Angiotensin 1-7 ameliorates 6-hydroxydopamine lesions in hemiparkinsonian rats through activation of MAS receptor/PI3K/Akt/BDNF pathway and inhibition of angiotensin II type-1 receptor/NF-kappa B axis

作者：Rabie Mostafa A; Abd El Fattah Mai A; Nassar Noha N; El Abhar Hanan S; Abdallah Dalaal M

来源：Biochemical Pharmacology, 2018, 151: 126-134.

DOI：10.1016/j.bcp.2018.01.047

• A-779
• Dopamine
• NADPH oxidase
• Neuroinflammation
• Tyrosine hydroxylase

MAS receptor (MASR), expressed in several brain areas, conferred neuroprotection against neurodegenerative disorders when activated by angiotensin (Ang) 1-7; however, its role in Parkinson's disease (PD) remains elusive. Intra-striatal post-administration of Ang1-7, using a 6-hydroxydopamine (OHDA) PD model, improved motor performance and muscle coordination. On the molecular level, Angl-7 upregulated the striatal expression of MASR and caused upsurge in its downstream targets (p-PI3K/p-Akt/p-CREB/BDNF) to phosphorylate TrKB, which in a positive feedback upregulates MASR. Moreover, Ang1-7 increased substantia nigral tyrosine hydroxylase (TH) expression and striatal dopamine (DA) content to indicate the preservation of the dopaminergic neuronal signal. This effect extended to inhibit the striatal expression of Ang II type-1 receptor (AT-1R) to hold the neurodegenerative effect and to boost Angl-7 anti-inflammatory/antioxidant effects by abating NADPH oxidase, along with lipid peroxidation. Indeed, Ang1-7 was able to decrease p-MAPK p38/NF-kappa B p65 to level the inflammatory and oxidative stress events off. The Ang1-7-mediated activation of MASR cue and the suppression of the AT-1R cascade were partially reversed by the intrastartial injection of A-779, a MASR antagonist. The current data suggests a novel therapeutic potential for the Ang1-7 against neurotoxicity associated motor impairment related to PD. The anti-parkinsonian effect of Angl-7, is in part, mediated by its binding to MASK and the initiation of PI3K/Akt/CREB/BDNF/TrKB cue to increase DA synthesis, besides the downreg-ulation/inhibition of AT-1R/MAPK p38/NF-KB p65/NADPH oxidase pathway.

• 出版日期2018-5