The angiotensin converting enzyme inhibitor captopril protects nigrostriatal dopamine neurons in animal models of parkinsonism

Sonsalla, Patricia K.; Coleman, Christal G.; Wong, Lai Yoong; Harris, Suzan L.; Richardson, Jason R.; Gadad, Bharathi S.; Li, Wenhao; German, Dwight C.

doi:10.1016/j.expneurol.2013.10.014

Cited by 67 publications

(55 citation statements)

References 61 publications

(84 reference statements)

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“…Several lines of evidence suggested a potential association of Ang II/AT1R axis with the progression of PD, since a significantly higher level of Ang II in the CSF or brain tissues was observed in PD animal models as well as patients with this disease [13, 14]. Here, in support of these findings, we showed that the level of Ang II in the SN was obviously elevated in a rotenone-induced rat model of PD.…”

Section: Discussionsupporting

confidence: 87%

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

Gao

Jiang

et al. 2017

Oncotarget

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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.

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Section: Discussionsupporting

confidence: 87%

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

Gao

Jiang

et al. 2017

Oncotarget

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“…Experimental data also support the involvement of brain RAS in dopaminergic degeneration [110,111,112]. It was demonstrated that AII increased the neurotoxic effect induced by low doses of 6-OHDA, and the treatment with inhibitors of ACE [113,114,112] or blockage of AT1Rs [98,95,96] resulted in a significant reduction of both the loss of dopaminergic neurons and the levels of protein oxidation and lipid peroxidation induced by the neurotoxins [115]. Furthermore antagonist of AT1Rs has been shown to be neuroprotective [116].…”

Section: Renin-angiotensin Systemmentioning

confidence: 79%

Dopamine Receptors and Neurodegeneration

Rangel‐Barajas¹,

Coronel²,

Florán³

2015

Aging and disease

182

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Dopamine (DA) is one of the major neurotransmitters and participates in a number of functions such as motor coordination, emotions, memory, reward mechanism, neuroendocrine regulation etc. DA exerts its effects through five DA receptors that are subdivided in 2 families: D1-like DA receptors (D1 and D5) and the D2-like (D2, D3 and D4). All DA receptors are widely expressed in the central nervous system (CNS) and play an important role in not only in physiological conditions but also pathological scenarios. Abnormalities in the DAergic system and its receptors in the basal ganglia structures are the basis Parkinson's disease (PD), however DA also participates in other neurodegenerative disorders such as Huntington disease (HD) and multiple sclerosis (MS). Under pathological conditions reorganization of DAergic system has been observed and most of the times, those changes occur as a mechanism of compensation, but in some cases contributes to worsening the alterations. Here we review the changes that occur on DA transmission and DA receptors (DARs) at both levels expression and signals transduction pathways as a result of neurotoxicity, inflammation and in neurodegenerative processes. The better understanding of the role of DA receptors in neuropathological conditions is crucial for development of novel therapeutic approaches to treat alterations related to neurodegenerative diseases.

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“…We have synthesised a nonapeptide, H-Pro-Pro-Thr-Thr-Thr-Lys-Phe-Ala-Ala-OH, which was named acein, which binds with high affinity and specificity to brain membranes of guinea pigs and rats. Acein binding sites were mainly localized in the dorsal striatum and substantia nigra areas of brain, where membrane-bound ACE is largely found (Zhuo et al, 1998;Sonsalla et al, 2013;Labandeira-Garcia et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

The novel nonapeptide acein targets angiotensin converting enzyme in the brain and induces dopamine release

Neasta

Valmalle

Coyne

et al. 2016

British J Pharmacology

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BACKGROUND AND PURPOSEUsing an in-house bioinformatics programme, we identified and synthesized a novel nonapeptide, H-Pro-Pro-Thr-Thr-Thr-LysPhe-Ala-Ala-OH. Here, we have studied its biological activity, in vitro and in vivo, and have identified its target in the brain. EXPERIMENTAL APPROACHThe affinity of the peptide was characterized using purified whole brain and striatal membranes from guinea pigs and rats . Its effect on behaviour in rats following intra-striatal injection of the peptide was investigated. A photoaffinity UV cross-linking approach combined with subsequent affinity purification of the ligand covalently bound to its receptor allowed identification of its target. KEY RESULTSThe peptide bound with high affinity to a single class of binding sites, specifically localized in the striatum and substantia nigra of brains from guinea pigs and rats. When injected within the striatum of rats, the peptide stimulated in vitro and in vivo dopamine release and induced dopamine-like motor effects. We purified the target of the peptide, a~151 kDa protein that was identified by MS/MS as angiotensin converting enzyme (ACE I). Therefore, we decided to name the peptide acein. CONCLUSION AND IMPLICATIONSThe synthetic nonapeptide acein interacted with high affinity with brain membrane-bound ACE. This interaction occurs at a different site from the active site involved in the well-known peptidase activity, without modifying the peptidase activity. Acein, in vitro and in vivo, significantly increased stimulated release of dopamine from the brain. These results suggest a more important role for brain ACE than initially suspected.

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The angiotensin converting enzyme inhibitor captopril protects nigrostriatal dopamine neurons in animal models of parkinsonism

Cited by 67 publications

References 61 publications

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

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

Dopamine Receptors and Neurodegeneration

The novel nonapeptide acein targets angiotensin converting enzyme in the brain and induces dopamine release

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