Correlation between angiotensin 1-7-mediated Mas receptor expression with motor improvement, activated STAT3/SOCS3 cascade, and suppressed HMGB-1/RAGE/NF-κB signaling in 6-hydroxydopamine hemiparkinsonian rats.
Biochem Pharmacol
; 171: 113681, 2020 01.
Article
em En
| MEDLINE
| ID: mdl-31669235
ABSTRACT
In the current investigation, a Parkinson's disease (PD) model was established by a single direct right intrastriatal injection of the 6-hydroxydopamine (OHDA) in male Wistar rats followed by 7 daily unilateral injection of angiotensin (Ang) 1-7 in the striatum. To confirm the putative role of Mas receptor (MasR), the selective antagonist A779 was also injected intrastriatally prior to Ang 1-7 injections and a correlation analysis was performed between MasR expression and the assessed parameters. Ang 1-7 upregulated MasR expression to correlate strongly with the improved rotarod (râ¯=â¯0.95, pâ¯=â¯0.003) and spontaneous activity task (râ¯=â¯0.99, pâ¯<â¯0.0001). This correlation extends to involve other effects of Ang 1-7, such as the increased striatal dopamine content (râ¯=â¯0.98, pâ¯=â¯0.0005), substantia nigra pars compacta tyrosine hydroxylase immune-reactivity (râ¯=â¯0.97, pâ¯=â¯0.001), active pY705-STAT3 (râ¯=â¯0.99, pâ¯<â¯0.0001) and SOCS3 (râ¯=â¯0.99, pâ¯<â¯0.0001). Conversely, Ang 1-7 inhibited inflammatory markers to correlate negatively with NF-κBp65 (r = -0.99, pâ¯<â¯0.0003) and its downstream targets, high mobility group box-1 (HMGB-1; râ¯=â¯-0.97, pâ¯=â¯0.002), receptor for advanced glycation end products (RAGE; râ¯=â¯-0.98, pâ¯=â¯0.0004), and TNF-α (râ¯=â¯-0.99, pâ¯<â¯0.0003), besides poly-ADP-ribose polymerase-1 (râ¯=â¯-0.99, pâ¯=â¯0.0002). In confirmation, the pre-administration of the selective MasR antagonist, A779, partially attenuated Ang 1-7-induced alterations towards 6-OHDA neurodegeneration. Collectively, our findings support a novel role for the anti-inflammatory capacity of the MasR axis to prove potential therapeutic relevance in PD via the upregulation/activation of MasR-dependent STAT3/SOCS3 cascade to negatively control the HMGB-1/RAGE/NF-κB axis hindering PD associated neuro-inflammation along with DA depletion and motor deficits.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
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Angiotensina I
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Proteínas
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Proteínas Proto-Oncogênicas
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Transtornos Parkinsonianos
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Receptores Acoplados a Proteínas G
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Atividade Motora
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article