oxide (NO) synthase inhibitors 7-nitroindazole (7-NINA) and lubeluzole. In general, these agents decreased neuronal loss following stretch injury alone, but were relatively ineffective against the combined injury paradigm. A combination of SOD with 7-NINA or lubeluzole offered no additional protection than single drug treatment against stretch alone or combined injury. These results suggest that the effects of primary mechanical damage and secondary ischemia to cortical neurons are cumulative, and drugs that scavenge superoxide or reduce NO production may not be effective for treating the secondary ischemia that often accompanies TBI.
Engel
Doortje C
DC
Department of Neuroscience, Erasmus MC, Rotterdam, The Netherlands.
Slemmer
Jennifer E
JE
Vlug
Angela S
AS
Maas
Andrew I R
AI
Weber
John T
JT
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology*; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D007191:Indazoles / Q000494:pharmacology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors; D010812:Physical Stimulation; D010880:Piperidines / Q000494:pharmacology; D013314:Stress, Mechanical; D013482:Superoxide Dismutase / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007191:Indazoles; D018696:Neuroprotective Agents; D010880:Piperidines; D013844:Thiazoles; D052248:Nitric Oxide Synthase Type I; D013482:Superoxide Dismutase; D019950:Mitogen-Activated Protein Kinase 1; C080122:7-nitroindazole; C097722:lubeluzole