Hydralazine inhibits compression and acrolein-mediated injuries in ex vivo spinal cord.
We have previously shown that acrolein, a lipid peroxidation byproduct, is significantly increased following spinal cord injury in vivo, and that exposure to neuronal cells results in oxidative stress, mitochondrial dysfunction, increased membrane permeability, impaired axonal conductivity, and eventually cell death. Acrolein thus may be a key player in the pathogenesis of spinal cord injury, where lipid peroxidation is known to be involved. The current study demonstrates that the acrolein scavenger hydralazine protects against not only acrolein-mediated injury, but also compression in guinea pig spinal cord ex vivo. Specifically, hydralazine (500 mumol/L to 1 mmol/L) can significantly alleviate acrolein (100-500 mumol/L)-induced superoxide production, glutathione depletion, mitochondrial dysfunction, loss of membrane integrity, and reduced compound action potential conduction. Additionally, 500 mumol/L hydralazine significantly attenuated compression-mediated membrane disruptions at 2 and 3 h following injury. This was consistent with our findings that acrolein-lys adducts were increased following compression injury ex vivo, an effect that was prevented by hydralazine treatment. These findings provide further evidence for the role of acrolein in spinal cord injury, and suggest that acrolein-scavenging drugs such as hydralazine may represent a novel therapy to effectively reduce oxidative stress in disorders such as spinal cord injury and neurodegenerative diseases, where oxidative stress is known to play a role.
Hamann
Kristin
K
Department of Basic Medical Sciences, Center for Paralysis Research, Purdue University, West Lafayette, Indiana 47907, USA.
Nehrt
Genevieve
G
Ouyang
Hui
H
Duerstock
Brad
B
Shi
Riyi
R
D000171:Acrolein / Q000009:adverse effects*; D000704:Analysis of Variance; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D003911:Dextrans; D004347:Drug Interactions; D005978:Glutathione / Q000378:metabolism; D006168:Guinea Pigs; D006830:Hydralazine / Q000627:therapeutic use*; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009431:Neural Conduction / Q000187:drug effects; D012235:Rhodamines; D013119:Spinal Cord Injuries / Q000139:chemically induced / Q000188:drug therapy / Q000209:etiology; D013481:Superoxides / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles
D000959:Antihypertensive Agents; D003911:Dextrans; C067661:Fluoro-Ruby; D012235:Rhodamines; D013778:Tetrazolium Salts; D013844:Thiazoles; D013481:Superoxides; D006830:Hydralazine; D000171:Acrolein; D007770:L-Lactate Dehydrogenase; C022616:thiazolyl blue; D005978:Glutathione