Agmatine-mediated inhibition of NMDA receptor expression and amelioration of dyskinesia via activation of Nrf2 and suppression of HMGB1/RAGE/TLR4/MYD88/NF-κB signaling cascade in rotenone lesioned rats.
Life Sci
; 311(Pt A): 121049, 2022 Dec 15.
Article
en En
| MEDLINE
| ID: mdl-36209830
Dyskinesia is characterized by abnormal involuntary movements (AIMs). Such movements are considered restrictive problem associated with the chronic use of L-dopa in Parkinson's disease (PD) treatment; the thing that renders the definite pathological mechanism unclear. However, there is a correlation between excitotoxicity of glutamatergic NMDA receptors, neuroinflammation, and oxidative stress in the lesioned nigrostriatal pathway; which mediates the firing of basal ganglia neurons involved in dyskinesia. AIMS: The current study investigated the novel neuroprotective effect of agmatine in ameliorating both PD and dyskinesia with a focus on its antioxidant, anti-inflammatory, and anti-apoptotic potentiality through Nrf2 activation and suppression of HMGB1/RAGE/TLR4/MYD88/NF-κB signaling pathway. MAIN METHODS: PD was induced in animals by ten consecutive doses of rotenone (3 mg/kg/day; s.c.). Agmatine (100 mg/kg/day; i.p.) was injected for 16 days after modeling PD either alone or in combination with L-dopa/carbidopa (50/25 mg/kg/day; i.p.). KEY FINDINGS: A statically significant deteriorating effect was showed on the behavioral, neurochemical, histopathological, and immunochemical analysis of PD rats. Moreover, dyskinesia observed in PD rats that received L-dopa. Agmatine improved animals' behavior and abolished dyskinetic AIMs. It inhibited NMDA receptors expression in nigral tissues leading to inhibition of inflammatory and oxidative stress cascades. It increased both nigral TH immunoreactive cells and striatal dopamine contents. Besides, it increased the antioxidant defense mechanism of Nrf2/TAC contents along with a significant decrease of HMGB1/RAGE/TLR4/MYD88/NF-κB protein expression. SIGNIFICANCE: The current investigated data signifies the novel role of agmatine in ameliorating both PD and dyskinesia through mediating NMDA receptors, Nrf2, and HMGB1/RAGE/TLR4/NF-κB signaling pathways.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Enfermedad de Parkinson
/
Discinesias
/
Proteína HMGB1
/
Agmatina
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Life Sci
Año:
2022
Tipo del documento:
Article
Pais de publicación:
Países Bajos