Abstract
BackgroundThe 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.MethodsAdult 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.ResultsThe 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.ConclusionsThe 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.
Highlights
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
Results eCB and fatty acid profiles in brain tissue In the frontal cortex AEA, 2-AG, and PEA were found significantly increased in BCCAO and reperfused (BCCAO/R) rats as compared to the sham-operated ones (p < 0.05) by 41, 51 and 37%, respectively (Fig. 1a–c), while docosahexaenoic acid (DHA) decreased by about 7% (p < 0.001) (Fig. 1d), and lipoperoxides, considered as a molecular marker of oxidative stress, increased by 57% (p < 0.05) (Fig. 1e)
ECB and fatty acid profiles in plasma In BCCAO/R rats, analysis of eCBs and congeners revealed that levels of AEA increased significantly by about 38% compared to sham rats (p < 0.05) (Fig. 1f ), whereas no change was observed in 2-AG, PEA, and OEA levels
Summary
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. Though the role of eCB system in neuroprotection is somewhat controversial, data on focal cerebral ischemia followed by reperfusion show that i) intraperitoneally administered PEA and AEA reduce the size of infarcted tissue [7], ii) both pharmacological blockade [24] and genetic deletion of CB1 receptor reduce the infarct volume and improve neurological function [25], and iii) CB2 activation attenuates the cerebral ischemia/reperfusion-induced microcirculatory dysfunction [13]
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