Angiotensin Type-1 Receptor Inhibition Reduces NLRP3 Inflammasome Upregulation Induced by Aging and Neurodegeneration in the Substantia Nigra of Male Rodents and Primary Mesencephalic Cultures

Antioxidants

Andrea Lopez-Lopez¹  Ana I. Rodriguez-Perez¹  Aloia Quijano¹  Carmen Diaz-Ruiz¹  Ana Muñoz¹  Begoña Villar-Cheda¹  Jose L. Labandeira-Garcia¹ 

[1]Laboratory of Cellular and Molecular Neurobiology of Parkinson’s Disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), Department of Morphological Sciences, IDIS, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain

关键词: aged;    dopamine;    inflammation;    inflammaging;    neuroinflammation;    oxidative stress;   

DOI  :  10.3390/antiox11020329

来源: DOAJ

【 摘 要 】

The tissue renin–angiotensin system (RAS) has been shown to be involved in prooxidative and proinflammatory changes observed in aging and aging-related diseases such as dopaminergic degeneration in Parkinson’s disease (PD). We studied the activation of the NLRP3 inflammasome in the substantia nigra with aging and early stages of dopaminergic degeneration in PD models and, particularly, if the brain RAS, via its prooxidative proinflammatory angiotensin II (AngII) type 1 (AT1) receptors, mediates the inflammasome activation. Nigras from aged rats and mice and 6-hydroxydopamine PD models showed upregulation in transcription of inflammasome-related components (NLRP3, pro-IL1β and pro-IL18) and IL1β and IL18 protein levels, which was inhibited by the AT1 receptor antagonist candesartan. The role of the AngII/AT1 axis in inflammasome activation was further confirmed in rats intraventricularly injected with AngII, and in primary mesencephalic cultures treated with 6-hydroxydopamine, which showed inflammasome activation that was blocked by candesartan. Observations in the nigra of young and aged AT1 and AT2 knockout mice confirmed the major role of AT1 receptors in nigral inflammasome activation. In conclusion, the inflammasome is upregulated by aging and dopaminergic degeneration in the substantia nigra, possibly related with a decrease in dopamine levels, and it is mediated by the AngII/AT1 axis.

【 授权许可】

Unknown