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Involvement of the Endocannabinoid System in the Physiological

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Involvement of the Endocannabinoid System in the Physiological Quartu et al. Lipids in Health and Disease (2017) 16:14 DOI 10.1186/s12944-016-0389-y RESEARCH Open Access Involvement of the endocannabinoid system in the physiological response to transient common carotid artery occlusion and reperfusion Marina Quartu*† , Laura Poddighe, Tiziana Melis, Maria Pina Serra, Marianna Boi, Sara Lisai, Gianfranca Carta, Elisabetta Murru, Laura Muredda, Maria Collu and Sebastiano Banni† Abstract Background: The transient global cerebral hypoperfusion/reperfusion achieved by induction of Bilateral Common Carotid Artery Occlusion followed by Reperfusion (BCCAO/R) may trigger a physiological response in an attempt to preserve tissue and function integrity. There are several candidate molecules among which the endocannabinoid system (ECS) and/or peroxisome-proliferator activated receptor-alpha (PPAR-alpha) may play a role in modulating oxidative stress and inflammation. The aims of the present study are to evaluate whether the ECS, the enzyme cyclooxygenase-2 (COX-2) and PPAR-alpha are involved during BCCAO/R in rat brain, and to identify possible markers of the ongoing BCCAO/R-induced challenge in plasma. Methods: Adult Wistar rats underwent BCCAO/R with 30 min hypoperfusion followed by 60 min reperfusion. The frontal and temporal-occipital cortices and plasma were analyzed by high performance liquid chromatography- mass spectrometry (HPLC-MS) to determine concentrations of endocannabinoids (eCBs) and related molecules behaving as ligands of PPAR-alpha, and of oxidative-stress markers such as lipoperoxides, while Western Blot and immunohistochemistry were used to study protein expression of cannabinoid receptors, COX-2 and PPAR-alpha. Unpaired Student’s t-test was used to evaluate statistical differences between groups. Results: The acute BCCAO/R procedure is followed by increased brain tissue levels of the eCBs 2-arachidonoylglycerol and anandamide, palmitoylethanolamide, an avid ligand of PPAR-alpha, lipoperoxides, type 1 (CB1) and type 2 (CB2) cannabinoid receptors, and COX-2, and decreased brain tissue concentrations of docosahexaenoic acid (DHA), one of the major targets of lipid peroxidation. In plasma, increased levels of anandamide and lipoperoxides were observed. Conclusions: The BCCAO/R stimulated early molecular changes that can be easily traced in brain tissue and plasma, and that are indicative of the tissue physiological response to the reperfusion-induced oxidative stress and inflammation. The observed variations suggest that the positive modulation of the ECS and the increase of proinflammatory substances are directly correlated events. Increase of plasmatic levels of anandamide and lipoperoxides further suggests that dysregulation of these molecules may be taken as an indicator of an ongoing hypoperfusion/reperfusion challenge. Keywords: Bilateral common carotid artery occlusion, Reperfusion, Endocannabinoid system, Lipoperoxides, COX-2, Cerebral cortex * Correspondence: [email protected] †Equal contributors Department of Biomedical Sciences, Cittadella Universitaria di Monserrato, 09042 Monserrato, CA, Italy © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Quartu et al. Lipids in Health and Disease (2017) 16:14 Page 2 of 11 Background In this study, we investigated whether the eCB system The transient Bilateral Common Carotid Artery Occlusion may be directly correlated to the oxidative events trig- followed by Reperfusion (BCCAO/R) is a model of transi- gered by the BCCAO/R-induced transient global hypo- ent global hypoperfusion [1]. This model does not lead to perfusion in rat brain, and we chose to examine the an authentic ischemic insult in the rodent brain due to the forebrain areas that are directly and selectively reached presence of efficient collateral systems, which allow for a by the internal carotid artery branches. With this aim, cerebral blood flow compensation within a few minutes we examined, prior to and after induction of BCCAO/R, [2]. However, it has been recently shown that, in the rat, cerebral tissue and plasmatic concentrations of eCBs the cerebral transient hypoperfusion followed by reperfu- and of oxidative stress markers such as polyunsaturated sion, such as that induced by the BCCAO/R, causes de- fatty acid (PUFA) hydroperoxides. Parallel immunochemi- tectable and consistent tissue changes such as a decrease cal analyses, carried out by means of Western Blot and of docosahexaenoic acid (DHA), one of the most abun- immunohistochemistry, investigated possible BCCAO/ dant polyunsaturated fatty acid in neuronal membrane R-induced changes in the occurrence and tissue distribu- phospholipids, an increase of the cyclooxygenase-2 tion of CB1 and CB2 receptors, COX-2, and the transcrip- (COX-2) [3] and significant microvascular alterations [4]. tion factor peroxisome-proliferator activated receptor The endocannabinoids (eCBs) are endogenous lipid (PPAR)-alpha. Results are discussed in view of the possible mediators involved in a wide variety of biological use of eCBs and lipoperoxides as markers of an ongoing processes. The most frequently studied eCBs are N- transient cerebral global hypoperfusion. arachidonoyl-ethanolamide (AEA, anandamide), belong- ing to the superfamily of N-acylethanolamides (NAEs), Methods and 2-arachidonoyl-glycerol (2-AG). AEA and 2-AG are Experimental procedure not stored in vesicles but they are synthesized ‘on demand’ Animals and keeping and released from plasmatic membranes immediately after For 1 week before the start of the experiment, fifty six their production when cells are challenged with poten- adult male Wistar rats (Harlan-Italy, Udine, Italy), weigh- tially harmful stimuli [5–7]. Accumulating data show that ing 210 ± 20 g (mean ± SD) were housed under controlled eCBs, with their signaling-mediating receptors, and en- temperature (21 ± 2 °C), relative humidity (60 ± 5%) and zymes involved in their synthesis and degradation, consti- artificial 12 h light/dark cycle, avoiding all stressful stimuli. tute an extensive system with relative basic levels of each Animal handling and care throughout the experimental component that is modulated by different and concurring procedures met with national (Legislative Decree n. 26, molecular mechanisms [8, 9]. Growing evidence supports 04/04/2014) and international (Directive 2010/63/EU in a general role for eCBs and congeners in the preservation Europe) laws and policies. The experimental protocols of metabolic homeostasis and responsivity of the brain to were carried out in compliance with the guidelines of the stress, and indicate that they are involved in inflammation Animal Ethics Committee of the University of Cagliari. and act as endogenous neuroprotectants in cerebral ische- Standard laboratory food (A04, Safe, Augy, France) and mia [5, 9–18]. As for the likely involvement of eCB in water were freely available ad libitum. neuroinflammation, it has been shown that 2-AG and According to the optimum standard for the evaluation AEA are substrates for COX-2 [19] and it is relevant that of lipids in tissue and plasma [6, 26], animals received the eCB neuroprotective activity may be mediated by no food for 12 h before surgery. Rats were randomly preventing excessive expression of COX-2 [11, 20, 21]. assigned to two groups (n = 12/group): one group was Conversely, COX-2 is a key regulator of eCB signalling submitted to BCCAO and reperfused (BCCAO/R) and [22]. Moreover, it has been shown that the peroxisome- one group was sham-operated. Surgery was performed proliferator activated receptor (PPAR)-alpha mediates the in all cases between 13:00 and 16:30 p.m.. anti-inflammatory effects of the non-cannabinoid pal- mitoylethanolamide (PEA) that behaves as one of its Surgery endogenous ligands [23]. Though the role of eCB Surgical procedure for induction of BCCAO/R was system in neuroprotection is somewhat controversial, adapted from the method of Iwasaki et al. [27] and per- data on focal cerebral ischemia followed by reperfusion formed in all cases between 13:00 and 16:30 p.m.. Rats show that i) intraperitoneally administered PEA and were anesthetized with intraperitoneal administration of AEA reduce the size of infarcted tissue [7], ii) both Equitesin (4.2% w/v chloral hydrate, 2.12% w/v MgSO4, pharmacological blockade [24] and genetic deletion of 16.2% w/w pentobarbital, 39.6% w/w propylene glycol, CB1 receptor reduce the infarct volume and improve and 10% w/w ethanol in sterile distilled H2O) (0.5 ml/ neurological function [25], and iii) CB2 activation 100 g bodyweight). After a midline cervical incision and attenuates the cerebral ischemia/reperfusion-induced blunt dissection of muscles, the common carotid arteries microcirculatory dysfunction [13]. (CCA) were exposed while leaving the vagus nerve Quartu et al. Lipids in Health and Disease (2017) 16:14 Page 3 of 11 intact. Cerebral blood flow reduction was produced by Tissue fatty acid quantifications placement of two atraumatic microvascular clips for Total lipids were extracted from different
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