Neurorestorative role of intrastriatal angiotensin 1-7 in 6-hydroxydopamine hemiparkinsonism by dual angiotensin 1-7/MASR axis activation and HMGB-1/RAGE signaling inhibition

[Speaker] Noha N Nassar:1
[Co-author] Mostafa A Rabie:1, Mai A Abd El-Fattah:1, Hanan S El-Abhar:1, Dalaal M Abdallah:1
1:Pharmacology and Toxicology, Faculty of Pharmacy Cairo University, Egypt

The renin angiotensin system (RAS) has emerged as an important partaker in the etiology of Parkinson's disease (PD), extending beyond its cardio-reno effects. The current study investigated the possible therapeutic effect of angiotensin (Ang) 1-7, a MAS receptor (MASR) agonist and a counter-regulatory peptide of RAS, on modulating Ang1-7/MASR and HMGB-1/RAGE axis in 6-hydroxydopamine (OHDA)-lesions PD model. Male Wistar rats were allocated into 6 groups (n=8): (1) sham-operated (SO), (2) SO+Ang1-7, (3) 6-OHDA unilateral intrastriatal injection to induce PD, (4) 6-OHDA+Ang1-7, (5) 6-OHDA+A-779, a MASR antagonist and (6) 6-OHDA+A-779+Ang1-7. Treatments were instilled intrastriatally for 7 consecutive days after establishment of valid PD by apomorphine test. Ang1-7 decreased apomorphine-induced contralateral turns and improved motor performance and muscle coordination. Moreover, Ang1-7 preserved dopaminergic neurons in substantia nigra noted by the increased tyrosine hydroxylase immunoreactivity. Additionally, Ang1-7 downregulated AT-1R, HMGB-1, and RAGE expression along with an increase in ρY705-STAT-3 and SOCS3. Furthermore, Ang1-7 reduced the increment in p38 (ρT180/Y182)-MAPK, p65-NF-κB, TNF-α, NADPH oxidase, TBARS and PARP-1. Conversely, the effect of Ang1-7 was partially reversed by coadminstration with A779. Our results suggest that Ang1-7 plays an important therapeutic role against neurotoxicity and motor impairment associated with PD by the suppression of HMGB-1/RAGE downstream oxidative-inflammatory events and the modulation of AT-1R mediated by Ang1-7/MASR cue

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