Reactive oxygen species (ROS) and lipid peroxidation (LPO) have been associated with numerous diseases that few other pathological factors can match, including aging, neoplasia, trauma, and ischemia-reperfusion injury (Halliwell and Gutteridge 1999). The mechanism of involvement of LPO has been an area of intense research aiming to prevent, slow down, and even reverse the development of various diseases. In the case of spinal cord injury, it is well established that LPO plays an important role in neuronal degeneration, cell death, and overall functional deficits (Hall 1989(Hall , 1991Hall and Braughler 1993). This is believed due in part to that fact that neuronal cells contain a relatively large proportion of polyunsaturated fatty acids and are rich in mitochondria, both of which are a potential target and source of free radicals. Because of these unique features, the CNS is particularly vulnerable to oxidative injury. In spite of strong evidence suggesting that post-trauma oxidative stress plays a critical role in the pathogenesis of spinal cord injury, conventional strategies aiming to scavenge free radicals have largely failed to produce any effective treatment that can curtail oxidative injury. Hence, further understanding of the mechanisms of oxidative stress and identification of a novel and more effective target is highly warranted and desirable.In addition to the much studied ROS, highly reactive a,b-unsaturated aldehydes, including malondialdehyde, 4-hydroxynonenal (HNE), and acrolein, are produced as a byproduct of LPO (Witz 1989;Esterbauer et al. 1991;Uchida 1999;O'Brien et al. 2005). Among them, acrolein has been shown to be by far the most reactive with various biomolecules including proteins, DNA, and glutathione, and reacts 110-150 times faster with glutathione than HNE or Abbreviations used: AD, Alzheimer's disease; CAP, compound action potential conduction; DTNB, 5,5¢-Dithiobis (2-nitrobenzoic acid); HE, dihydroethidium; HNE, 4-hydroxynonenal; LDH, lactate dehydrogenase; LPO, lipid peroxidation; PB, phosphate buffer; PBS, phosphatebuffered saline; ROS, reactive oxygen species; SOD, superoxide dismutase; TMR, tetramethyl rhodamine dextran. AbstractWe 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 lmol/L to 1 mmol/L) can significantly alleviate acrolein (100-500 lmol/ L)-induced superoxide production, glutathione depletion, mitochondrial dysfunction, loss of membrane integrity, and reduced compound act...