Atrial Natriuretic Peptide Acts as a Neuroprotective Agent in in Vitro Models of Parkinson’s Disease via Up-regulation of the Wnt/β-Catenin Pathway

Abstract

In the last decades increasing evidence indicated a crucial role of the Wnt/β-catenin signaling in development of midbrain dopaminergic (mDA) neurons. Recently dysregulation of this pathway has been proposed as a novel pathomechanism leading to Parkinson’s disease (PD) and some of the molecules participating to the signaling have been evaluated as potential therapeutic targets for PD. Atrial natriuretic peptide (ANP) is a cardiac-derived hormone having a critical role in cardiovascular homeostasis. ANP and its receptors (NPRs) are widely expressed in mammalian central nervous system (CNS) where they could be implicated in the regulation of neural development, synaptic transmission and information processing, as well as in neuroprotection. Until now, the effects of ANP in the CNS have been mainly ascribed to the binding and activation of NPRs. We have previously demonstrated that ANP affects the Wnt/β-catenin signaling in colorectal cancer cells through a Frizzled receptor-mediated mechanism. The purpose of this study was to investigate if ANP is able to exert neuroprotective effect on two in vitro models of PD, and if this effect could be related to activation of the Wnt/β-catenin signaling. As cellular models of DA neurons, we used the proliferating or RA-differentiated human neuroblastoma cell line SH-SY5Y. In both DA neuron-like cultures, ANP is able to positively affect the Wnt/β-catenin signaling, by inducing β-catenin stabilization and nuclear translocation. Importantly, activation of the Wnt pathway by ANP exerts neuroprotective effect when these two cellular systems were subjected to neurotoxic insult (6-OHDA) for mimicking the neurodegeneration of PD. Our data support the relevance of exogenous ANP as an innovative therapeutic molecule for midbrain, and more in general for brain diseases for which aberrant Wnt signaling seems to be involved.

HIF-1α/microRNA-128-3p axis protects hippocampal neurons from apoptosis via the Axin1-mediated Wnt/β-catenin signaling pathway in Parkinson’s disease models

“…Furthermore, AXIN1 inhibits activation of the Wnt/β-catenin signaling pathway, which leads to degeneration of hippocampal neurons [22], suggesting that silenced Axin1 could alleviate hippocampal neurodegeneration by activating the Wnt/β-catenin signaling pathway. Additionally, miR-128-3p can promote activation of the Wnt/β-catenin signaling pathway [38], whereas Baldeschi et al have revealed that dysregulation of the Wnt/β-catenin signaling pathway is implicated in PD [39]. These findings support our contention that up-regulation of HIF-1α/miR-128-3p axis could suppress apoptosis of hippocampal neurons in MPTP-lesioned mice via inhibition of Axin1 and activation of the Wnt/β-catenin signaling pathway.…”

Natriuretic Peptides, Cognitive Impairment and Dementia: An Intriguing Pathogenic Link with Implications in Hypertension

“…In fact, it is known that NPs are involved in neural development, in neurotransmitter release, in synaptic transmission, in regulation of inflammatory processes at the level of microglia and in neuroprotection [ 27 , 28 , 29 , 30 ]. Consistently, ANP has been shown as a neuroprotective agent via upregulation of the Wnt/β-catenin pathway in an in vitro model of Parkinson disease [ 31 ]. An increase of ANP upon neprilysin inhibition therapy protected from stroke occurrence in a high-salt-fed stroke-prone spontaneously hypertensive rat model [ 32 ].…”

Atrial Natriuretic Peptide Promotes Neurite Outgrowth and Survival of Cochlear Spiral Ganglion Neurons in vitro Through NPR-A/cGMP/PKG Signaling

“…Pretreatment with ANP alleviated nitric oxide-induced neuronal apoptosis of a cholinergic-neuron-like cell line NG108-15, associated with elevation of cGMP levels ( Cheng Chew et al, 2003 ). ANP could protect dopaminergic neuron-like models in vitro against neurotoxic insult for mimicking the neurodegeneration of Parkinson’s disease, which might be strongly dependent on the activation of the Wnt/β-catenin pathway ( Colini Baldeschi et al, 2018 ). CNP was also shown to function as an innate neuroprotectant which improved neuronal survival of neonatal brain in mice from hypoxia–ischemia insult through its receptor NPR-B ( Ma and Zhang, 2018 ).…”

“…Besides, cGMP signaling elicited by the CNP/NPR-B pathway regulates neurite outgrowth and pathfinding of sensory ganglion neurons within DRG ( Schmidt et al, 2002 , 2007 ; Kishimoto et al, 2008 ; Schmidt et al, 2009 ; Zhao et al, 2009 ; Xia et al, 2013 ; Ter-Avetisyan et al, 2014 ; Schmidt et al, 2016 ; Dumoulin et al, 2018a , b ; Schmidt et al, 2018 ; Ter-Avetisyan et al, 2018 ; Tröster et al, 2018 ) and cochlear spiral ganglion (SG) ( Lu et al, 2011 , 2014 ; Ter-Avetisyan et al, 2014 , 2018 ; Wolter et al, 2018 ; Schmidt and Fritzsch, 2019 ) during development. Additionally, all three NPs possess neuroprotective ability on retinal and central neurons through GC-coupled NPR stimulation ( Fiscus et al, 2001 ; Cheng Chew et al, 2003 ; Kuribayashi et al, 2006 ; Ma et al, 2010 ; Colini Baldeschi et al, 2018 ). All these clues indicate that NPs and their receptors could probably be associated with the maintenance of various aspects of neuronal functions.…”