Identification of Caffeic Acid Phenethyl Ester (CAPE) as a Potent Neurodifferentiating Natural Compound That Improves Cognitive and Physiological Functions in Animal Models of Neurodegenerative Diseases.

Kapaettu Satyamoorthy,Aashika Nayak,Anupama Chaudhary,Sunil C Kaul,Kanive P Guruprasad,Keiji Terao,Arpita Konar,Rajkumar Singh Kalra,Renu Wadhwa,Yoshiyuki Ishida

doi:10.3389/fnagi.2020.561925

Abstract

Cell-based screening of bioactive compounds has served as an important gateway in drug discovery. In the present report, using human neuroblastoma cells and enrolling an extensive three-step screening of 57 phytochemicals, we have identified caffeic acid phenethyl ester (CAPE) as a potent neurodifferentiating natural compound. Analyses of control and CAPE-induced neurodifferentiated cells revealed: (i) modulation of several key proteins (NF200, MAP-2, NeuN, PSD95, Tuj1, GAP43, and GFAP) involved in neurodifferentiation process; and (ii) attenuation of neuronal stemness (HOXD13, WNT3, and Msh-2) and proliferation-promoting (CDC-20, CDK-7, and BubR1) proteins. We anticipated that the neurodifferentiation potential of CAPE may be beneficial for the treatment of neurodegenerative diseases and tested it using the Drosophila model of Alzheimer’s disease (AD) and mice model of amnesia/loss of memory. In both models, CAPE exhibited improved disease symptoms and activation of physiological functions. Remarkably, CAPE-treated mice showed increased levels of neurotrophin-BDNF, neural progenitor marker-Nestin, and differentiation marker-NeuN, both in the cerebral cortex and hippocampus. Taken together, we demonstrate the differentiation-inducing and therapeutic potential of CAPE for neurodegenerative diseases.

Highlights

Advancement in living standards and healthcare has significantly extended the average human lifespan globally
We have identified and characterized caffeic acid phenethyl ester (CAPE) as a potent neurodifferentiating natural compound that improves cognitive and physiological functions in in vivo models
Multiple reports elucidated the role of CAPE in maintaining brain function homeostasis by inhibiting cytotoxicity in cerebellar granule cells induced by low K(+) levels (Amodio et al, 2003), H2O2 led-oxidative stress (Chen et al, 2012), acroleininduced toxicity in hippocampal cells (Huang et al, 2013), and pentylenetetrazole-induced status epilepticus (Yiset al., 2013)

Summary

Introduction

Advancement in living standards and healthcare has significantly extended the average human lifespan globally. Given the close association between aging and brain dysfunctions, the incidences of brain pathologies are on the rise. Brain aging is accompanied with deteriorative anatomical and molecular changes coupled with increasing metabolic inefficiency that make the brain cells vulnerable to toxic insults (Konar et al, 2016). The cognitive capacities of the brain are severely compromised and give rise to neurodegenerative conditions, viz. Alzheimer’s disease (AD) and Parkinson’s disease (PD). ∼30 million people are affected by neurodegenerative diseases globally, and this number is predicted to rise to 150 million by 2050 (Vanni et al, 2020). The etiology and consequences of brain pathologies are complex and involve the genetic and epigenetic changes and altered molecular signaling, connectivity, cellular morphology, and physiological behavior (Yankner et al, 2008). Only a few drugs, namely rivastigmine and memantine have achieved partial clinical success, primarily by alleviating the disease progression, yet constraints of the blood-brain barrier and bioavailability compromised their efficacy (Becker et al, 2008; Casey and Jones, 2010)

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