LAUSR

Dear Editor, The recent paper by Fawad-Ali Shah on this journal describes the role of the flavonoid quercetin in a cerebral ischemia model induced in adult Sprague–Dawley male rats by middle cerebral artery occlusion (MCAO) [1]. The authors reported that quercetin in MCAO-induced ischemia modulated the expression of the enzymes isocitrate dehydrogenase [NAD+] (which is present in two isoforms, EC. 1.1.1.41 and EC 1.1.1.42), adenosyl-homocysteinase (EC, 3.3.1.1), pyruvate kinase (EC 2.7.1.40), ubiquitin carboxy terminal hydrolase L1 (EC, 3.1.2.15), besides to the proteins heat shock protein 60 (hsp60) and collapsin response mediator protein 2 (CRMP2) [1]. Actually, many further important proteins are upregulated (and some of them down-regulated) by quercetin in the reported MCAO model [1]. Following Fawad-Ali Shah et al.’s paper, we hypothesized that the upor down-regulation of the many specific proteins by quercetin might deal with the occurrence of an autophagic mechanism, directly or indirectly promoted by the flavonoid itself in the MCAO-induced ischemia [1]. Autophagy is a regular, physiological process adopted by cells to disassembly dysfuncional, damaged or unnecessary components, including organelles such as mitochondria (mitophagy). It usually involves a cascade of events starting with the phosphorylation of beclin-1 (the mammalian homologue of Atg6) [2]. The cell self-digesting mechanism that is responsible for the removal of long-lived proteins and damaged organelles by lysosomes, which form vacuolar autophagosomes, is called macro-autophagy and is crucial for cell survival [3]. Despite this, autophagy can also rule a complex interplay with apoptosis, triggering with caspases a death signal and contributing in the pathogenesis of several diseases [4]. Therefore, a complex cross-talk between autophagy and apoptosis is finely tuned in order to ensure cell survival or promote its death when cell function is damaged or compromised [5]. Quercetin has a fundamental role both in autophagy and apoptosis. The flavonol attenuates that neuronal autophagy leading to apoptosis in brain injury, and further papers reported that the flavonol, as well as isoflavones, induced neuronal autophagy after brain injury, in order to prevent neurotoxicity and cell death [6–8]. However, the role of quercetin in the autophagy-mediated mechanisms of cell survival is particularly complex, due to the numerous targeted molecules involved in the process. Depending on the level of damage caused by ischemia or oxidative injury, quercetin inhibits autophagy if the autophagic response is not addressed as a survival but as a pro-apoptotic signal [9]. Actually, because of the existence of the many different targeted molecules from quercetin as a pro-survival molecule, the flavonol can prevent or reduce a cellular damage acting on the autophagic machinery. Evidence was reported showing that in oxidative damage and in ischemia-induced models quercetin may trigger a protective action by promoting autophagy [10]. Therefore, during brain injury following ischemia, quercetin may induce pro-survival mechanisms leading to autophagy as occurring for other cell damaging events [11–14]. Quercetin exerts a protective role on MCAO-induced apoptosis in neuronal cells and induces autophagy-mediated cell survival in neuronal PC12 cells [15, 16]. The reported role of quercetin on autophagy-mediated cell survival, in order to counteract brain injury-induced apoptosis, suggested us to comment the reported data by * Salvatore Chirumbolo [email protected]