Nanoformulated anandamide in the neuroinflammation linked to hypertension

GARCÍA SEBASTIÁN; FERES MOCAYAR; VIRNA MARTÍN GIMENÉZ; LUCIANA MAZZEI; WALTER MANUCHA

Mendoza

Simposio; XL Reunión Anual de la Sociedad de Biología de Cuyo; 2022

Sociedad de Biología de Cuyo

Hypertension is considered one of the most significant risks of cardiovascular diseases with exaltation of the renin-angiotensin-aldosterone system, systemic and neural inflammation. In addition, it is a path to cognitive deterioration, dementia and behavioral alterations. Thus, the pathophysiology mechanism that links hypertension with cognitive-behavioral changes is complex. The confluence of cognitive deterioration, depression and hypertension warns of the need for more and better knowledge. To highlight, the spontaneously hypertensive rats (SHR) is a validated model of essential hypertension, neuroinflammation and cognitive deficits. Parallel, an endocannabinoid called anandamide (AEA) would protect neurons from inflammatory damage, and its signaling decreases in the hypertensive brains. However, trials with the conventional formulation with AEA have revealed multiple side effects. At the same time, the nanotechnological design with nano-structured scaffolds could reduce side effects and rescue protective actions at the central and peripheral levels. Therefore, we decided to evaluate if the implementation of nanoformulated AEA manages to reduce blood pressure values, improve the profile of the systemic inflammatory state as well as at the nervous system level and finally, if its possible impact at the behavioral level is evidenced. Adult male normotensive (WKY) and hypertensive (SHR) rats were used, treated or not with AEA nanoformulated in polycaprolactone epsilon (AEA/PCL) (N=10, per group), at a weekly dose of 5 mg/Kg IP, for four weeks. Systolic blood pressure (SBP) was obtained using the tail-cuff method (CODA). Behavioral tests such as Plus Maze Test and Open Field Test were performed at the end of treatment. The cerebral cortex was also harvested for western blot assays. Inflammatory markers were determined in plasma by ELISA. AEA/PCL produced a significant reduction in SBP, and a decrease in inflammatory markers and markers of oxidative stress (NADPH oxidase and nitrites). Protein expression of WT-1, AT-1 and iNOS was higher in the cerebral cortex of SHR, while AEA/PCL decreased it. In contrast, Hsp70 expression increased after treatment within the cerebral cortex. Abnormal behaviors observed by Plus Maze Test (open arm dwell time), and Open Field Test (exploration time), also decreased after AEA/PCL treatment. These results allow suggesting antihypertensive and anti-inflammatory properties of nano-formulated AEA. This novel nano-scaffold could regulate inflammation through the AT-1-Hsp70-iNOS pathway and improve cognitive-behavioral functions in SHR rats.