Research paperAcrolein is involved in ischemic stroke-induced neurotoxicity through spermidine/spermine-N1-acetyltransferase activation
Graphical abstract
Introduction
Ischemic stroke, characterized by the disturbance of the blood supply to the brain, is the most common type of cerebrovascular event and is responsible for approximately 85% of all strokes (Flynn et al., 2008; Mathers et al., 2009). Identifying reliable biomarkers present during the early phases of a stroke remains a challenge (Makris et al., 2018). Polyamines (putrescine, spermidine and spermine) are ubiquitous cellular polycations essential for optimal rates of cell growth and differentiation (Pegg, 2009). The polyamine system is prone to various pathological states in the brain and is perturbed after cerebral ischemia (Baskaya et al., 1997; Baskaya et al., 1996; Seiler, 2000). Spermidine/ Spermine N1-acetyltransferase (SSAT) is the rate-limiting enzyme in polyamine catabolism that acts through the acetylation of spermidine and spermine (Pegg, 2008). Previous studies have shown that the transcription and enzymatic activity of SSAT increase in response to cerebral ischemia (Nagesh Babu et al., 2001; Zoli et al., 1996).
Acrolein, an α,β-unsaturated aldehyde, can be formed endogenously by lipid peroxidation or amino acid metabolism, including polyamine oxidation (Stevens and Maier, 2008). Recent studies have shown that acrolein is predominantly formed from 3-aminopropanal (NH2[CH2]2CHO) produced effectively from spermine by spermine oxidase (SMO) and less effectively from 3-acetamidopropanal (CH3CONH[CH2]2CHO), which is produced from spermine and spermidine by SSAT and acetylpolyamine oxidase (AcPAO) (Igarashi and Kashiwagi, 2011; Kimes and Morris, 1971; Saiki et al., 2011; Wang and Casero Jr., 2006). Additionally, acrolein has been reported to be more toxic than H2O2 (Sharmin et al., 2001) and slightly more toxic than ·OH (Yoshida et al., 2009) in cell culture systems due to its high reactivity with various cellular components such as proteins, which results in protein dysfunction. Acrolein reacts with lysine residues within proteins to form Nε-(3-formyl-3,4-dehydropiperidino)lysine (FDP-lysine) and (Nε-(3-methylpyridium)lysine] (MP-lysine) (Furuhata et al., 2003; Stevens and Maier, 2008; Uchida et al., 1998), which has been used to detect acrolein levels in human tissues and serum (Calingasan et al., 1999; Igarashi and Kashiwagi, 2011). Previous studies have shown that levels of acrolein-protein conjugates (Acr-PC) in plasma are associated with disease severity in stroke patients (Igarashi and Kashiwagi, 2011; Saiki et al., 2009; Tomitori et al., 2005; Yoshida et al., 2010; Yoshida et al., 2011). Reduction of acrolein levels has been shown to reduce infarction size and protect against neuronal damage in animal experiments (Saiki et al., 2009; Suabjakyong et al., 2015). Therefore, acrolein has been suggested as a primary culprit of neuronal damage in stroke patients. However, the mechanism by which acrolein induces neuronal damage is not clear.
The governing pathobiology of ischemic brain stroke initially unfolds due to a focal deficit in metabolism driven primarily by oxygen and glucose deprivation (OGD); most ischemic strokes (~80%) occur in the middle cerebral artery (MCA). MCA occlusion (MCAO) in animals is commonly used to model focal brain ischemia in humans (Carmichael, 2005; Durukan and Tatlisumak, 2007; Taniguchi and Andreasson, 2008) and OGD is widely used as an in vitro model for stroke, due to similarities with in vivo models of brain ischemia (Tasca et al., 2015). To clarify the role of acrolein in neuronal damage during stroke, we collected blood and urine samples from 49 stroke patients within 24 h (day 1) after stroke and from 99 healthy subjects. Urinary 3-HPMA, an acrolein-glutathione (GSH) metabolite, plasma acrolein-protein conjugates (Acr-PC) and plasma GSH levels were analyzed to correlate disease severity and prognosis of stroke patients. Furthermore, the mechanisms by which acrolein induces neuronal damage were investigated using MCAO animal models and an in vitro OGD stroke model.
Section snippets
Subjects and collection of blood and urine
Baseline sociodemographic variables are shown in Table 1. From the 148 patients recruited, 49 patients were gender- and smoking history-matched stroke patients, and 99 patients were gender- and smoking history-matched healthy control subjects without any history of dementia. All stroke subjects were clinically followed for 1–2 years. (Table 1). The demographic data for all patients are shown in Table 1. Of the stroke patients, 81% (39/49) were diagnosed with a minor stroke (NIHSS <5), and the
Subjects and collection of blood and urine
Volunteers recruited in this study included 99 control subjects without any history of dementia and 49 stroke subjects as described in Supplementary Methods. Informed consent was given by each participant or his (or her) relative, and our study protocol was approved by the Institutional Review Board of Taipei Veterans General Hospital (IRB# 2017–11-003 BCE). The experiments were conducted in accordance with the Declaration of Helsinki principles.
Procedures for middle cerebral artery occlusion (MCAO)
All animal experiments were approved by the
Discussion
Acrolein, an α,β-unsaturated aldehyde, has been suggested as a primary culprit of neuronal damage in stroke patients (Igarashi and Kashiwagi, 2011; Saiki et al., 2009; Tomitori et al., 2005; Yoshida et al., 2010; Yoshida et al., 2011). However, the mechanism by which acrolein induced neuronal damages during ischemic stroke is not clear. In this study, a deregulated acrolein metabolism, including significantly increased plasma Acr-PC levels, decreased urinary 3-HPMA levels and decreased plasma
Acknowledgements
We thank Ms. Ching-Wei Lin, Ms. Shao-Yu Lin, Ms. Shiu-Hao Tai, Ms. Hui-Chi Huang, and Ms. Jui-Yao Tsai from Department of Nursing, Taipei Veterans General Hospital, Taipei, Taiwan, ROC for their great help with collection of clinical samples.
Sources of funding
This work was supported by Ministry of Science and Technology, Taiwan under [107-2321-B-010-006 (H-T Wang); 107-2320-B-010-018 (H-T Wang)].
Declaration of Competing Interest
The authors have no actual or potential conflicts of interest.
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