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Acrolein As a Novel Therapeutic Target for Motor and Sensory Deficits in Spinal Cord Injury

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Acrolein As a Novel Therapeutic Target for Motor and Sensory Deficits in Spinal Cord Injury [Downloaded free from http://www.nrronline.org on Wednesday, September 11, 2019, IP: 128.210.106.129] NEURAL REGENERATION RESEARCH April 2014,Volume 9,Issue 7 www.nrronline.org SPECIAL ISSUE Acrolein as a novel therapeutic target for motor and sensory deficits in spinal cord injury Jonghyuck Park1, 2, Breanne Muratori2, Riyi Shi1, 2 1 Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN, USA 2 Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA Abstract Corresponding author: In the hours to weeks following traumatic spinal cord injuries (SCI), biochemical processes are Riyi Shi, M.D., Ph.D., initiated that further damage the tissue within and surrounding the initial injury site: a process Department of Basic Medical Sciences, termed secondary injury. Acrolein, a highly reactive unsaturated aldehyde, has been shown to play College of Veterinary Medicine, Purdue a major role in the secondary injury by contributing significantly to both motor and sensory defi- University, West Lafayette, IN 47907, cits. In particular, efforts have been made to elucidate the mechanisms of acrolein-mediated dam- USA, [email protected]. age at the cellular level and the resulting paralysis and neuropathic pain. In this review, we will highlight the recent developments in the understanding of the mechanisms of acrolein in motor doi:10.4103/1673-5374.131564 and sensory dysfunction in animal models of SCI. We will also discuss the therapeutic benefits of http://www.nrronline.org/ using acrolein scavengers to attenuate acrolein-mediated neuronal damage following SCI. Accepted: 2014-04-08 Key Words: oxidative stress; spinal cord injury; 3-hydrxypropyl mercapturic acid; acrolein-lysine ad- duct; hydralazine Park J, Muratori B, Shi RY. Acrolein as a novel therapeutic target for motor and sensory deficits in spinal cord injury. Neural Regen Res. 2014;9(7):677-683. Introduction are highly warranted. Traumatic spinal cord injury (SCI) is one of the major As both a product of and catalyst for lipid peroxidation, causes of irreversible nerve injury, resulting in both motor the highly reactive α, β-unsaturated aldehyde, acrolein, in- and sensory dysfunction. One of the critical contributing duces a vicious cycle of oxidative stress, dramatically ampli- factors of SCI pathology is the secondary cascade of events fying its effects and perpetuating cellular damage (Hamann occurring in the hours, days, and weeks after initial physical and Shi, 2009). Furthermore, acrolein remains active in the impact. This process exacerbates injury at the initial lesion body much longer than the more commonly studied reactive site of impact and also results in spreading of the damage to oxidative species (Ghilarducci and Tjeerdema, 1995). We adjacent tissue throughout the spinal cord. Secondary injury have demonstrated that acrolein plays a critical role in oxi- includes ischemia/reperfusion injury, inflammation, oxida- dative stress and likely plays an important role in neuronal tive stress, and glutamate excitotoxicity (Braughler and Hall, trauma and degenerative disorders (Shi et al., 2002; Luo and 1989; Juurlink and Paterson, 1998; Hall and Springer, 2004), Shi, 2004). In particular, we have demonstrated that acrolein which all contribute to the eventual tissue degeneration and concentrations are increased in animal models of SCI and functional loss. likely play a role in motor paralysis and neuropathic pain As a hallmark of secondary injury, oxidative stress plays after SCI (Luo et al., 2005; Due et al., 2014; Park et al., 2014). an important role in mediating functional loss after SCI Therefore, acrolein may be a key factor in propelling oxida- and, furthermore, has been implicated in several neurode- tive stress, and subsequently disrupting motor function and generative diseases (Hall and Braughler, 1993; Smith et al., sensory hypersensitivity after traumatic SCI. In this review, 1999). Under the high level of oxidative stress, the endoge- we will focus on the discussion of possible mechanisms of nous system of antioxidants, such as glutathione, vitamin E, acrolein in motor and sensory dysfunction after traumat- ic SCI in a clinically relevant contusive SCI animal model. and ascorbic acid, may be overwhelmed and depleted (Hall, Furthermore, we will demonstrate that acrolein scavenging 1996) which results in further damage in tissue following strategies could be an effective treatment for neurological SCI. Although there is strong evidence that oxidative stress deficits to SCI victims. plays a critical role in the pathogenesis after SCI, clinical tri- als of free radical scavenging have not produced any effective treatments to promote functional recovery after traumatic The origin of acrolein and mechanisms of SCI (George et al., 1995; Suberviola et al., 2008). Therefore, acrolein-mediated damage further understanding of the mechanisms of oxidative stress Acrolein can originate through endogenous pathways such as and identification of novel, more effective therapeutic targets lipid peroxidation (LPO) or produced and ingested from ex- 677 [Downloaded free from http://www.nrronline.org on Wednesday, September 11, 2019, IP: 128.210.106.129] Park J, et al. / Neural Regeneration Research. 2014;9(7):677-683. ogenous sources. Environmental exposure of acrolein occurs of the acrolein metabolite 3-HPMA in urine is used to cor- through incomplete combustion of organics, manufacturing relate the amount of acrolein present in the rat SCI model. processes, and cigarette smoke (Ghilarducci and Tjeerdema, This method uses liquid chromatography (LC) to separate 1995; Kirkham et al., 2003). Further, since acrolein is both a the diverse chemical species in urine and then tandem mass product and initiator of LPO, it has been implicated in many spectroscopy (MS) to quantify the amount of 3-HPMA in damaging biochemical mechanisms in diseases such as dia- the sample. betes, cancer, and rheumatoid arthritis (Uchida, 1999). The detection of 3-HPMA via LC/MS/MS methods using Acrolein has been shown to be the most reactive electro- urine samples is a beneficial technique due to its noninvasive phile produced by LPO and is found in at least 40 times nature and ability to be performed quickly. However, there are greater concentration than other much studied reactive ox- differences between the results of dot blotting and 3-HPMA idative species (ROS). It can react with glutathione (GSH), detection when the two methods are used in tandem. For ex- an endogenous antioxidant, 100–150 times faster than 4-hy- ample, elevated levels of 3-HPMA are only detected for three droxynonenal (HNE). In addition, the half-life of acrolein days following SCI. With dot blotting, these elevations can is significantly longer than transient ROS (on the order of be detected up to two weeks following injuries (Zheng et al., days compared to fractions of a second, respectively). Fur- 2013; Park et al., 2014). This may be due to the limited diffu- thermore, acrolein conjugates, which form with proteins sion of acrolein into the blood stream. Also, urine assays can and GSH, have much longer half-lives than free acrolein and only indicate that there is a whole-body increase in acrolein have been shown to be highly reactive (Adams and Klaid- levels; this elevation cannot be pin-pointed to a certain tissue. man, 1993; Burcham et al., 2004; Kaminskas et al., 2004a). As Using the two methods together offers a more accurate view an unsaturated aldehyde, acrolein presents a threat to pro- of the production of acrolein following SCI. Reliable acrolein teins, DNA, phospholipids, and other biomolecules. Within detection is imperative for studying acrolein elevation in re- proteins, acrolein binds to cysteine, histidine, and lysine resi- lation to neurological injury models as well as the efficacy of dues, forming carbonyl acrolein-protein oligomers. Acrolein therapies that target endogenous acrolein. can also react with the nucleophilic bases of DNA to form exocyclic adducts (Kehrer and Biswal, 2000). Through this Acrolein scavenging process, acrolein plays a critical role in oxidative stress and Since acrolein may play an important role in secondary in- poses a threat to many biochemical processes. jury after traumatic primary SCI, acrolein scavenging is an effective method to examine the role of acrolein in SCI by Acrolein detection reducing acrolein levels and observing possible mitigation of The detection of free acrolein is technically challenging be- detrimental effects. Many studies have shown that attenuat- cause of its high reactivity and volatility. Acrolein is capable ing oxidative stress, particularly in the case of methyprednis- of undergoing spontaneous polymerization, Diels-Alder olone, could be a valuable means of therapeutic intervention condensations, oxidation, and reduction due to the presence for SCI treatment (Bracken et al., 1997; Bracken et al., 1998; of the carbonyl and vinyl functional groups on the molecule Fehlings and Baptiste, 2005). However, because of its serious (Shi et al., 2011a). Based on this current understanding of side effects, including pulmonary embolism, respiratory the nature of acrolein, it is reasonable to estimate that the tract infection, urinary tract infection, and gastrointestinal majority of acrolein exists in acrolein-protein adducts or is problems, methylprednisolone is not an attractive therapeu- metabolized by endogenous antioxidants such as GSH. tic for SCI (George et al., 1995). Acrolein-lysine
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