Neuroprotective Effect of Cyclo-(L-Pro-L-Phe) Isolated from the Jellyfish-Derived Fungus Aspergillus flavus.

Dan-Dan Li,Jongki Hong,Ying Wang,Eun La Kim,Jee H Jung

doi:10.3390/md19080417

Abstract

Peroxisome proliferator-activated receptor (PPAR) expression has been implicated in pathological states such as cancer, inflammation, diabetes, and neurodegeneration. We isolated natural PPAR agonists—eight 2,5-diketopiperazines—from the jellyfish-derived fungus Aspergillus flavus. Cyclo-(L-Pro-L-Phe) was the most potent PPAR-γ activator among the eight 2,5-DKPs identified. Cyclo-(L-Pro-L-Phe) activated PPAR-γ in Ac2F rat liver cells and SH-SY5Y human neuroblastoma cells. The neuroprotective effect of this partial PPAR-γ agonist was examined using the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, lactate dehydrogenase release, and the Hoechst 33342 staining assay in SH-SY5Y cells. Our findings revealed that cyclo-(L-Pro-L-Phe) reduced hydrogen peroxide-induced apoptosis as well as the generation of reactive oxygen species. Rhodamine 123 staining and western blotting revealed that cyclo-(L-Pro-L-Phe) prevented the loss of mitochondrial membrane potential and inhibited the activation of mitochondria-related apoptotic proteins, such as caspase 3 and poly (ADP-ribose) polymerase. Moreover, cyclo-(L-Pro-L-Phe) inhibited the activation and translocation of nuclear factor-kappa B. Thus, the partial PPAR-γ agonist cyclo-(L-Pro-L-Phe) demonstrated potential neuroprotective activity against oxidative stress-induced neurodegeneration in SH-SY5Y cells.

Highlights

Neurodegenerative diseases are a group of heterogeneous disorders characterized by a gradual loss of neuronal structure or function and include conditions such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis, and Huntington’s disease (HD) [1,2]
Concentrations of 10 and 40 μM and rosiglitazone (40 μM) were selected for Peroxisome proliferator-activated receptor (PPAR) (PPAR-α, PPAR-β/δ, and PPAR-γ) transactivation assays; WY-14643, GW501516, and rosiglitazone were used as positive controls for PPAR-α, PPAR-β/δ, and PPAR-γ activation, respectively
When compound 8 was compared to the PPAR-γ full agonist rosiglitazone, using one-way analysis of variance and Tukey’s HSD-post hoc test, the significance of activity was observed at 40 μM

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Neurodegenerative diseases are a group of heterogeneous disorders characterized by a gradual loss of neuronal structure or function and include conditions such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis, and Huntington’s disease (HD) [1,2]. Accumulating evidence has indicated the potential role of oxidative stress, mitochondrial dysfunction, inflammation, autophagy, and apoptotic dysfunction in neurodegenerative diseases [3,4,5,6].

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Results

Conclusion