Morinda citrifolia and Its Active Principle Scopoletin Mitigate Protein Aggregation and Neuronal Apoptosis through Augmenting the DJ-1/Nrf2/ARE Signaling Pathway.

Kishore Kumar S Narasimhan,Namakkal Soorappan Rajasekaran,Saraswathi Uthamaraman,Ashokkumar Srinivasan,Thangarajeswari Mohan,Deepthy Jayakumar,Divya Bhavani Ravi,Kalaiselvi Periandavan,Yogesh Kanna Sathyamoorthy,Prema Velusamy

doi:10.1155/2019/2761041

Kishore Kumar S Narasimhan, Namakkal Soorappan Rajasekaran + Show 8 more

Open Access

https://doi.org/10.1155/2019/2761041

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Abstract

Given the role of oxidative stress in PD pathogenesis and off-target side effects of currently available drugs, several natural phytochemicals seem to be promising in the management of PD. Here, we tested the hypothesis that scopoletin, an active principle obtained from Morinda citrifolia (MC), efficiently quenches oxidative stress through DJ-1/Nrf2 signaling and ameliorates rotenone-induced PD. Despite reducing oxidative stress, the administration of MC extract (MCE) has lessened protein aggregation as evident from decreased levels of nitrotyrosine and α-synuclein. In vitro studies revealed that scopoletin lessened rotenone-induced apoptosis in SH-SY5Y cells through preventing oxidative injury. Particularly, scopoletin markedly upregulated DJ-1, which then promoted the nuclear translocation of Nrf2 and transactivation of antioxidant genes. Furthermore, we found that scopoletin prevents the nuclear exportation of Nrf2 by reducing the levels of Keap1 and thereby enhancing the neuronal defense system. Overall, our findings suggest that scopoletin acts through DJ-1-mediated Nrf2 signaling to protect the brain from rotenone-induced oxidative stress and PD. Thus, we postulate that scopoletin could be a potential drug to treat PD.

Highlights

The causal mechanisms of Parkinson’s disease (PD) remain elusive, excess production of reactive oxygen species (ROS), mitochondrial dysfunction, neuroinflammation, and environmental toxins are reported to promote the loss of dopaminergic neurons in PD [1]
Intracellular inclusions known as Lewy bodies (LBs) are regarded as a hallmark of common pathological manifestation in both familial and sporadic PD patients with α-synuclein (α-Syn) serving as the main component of LB [3]. α-Syn is natively unfolded and is prone to form fibrils during oxidative stress [4], indicating that redox signaling may play a significant role in the aggregation of α-Syn
Histochemical analysis of substantia nigra pars compacta (SNPc) along with the striatum makes it convenient to understand the efficacy of the MC extract (MCE) treatment

Summary

Introduction

The causal mechanisms of Parkinson’s disease (PD) remain elusive, excess production of reactive oxygen species (ROS), mitochondrial dysfunction, neuroinflammation, and environmental toxins are reported to promote the loss of dopaminergic neurons in PD [1]. Oxidative stress has been shown to induce misfolding, aggregation, and accumulation of such aggregates leading to the pathogenesis of many neurodegenerative diseases including. A key example includes DJ-1/PARK7, a molecular chaperone known to regulate Keap1-Nrf signaling, which is the primary sensor for reactive electrophiles activating Nrf nuclear translocation and transactivation of the antioxidant response element (ARE) in a battery of cytoprotective genes facilitating protection from oxidative stress pathogenesis [7] including experimental models of PD [8]. Pharmacological activation of the Nrf in the brain is likely to preserve neuronal health.

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