Azilsartan ameliorates apoptosis of dopaminergic neurons and rescues characteristic parkinsonian behaviors in a rat model of Parkinson’s disease

Abstract

Loss of dopaminergic neurons within the substantia nigra (SN) is a pathological hallmark of Parkinsons disease (PD), which leads to the onset of motor symptoms. Previously, our in vitro studies revealed that Angiotensin II (Ang II) induced apoptosis of dopaminergic neurons through its type 1 receptor (AT1R), but these findings needed to be confirmed via animal experiments. Here, using a rotenone-induced rat model of PD, we observed an overactivation of Ang II/AT1R axis in the SN, since Ang II level and AT1R expression were markedly increased. Furthermore, we provided in vivo evidence that Ang II directly elicited apoptosis of dopaminergic neurons via activation of AT1R in the SN of rats. More importantly, we showed for the first time that oral administration of azilsartan, a newly developed AT1R blocker approved by the U.S. Food and Drug Administration for hypertension treatment, rescued the apoptosis of dopaminergic neurons and relieved the characteristic parkinsonian symptoms in PD rats. These results support the application of AT1R blockers in PD therapy, and strengthen the notion that many therapeutic agents may possess pleiotropic action in addition to their main applications.

Role of brain renin angiotensin system in neurodegeneration: An update

“…Ang II could also facilitate apoptosis via mitochondrial ROS mediated upregulation of both adenosine monophosphate activated protein kinase and peroxisome proliferator-activated receptor coactivator 1a cascades, thereby stimulating Bax, a pro-apoptotic protein that causes the death of neuronal cells . In a study when ang II was administered in PD rat model, caspase 3 levels increased abruptly leading to the death of dopaminergic neurons due to cleavage of neuronal membrane proteins (Gao et al, 2017). Additionally, AT1R regulated autophagy stimulation and mitochondrial mediated cell death cascades were also reported as separate mechanisms that may cause ang II induced dopaminergic cell death Ou et al, 2016).…”

Metal Chelation Therapy and Parkinson’s Disease: A Critical Review on the Thermodynamics of Complex Formation between Relevant Metal Ions and Promising or Established Drugs

“…Aminothiazoles derivatives as SUMOylation activators [124] AMN082 [115] Amodiaquine [125,126] Antagonist of the A(2A) adenosine receptor-derivative 49 [127] Apigenin [128][129][130][131] Apomorphine [132,133] l-Arginine [134] Aromadendrin [128] Ascorbic acid [135,136] ASI-1 [12] ASI-5 [12] Astilbin [137] Azilsartan [138] Baicalein [139][140][141] Benserazide [142,143] 7H-Benzo, perimidin-7-one derivatives (R6 = OH) [144] 4H-1-Benzopyran-4-one [145] 8-Benzyl-tetrahydropyrazino, purinedione derivatives (derivative n.57) [146] Bikaverin [147]…”

Up-regulation of angiotensin-converting enzyme in response to acute ischemic stroke via ERK/NF-κB pathway in spontaneously hypertensive rats

“…Western blot assay was performed according to manufacture’s instructions [ 35 ]. Briefly, the peri-infarct regions and corresponding area of sham-operated rats was homogenized in lysis buffer (Beyotime Inc.).…”