Acrolein is involved in ischemic stroke-induced neurotoxicity through spermidine/spermine-N1-acetyltransferase activation

Abstract

Background and purposeIschemic stroke is the most common type of cerebrovascular event and is responsible for approximately 85% of all strokes in Taiwan. Neurons contain high concentrations of polyamines, which are prone to various pathological states in the brain and are perturbed after cerebral ischemia. Acrolein, an α,β-unsaturated aldehyde, has been suggested as the primary culprit of neuronal damage in stroke patients. However, the mechanism by which acrolein induces neuronal damage during ischemic stroke is not clear. MethodsUrinary 3-hydroxypropyl mercapturic acid (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 compared with control subjects. In vivo middle cerebral artery occlusion (MCAO) animal models and an in vitro oxygen glucose deprivation (OGD) stroke model were used to investigate the mechanisms of acrolein-induced neuronal damage. ResultsA deregulated acrolein metabolism, including significantly increased plasma Acr-PC levels, decreased urinary 3-HPMA levels and decreased plasma GSH levels, was found in stroke patients compared to control subjects. We further observed that acrolein was produced during ischemia resulting in brain damage in in vivo MCAO animal model. The induction of acrolein in neuronal cells during OGD occurred due to the increased expression of spermidine/spermine N1-acetyltransferase (SSAT) by NF-kB pathway activation. In addition, acrolein elicited a vicious cycling of oxidative stress resulting in neurotoxicity. Finally, N-acetylcysteine effectively prevented OGD-induced neurotoxicity by scavenging acrolein. ConclusionOverall, our current results demonstrate that acrolein is a culprit of neuronal damage through GSH depletion in stroke patients. The mechanism underlying the role of acrolein in stroke-related neuronal damage occurs through SSAT-induced polyamine oxidation by NF-kB pathway activation. These results provide a novel mechanism of neurotoxicity in stroke patients, aid in the development of neutralizing or preventive measures, and further our understanding of neural protection.