Angiotensin Type 1 Receptor Antagonists Protect Against Alpha-Synuclein-Induced Neuroinflammation and Dopaminergic Neuron Death

Ana I. Rodriguez-Perez, Diego Sucunza, Maria A. Pedrosa, Pablo Garrido-Gil, Jaime Kulisevsky, Jose L. Lanciego, Jose L. Labandeira-Garcia

Research output: Contribution to journalArticleResearch

22 Citations (Scopus)

Abstract

© 2018, The Author(s). The loss of dopaminergic neurons and α-synuclein accumulation are major hallmarks of Parkinson’s disease (PD), and it has been suggested that a major mechanism of α-synuclein toxicity is microglial activation. The lack of animal models that properly reproduce PD, and particularly the underlying synucleinopathy, has hampered the clarification of PD mechanisms and the development of effective therapies. Here, we used neurospecific adeno-associated viral vectors serotype 9 coding for either the wild-type or mutated forms of human alpha-synuclein (WT and SynA53T, respectively) under the control of a synapsin promoter to further induce a marked dopaminergic neuron loss together with an important microglial neuroinflammatory response. Overexpression of neuronal alpha-synuclein led to increased expression of angiotensin type 1 receptors and NADPH oxidase activity, together with a marked increase in the number of OX-6-positive microglial cells and expression of markers of phagocytic activity (CD68) and classical pro-inflammatory/M1 microglial phenotype markers such as inducible nitric oxide synthase, tumor necrosis factor alpha, interleukin-1β, and IL-6. Moreover, a significant decrease in the expression of markers of immunoregulatory/M2 microglial phenotype such as the enzyme arginase-1 was constantly observed. Interestingly, alpha-synuclein-induced changes in microglial phenotype markers and dopaminergic neuron death were inhibited by simultaneous treatment with the angiotensin type 1 blockers candesartan or telmisartan. Our results suggest the repurposing of candesartan and telmisartan as a neuroprotective strategy for PD.
Original languageEnglish
Pages (from-to)1063-1081
JournalNeurotherapeutics
Volume15
DOIs
Publication statusPublished - 14 Oct 2018

Keywords

  • Candesartan
  • Microglia
  • Neurodegeneration
  • Parkinson
  • Telmisartan
  • Viral vectors

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